Computers in Biology and Medicine 117 (2020) 103621

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Computers in Biology and Medicine

journal homepage: http://www.elsevier.com/locate/compbiomed

Extension of the Quantum Universal Exchange Language to precision

medicine and drug lead discovery. Preliminary example studies using the
mitochondrial genome
Barry Robson a, b, *
a
Ingine Inc., Delaware, USA
b
The Dirac Foundation, OxfordShire, UK

A R T I C L E I N F O A B S T R A C T

Keywords: The Quantum Universal Exchange Language (Q-UEL) based on Dirac notation and algebra from quantum me­
Data analytics chanics, along with its associated data mining and Hyperbolic Dirac Net (HDN) for probabilistic inference, has
Data mining proven to be a useful architectural principle for knowledge management, analysis and prediction systems in
Genomics
medicine. It has been described in several papers; here is described its extension to clinical genomics and pre­
Bioinformatics
Universal exchange language
cision medicine. Two use cases are studied: (a) bioinformatics in clinical decision support especially for risk for
Quantum mechanics type 2 diabetes using mitochondrial patient DNA sequences, and (b) bioinformatics and computational biology
Dirac notation (conformational) research examples related to drug discovery involving the recently discovered class of mito­
Inference net chondrial derived peptides (MDPs). MDPs were surprising when first discovered as coded in small open reading
Hyperbolic Dirac net frames (sORFs), and are emerging as having a fundamental role in metabolic control, longevity and disease. This
Bayes net project originally represented a language specification study relating to what information related to genomics is
Clinical decision support essential or useful to carry, and what processing will be needed. However, novel aspects introduced or discovered
include the HDN-like neural nets and their use, along with more established methods, for prediction of type 2
diabetes, and in particular for proposals for over 80 natural MDPs most of which that have not previously been
described at the time of the study, as potential drug lead targets. Also, use of many medical records with
simulated joining of mtDNA as performance tests led to some insightful observations regarding the behavior of
HDN predictions where independent factors are involved.

1. Introduction and review
1.1. Background
The DNA sequences of a patient and protein sequences deduced from
them increasingly provide a crucial source of information for the
implementation of a personalized medicine tailored specifically to that
patient [1]. The required support discipline for analyzing DNA, RNA,
and protein sequences and structures by computer is well-known as
bioinformatics, first established as a set of protein sequencing support,
comparison, and prediction software tools as early as 1965–1975 when
protein sequencing, but not routine nucleic acid sequencing, was
available. For example, see Ref. [2] that describes the above historical
developments particularly in regard to peptide and protein structure and
function, which are themes in the present paper. Prediction algorithms
related to those in more general use today were probably first developed
in bioinformatics and protein science, albeit framed in a Bayesian in­
formation theoretic approach (see Chapter 9 of ref [2] for review). They
can be shown applicable to clinical decision support systems (CDSS); see
Table 8.1, Prediction of Congestive Heart Failure, and associated dis­
cussion in Ref. [1]). However, they remained largely confined to the
bioinformatics domain, and the Bayes Net (BN) in the form due to Pearl
[3] became popular for more general applications, followed by neural
nets as discussed in this paper. Probabilistic inference nets, of which the
BN is the well-known example, are said to work top down by
pre-assigning weights as probabilities based on prior knowledge,
including that obtained by data mining. In contrast, neural nets are said
to work bottom up by comparing prediction with observation and cali­
brating weights by minimizing the discrepancy; there is no use of pre­
formed knowledge in the usual sense. More recently, to overcome

* Ingine Inc., Delaware, USA.

E-mail address: barryrobson@ingine.com.

https://doi.org/10.1016/j.compbiomed.2020.103621
Received 10 October 2019; Received in revised form 12 January 2020; Accepted 12 January 2020
Available online 20 January 2020
0010-4825/© 2020 Elsevier Ltd. All rights reserved.
B. Robson
certain limitations in the BN discussed below for use in CDSS, the pre­
sent author proposed the Hyperbolic Dirac Net (HDN) [4,5] based on
quantum mechanical principles [6]. The HDN is just one of several tools
used in the present paper, but of general importance throughout is the
associated Q-UEL language for probabilistic semantics and interopera­
bility in medicine, as follows.
1.2. Q-UEL and the context and purpose of the present paper
The essential features of Q-UEL were captured in a paper in 2013 [7]
and reflected the general specification in Q-UEL manuals around that
time. Several special specifications of Q-UEL for different medical do­
mains and use cases have been developed over the past seven years in
many Q-UEL papers, examples of which are cited in context below.
These papers did not attempt in any depth a special specification for
management of knowledge in clinical genomics, but some such standard
is needed [8]. A special specification of any knowledge representation
language like XML [9] or Q-UEL is required when applied to a new
domain. Similarly, HL7 Version 3 and descendent versions are particular
embodiments or uses of XML for medical records and healthcare com­
munications, must obey XML rules, but took considerable effort to
develop [1]. In the present paper, Q-UEL is extended from recent clinical
medicine, which made relatively little use of knowledge of a patient’s
DNA, to include genomics and bioinformatics [1]. When a specification
relates to something like Q-UEL which is interoperability, knowledge
management, automation and reasoning language [7], a specification
study takes on the character of artificial intelligence research. Formally,
any specification, general or special, is properly a description that is
precise, defines the behavior of the system, itself involves formal se­
mantics and reasoning laws, and requires an understanding of the
problem. A special specification study for extension of an interopera­
bility language to a new domain must also determine what information
and transformations of it are absolutely required for that domain, and
whether any additional information, perhaps redundant information in
another form, will enhance efficiency and facilitate use. The account
given in the present paper is not as rigorous as that suggests. Like the
above paper that first introduced Q-UEL in significant detail [7], it is not
the specification manual itself, but rather describes the work through
examples, highlighting general principles and observations that are of
more general scientific interest.
Most standards for giving structure to information, including XML
and HL7 Version 3, have origins in specifications in earlier efforts with
different names or guises. Q-UEL similarly has its roots in two earlier
descriptions that can be considered as specifications of a kind. Q-UEL is
an acronym for Quantum Universal Exchange Language, because (a) it
follows closely the form and algebra of Dirac’s braket notation (or bracket
notation) a standard for representing probabilistic knowledge and
inference from it in quantum mechanics (QM) since the 1930s, and
because (b) it was a response to a call by the (US) President’s Council of
Advisors on Science and Technology (PCAST) for a universal exchange
language for medicine (UEL) (see Ref. [7] for discussion). The Dirac
notation, although mathematically rigorous, was slightly slack in its
demands for specific format on certain points, primarily in regard to
features called attributes in the present paper, and discussed extensively
below. As a specification the PCAST requirements were vaguer still,
although the kind of capabilities required were outlined in significant
detail. The motivation for the PCAST report was that a UEL was seen as
needed to overcome lack of interoperability in medical information
technology [7]. Arguably, the interoperability situation has not in
practice greatly improved since, and certainly links between routine
clinical medicine and bioinformatics are poor (see Ref. [8], especially
Chapter 9, for independent appraisals of this). Q-UEL was also motivated
by the desire to make the Semantic Web (SW) [9] probabilistic [7].
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Computers in Biology and Medicine 117 (2020) 103621
1.3. Context of the present study in relation to previous major efforts
Q-UEL is not a major international standards effort, and currently,
researchers tend to look to linked data formats based on SW technolo­
gies. These include Resource Description Framework (RDF), Web
Ontology Language (OWL), Simple Knowledge Organization System
(SKOS), and SPARQL [9]. Others look to the original XML, often also
considered as a tool of the Semantic Web (SW), but in any case attractive
for linking information on the World Wide Web (WWW). The PRISMA
approach to structured systematic reviews in medicine and for epide­
miology [9] should be mentioned because Q-UEL has also been used for
that purpose. However, for certain interoperability aspects of PRISMA, it
was found that an XML solution was more useful [9]. Bayes nets [3] and
its causal model [10] have been also expressed in XML (e.g. see Ref. [7]
for review). In contrast, PROforma is another and very different lan­
guage that has been recommended for clinical decision support systems,
and is based on Backus Naur Form (BNF) [11]. It appears to be
moderately straightforward to convert PROforma to legal Q-UEL,
though the converse has not yet been completed, and results will be
reported elsewhere. Q-UEL owes most to XML, although unlike XML, its
main function is not as a markup language (see Section 1.4). Q-UEL was
inspired by the coincidental similarities between Dirac notation and
XML, and borrows some XML format and ideas, so it should be kept in
mind that Q-UEL is not XML. The use of hyphens in tag names such as
Q-UEL-PATIENT-DNA is even encouraged to make sure it is not misread
as XML (where they are illegal). The major differences are discussed in
Section 1.4.
None of the main tools of the SW are extensively intrinsically prob­
abilistic, although there have been diverse proposals [7], many of which
are based on the BN [3] expressed in XML [9]. That is unfortunate. Not
only does uncertainty abound in medicine but probabilities, or measures
based on them, are needed as the basis of important metrics in evidence
based medicine (and in epidemiology and public health generally). In
effect, a physician is concerned with the probabilities that particular
diseases are currently the best interpretation of the symptoms and
clinical laboratory results (differential diagnosis), with the risk of
specified diseases occurring in the future (risk factors, prognoses), with
most probable causes (etiology), and with finding the therapeutic
intervention that provides the probable opportunities for success [1].
The pharmaceutical industry is concerned with selecting for develop­
ment the drug candidates that will most probably succeed. Genomics
usually introduces a whole new probabilistic element [1]. Common
inherited diseases often represent a complex interaction of many genes,
involving control systems affected by past environment and therapeutic
interventions. While for some diseases like sickle cell anemia and cystic
fibrosis detection of one inherited mutation in each copy of DNA from
the parents is a very persuasive indicator, mutations such as BRCA1 and
BRCA2 represent a risk, not guarantee, of breast cancer, and absence of
these mutations does not guarantee avoidance. As discussed further in
Section 15 below, such probabilistic outcome is similarly most
commonly the case for other cancers, and cardiovascular, diabetic,
behavioral, and many other disorders.
The Bayes Net is probabilistic, but as a basis for probabilistic
knowledge in the SW and clinical decision support it has other limita­
tions. It is possible that the total adoption of BN-based methods as a
standard for medicine have been impeded by controversy over the
interpretation of BNs as a Directed Acyclic Graph (DAG) of probabilistic
knowledge, originally justified by a causal model [10] that is subject to
some criticism (e.g. Refs. [4,5,12]]. The DAG used to represent a net of
probabilistic knowledge seems inconsistent with querying by a set (not
ordered list) of tuples (e.g. ref 13]), with classical statistics and its adage
that “Correlation does not imply causation” [14], the physics of bidi­
rectional transitions in nature (e.g. Ref. [15]), and not least with the
spirit of the WWW and SW that emphasize connectedness and a general
“Web of Data consisting of all sorts of data types and forms” [9]. The
HDN allows the Bidirectional General Graph (BGG) [5]. Q-UEL should
B. Robson
also not be confused with an ingenious but now obsolete query language
called QUEL [13]. It was not probabilistic, though Q-UEL by similar
name honors it because in hindsight there are common principles based
on the tuple calculus developed by Codd, inventor of the relational data
base [13]. Similarly in Q-UEL one can imagine a set of column names
(headers), associated with an item or column of data below it, the as­
sociation being called an attribute by analogy with the similar appear­
ance XML’s attributes.
1.4. Comparison of Q-UEL and XML
Q-UEL is sometimes presented as an XML extension, with modifica­
tions to XML to facilitate application to probabilistic semantics. The
differences are primarily the introduction of the ‘|’ delimiter that relates
to relationships, explicit or implicit operators such as logical operators
between attributes, and optionally more elaborate attributes
with ontological structure using an attribute metadata language
(AML) [7]. Q-UEL can be used like XML as a markup language, with start
< … | and end | … > tags surrounding sections of text [7], but this is
rare, primarily to represent a first step in Q-UEL and XML interconver­
sion, and most tags are stand-alone tags. The most prominent kind of
XML-like tag in Q-UEL corresponds to Dirac’s bra-operator-ket.
< subject expression | relationship operator expression |
object expression>
However, Q-UEL differs most fundamentally from XML in having
algebraic and arithmetic force, as do the corresponding elements in
Dirac notation, such that its XML-like tags can behave as variables in a
software application. The most important values are probabilities,
actually pairs of probabilities that are expressed as a complex number
[7] as described later below, for the following reason. Attributes in
Q-UEL appear as arguments in logical or other expressions, which are
related to each other, in a mode analogous to a natural language.
Although it can be rendered in valid XML, it is then relatively inelegant,
and a means of making algebraic and arithmetic interpretation would
need to be available to the XML representing it. Building on Dirac ap­
pears to provide a more natural and extensive approach than Codd’s.
The above is a scalar variable that can be related to probability (Section
2.1) but also an expression, with a < … | bra row, | … > ket column, as
the braket, and a relationship part which is an operator or matrix. These
entities and the braket < … | … > where the ‘|’ can be read if logical IF,
and the ketbra |.>< … | (an operator) also appear as valid Q-UEL tags.
Unlike in XML, such tags can appear inside other tags, and this is easily
demonstrated to be consistent with Dirac’s method, though this requires
a deep discussion of the adjoint operation that is not required in this
paper. The present paper also relates this to the neural net. Although
Q-UEL is currently used today as a local architectural principle for
knowledge management in AI, the present paper is more characteristic
of early Q-UEL studies envisaging a future “Thinking Web”. Here this
means interoperability of a local clinical system with bioinformatics
tools and data already on the web, and developed by others. Of course
for privacy and security these tools and data could be reproduced in a
cloud or behind a firewall generally; the principles would stay the same.
1.5. Precision medicine
Precision medicine (e.g. Ref. [8]) is usually portrayed as a kind of
personalized and preventative medicine in which probabilities and
prediction methods and some understanding of the impact of a patient’s
DNA play an important role. This presents challenges to many current
physicians. None of the topics discussed so far above as yet appear as
core features on most nationally approved medical syllabuses, except
perhaps as glimpses in a basic teaching of evidence based medicine,
epidemiology and biostatistics. This is all of some concern because a
physician takes ultimate responsibility in using a CDSS. The omissions in
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Computers in Biology and Medicine 117 (2020) 103621
courses are understandable because of the large amount of medical in­
formation that a student must already absorb [1], but a grasp of bioin­
formatics stands out as needed because of the rise of translational
research, capable of delivering new genomics discoveries that impact
diagnosis, best therapy, and risk on a daily, even real time, basis [1].
Nonetheless, even bioinformatics would be not be essential, were it not
for the fact that focus of personalized medicine today is increasingly on
DNA and protein sequences. This is arguably a characteristic feature of
precision medicine because it contrasts with the older or separate term
genomic medicine that has largely been associated with the idea of
ordering tests for highly localized inherited mutations, typically single
base changes [1,8]. These differences were originally called single
nucleotide polymorphisms (SNiPs) later seen as genomic biomarkers.
Detecting the presence of such in the patient’s DNA is traditionally or­
dered to be done by a lab, and is reported and used in much the same
way as any test. However, while SNiPs are the most common kinds of
mutation, this does not mean that a single SNiP is always alone
responsible for a disease. Admittedly, there are perhaps some 9000
diseases like sickle cell anemia and cystic fibrosis discussed above for
which a single genomic localized biomarker (in those cases from each
parent) is typically sufficient evidence [1,8]. But most of these are
relatively rare while, as introduced 1.3 above, many very common
diseases such as heart disease and stroke, cancers, type 2 diabetes, and
behavioral disorders have a complex polygenic basis in which many
genes interact with each other and with influences from the environ­
ment. This requires bioinformatics, and the need is pressing. The cost of
routine extensive genome sequencing is becoming cheaper than an MRI
scan, but more importantly still for immediate application as discussed in
the present paper, an increasing number of patients have already had
their mitochondrial and Y-chromosomal DNA sequenced because of
their interests in genealogy, i.e. for discovering less immediate family
relationships and prehistoric genetic origins. Notably, mitochondrial
DNA (mtDNA) is easy to sequence and lots of sequences are available
because of its relatively very small size and multiple copies per cell [16].
Not least, it plays a key general role in health and disease. See Sections
1.7 and 1.8.
1.6. Integrative bioinformatics
In the early decades of bioinformatics the tools were rather discon­
nected, requiring some knowledge of computer science and communi­
cations such as file transfer protocols. It still requires some expertise
today. Making the use of bioinformatics more digestible is the aim of
integrative bioinformatics. The present paper is also a study in that
discipline, since Q-UEL tags facilitate automation. Arguably the most
popular freely available and user-friendly bioinformatics integration
effort has been the Biology Workbench (recently hosted at the San Diego
Supercomputer Center) that comprised a comprehensive set of bioin­
formatics tools and data bases in a unified intuitive workbench envi­
ronment. Unfortunately it has been out of action for some time,
purportedly for lack of funding [17], giving an added motivation for the
present study. An industrial version, the Bioinformatics Workbench
developed for the holding company forming Craig Venter’s Celera Ge­
nomics that produced the first draft of the human genome, was partic­
ularly well integrated with the storage and provenance of incoming
large amounts of DNA sequences [18], but it is not freely publicly
available in that form. Other workbench-like efforts include those by
CLC, Taverna, Characterization visual Laboratory, Genomics Virtual and
many others, but to the author’s experience and understanding they are
either more limited or not free. Still freely available public bioinfor­
matics sites include, for example, the European Bioinformatics Institute
(EBI), European Molecular Biology (EMBL), National Center for
Biotechnology Information (NCBI), Broad Institute of Harvard and MIT,
ExPASy Bioinformatics Resource Portal, the DNA Databank of Japan
(DDBJ), and for mitochondrial research Mitochondrial Disease Sequence
Data Resource (MseqDR) Consortium, and particularly for present
B. Robson
purposes MITOMAP and MITOMASTER and others discussed in context
below. All these and others would benefit from unification in a Q-UEL
approach. Currently, there is no single integrative surface as in the
Biology Workbench, and even that lacked some of the more clinically
related tools. Professional users use them all largely by explicitly
uploading and downloading files and typically cutting and pasting bio­
informatics data between webpages for diverse tools and systems. The
present paper explores use of Q-UEL based techniques to bypass this
difficulty, or at least to make it invisible.
1.7. Choice of focus on mitochondrial DNA in the present study
It is increasingly the case that DNA sequences are being added to the
patient record but mitochondrial DNA (mtDNA) sequences have had a
head start because, as discussed in section 1.5, many patients have them
already because of their genealogical interests. Mitochondria are or­
ganelles in eukaryotic cells that reside in the cytoplasm outside the
nucleus, responsible for the bulk of ATP production [16]. Deduced as
being of prokaryotic (bacterial) origin before the rise of multicellular
organisms, the mitochondrion represents an extreme accepted symbiont
with its own double stranded mitochondrial DNA of circa 16,570 base
pairs. It represents a part of the human genome that (except in rare
cases) is inherited from the mitochondria of the mother (as Y chromo­
somes are inherited from the mammalian father) [16]. Obtaining
mtDNA is easier than for Y and other chromosomes because there may
be 1000 to 2000 mitochondria in some cells, making up a fifth of the cell
volume, and each may contain several mtDNA copies. mtDNA has for
some years been of taxonomic and diagnostic [16], biological and
biomedical research [19,20], forensic [21,22], and genealogical [23]
interest, but precision medicine has so far tended to neglect mtDNA [8],
perhaps because mtDNA research is enjoying a revival that presents
some mysteries and surprises. The number of publications on mito­
chondria has recently exploded and overtaken those for each of the other
cell components taken individually. Yet the picture is now clarifying,
showing how mtDNA expression plays a central role in metabolic control
and aging, responding to physiological stress, oxidative stress, and
testosterone, while involved in many disease states, both rare and
common, such as heart disease and stroke, cancers, obesity, and type2
diabetes. Recent mitochondrial research adds Alzheimer’s, Parkinson’s
Huntington’s diseases, and epilepsy [18,24]. mtDNA thus spans the
main concerns in popular health culture. Importantly for the pharma­
ceutical industry, the mechanisms are also increasingly better under­
stood as to how mitochondria communicate richly with each other and
rest of the cell to control housekeeping functions, modulate synaptic
transmission within the brain, release molecules that contribute to
oncogenic transformation, trigger inflammatory responses systemically,
and influence the regulation of complex physiological systems and
aging.
1.8. Brief review of probabilistic aspects of mitochondrial genomics
A probabilistic approach has long been required in mitochondrial
genomics, not least because of its genealogical and forensic applications.
In this paper, no sequencing errors are presumed: conventional DNA
sequencing has been fine-tuned to achieve read-lengths of up to ~1,000
bp per section with per-base error rates as low as probability 10 5. Aided
by reference to standard well-studied mtDNA sequences to focus atten­
tion on possible anomalies, reliability of sequences is a reasonable initial
assumption. There may be many independent mutations in one indi­
vidual, resulting in heteroplasmy (mtDNA diversity) with each mutation
found in about 1–2% of all the mitochondrial genomes, but the average
sequence usually reflects the inherited sequence in healthy tissues. The
chance of picking two individuals at random in the world and finding an
identical mtDNA is estimated to be 1 in several trillions [21,22]
(although a conservative random match probability of one in a billion
has become standard for UK court reporting purposes [22]). Any two
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Computers in Biology and Medicine 117 (2020) 103621
contemporary people will normally have identical mtDNA if they are
related by a unbroken maternal lineage in which mutations have not
occurred. The accepted (inherited) mutation rate is about 1–4% per
generation. One has a 50% chance of sharing a common maternal
ancestor within the last 5 generations (circa 125 years), and a 95%
chance of a full sequence match for 22 generations (circa 550 years)
[23]. An individual with no living recent relatives could have a unique
mtDNA sequence. Mutations associated with serious diseases may not be
passed down through many generations [24]. For many years differ­
ences were reported primarily in just two hypervariable regions as
“hotspots” for mutation: HVR1 and HVR2. These determine one’s hap­
logroup which is still used as a classifier today. These regions are more
sensitive for genealogical and forensic purposes, although in forensics
percentage probabilities of variously 0.1%–1% are deliberately used as
conservative estimates of significant match (e.g. Refs. [25–27]). Prob­
abilistic considerations in linking mtDNA to disease concern (a) heter­
oplasmy that increases in diseased cells and especially in cancer, (b) the
polygenic nature of the more common diseases, (c) involvement of
mutations in nuclear DNA (nDNA), and the fact that mtDNA mutation
rates are some 10 time times higher than in nDNA, (d) estimated
probabilities of maternal versus paternal transmission of diseases, and
(e) metabolic regulation effects (e.g. Refs. [28,29]). In the near future,
we should expect that probabilities for diagnosis and perhaps prediction
of disease might be linked even more precisely to Mitochondrial Derived
Peptides (MDPs) [19,20], inherited mutations in them, and to their
expression levels. MDPs appear to be responsible for much of the
crosstalk between mitochondria and the rest of the cell. At the time of
writing some three general types of MDPs are said to be known,
humanin, MOTS-c, and a diverse class SHLP1-6. The first two classes are
down-regulated in type 2 diabetes [30] but all MDPs might have a
distinct action associated with distinct important diseases. It suggests
the design of peptomimetic drugs, i.e. designs that introduce, for
example, D-amino acids [2], possibly leading to more traditional small
drug “molecules in a pill”. As an example of use in drug discovery
research, Q-UEL uses bioinformatics to identify potential new MDPs in
the present paper, so laying the basis for a study of inherited mutations
affecting MDP structure and expression, and linking mtDNA genomics
more tightly to disease prediction.
1.9. Other work related to use of Q-UEL in the present paper
In the author’s understanding and opinion at time of writing, there
are no published efforts by other workers that closely relate to the HDN
and Q-UEL. At least, they relate no more closely than the Bayes Net and
XML as reviewed in Ref. [7]. It was found that neural nets using related
algebra [31] have been used for some time as discussed below, but most
of the closely related efforts are by the present author and collaborators
(e.g. Refs. [32–36]). That also includes aspects concerned with infor­
mation theory for generalizing the approach to allow use of sparse data
[32] that had early origins in bioinformatics [37] later extended to
biomedical data-mining [38–40]. See also refs [1,2]. The present
approach in genomics makes much use of links to bioinformatics tools
developed by other workers given at appropriate points throughout his
paper. Other efforts in genomics and bioinformatics that inspired some
ideas in the present work include the Mitomap and Mitomaster systems
provided by the Center for Mitochondrial and Epigenomic Medicine at
the Children’s Hospital of Philadelphia [42]. Experience with the
Genomic Messaging System [43], genomic knowledge gathered by the
MARPLE system [44]. Mitomap and Mitomaster, and the XTRACTOR
component of MARPLE, were also used directly. In developing the sys­
tem for integration of the above and the stored knowledge required by
them, brain models developed by neuroscience were helpful [45] (See
Section 4.1). As to areas of application, many other workers have of
course carried out investigative work on MDPs as indicated above (see
also refs [46,47]), as have studies on relationships between mtDNA
mutations and type 2 diabetes (T2D) [48–52].
B. Robson
1.10. Other work using Clifford calculus and related algebras
A broader body of work by other authors is relevant if one focuses on
a particular characteristic feature of the mathematics behind HDN and
Q-UEL, namely the use of a kind of algebra that belongs to the Clifford
calculus [53]. Primarily this affects the way that probabilities are rep­
resented and managed in Q-UEL (see Theory Section 2). Dirac redis­
covered it in a particular algebraic form now called the Clifford-Dirac
algebra. In general, algebras of this kind involve imaginary numbers
which follow the anticommutative law ab ¼ -ba, create a new imaginary
number on multiplication, ab ¼ c, and for which a square such as aa, bb
or cc is either þ1 or 1 (and in Grassmann algebras 0) as defined. It is
one such imaginary number called h in Q-UEL, such that hh ¼ þ1, that is
of interest for enabling Dirac notation to be used for clinical decision
support, an idea that appears to go back to a speculative paper by the
present author [54]. Normally one tends to think of quantum mechanics,
including Dirac’s brakets and the associated algebra, as i-complex, based
on the familiar imaginary number i as the square root of minus one, i.e.
ii ¼ 1. A number with the properties of h has been rediscovered by
many authors many times in various names and guises (perhaps 20 or
more, e.g. Ref. [6]), including by Dirac: it appears in the Clifford-Dirac
algebra. The original discovery was almost certainly by Cockle in
1848–1849 [56,57]. Recently it has most often been called the split
complex number or hyperbolic number. Without any reference to theo­
retical physics, several neural networks have used related algebra that
has been found efficient [58–62]. This is possibly in large part because
the so-called XOR problem, can be solved in a single h-complex neuron
[62]. Neural Nets represent a different, “bottom up”, approach as
described earlier above, but arguably the commonality of the algebra
gives some credibility to the HDN and Q-UEL. The notion of a purely or
extensively h-complex QM has only fairly recently been emphasized, by
Khrennikov (e.g. refs [63, 64]) and he also expected his interpretation of
an h-complex QM to be applicable to a theory of mind [65], but did not
develop a specific computational artificial-intelligence-style approach
based on h. Indeed, while such efforts are emerging, they are still rather
few (e.g. Refs. [66,67]).
1.11. Other work relating to probabilistic semantics
There is also a body of work related to probabilistic semantics, which
for Q-UEL plays an important part not only in automated inference but
also in extending it to new domains such as bioinformatics that use
different ontologies. The term “probabilistic semantics” was assigned to
Q-UEL by the present author but is certainly not original, since Google
obtains 36,900 hits on that term at the time of writing. However, de­
scriptions of probabilistic semantics meaning essentially the same thing
as in Q-UEL are less common than might be expected. The Wikipedia
entry on that term [68] at the time of writing is short and in a reasonable
accord with the Q-UEL notion. It simply notes that one of the most severe
limitations of the Semantic Web is its inability to deal with uncertain
knowledge, and that probabilistic semantics extends the current se­
mantic technology to overcome that limitation but can describe only
those uncertainties that can be quantified, namely they cannot model
conceptual uncertainty [68]. It cites just one author [69]. Nonetheless,
Q-UEL research has for some years been attempting to map Dirac no­
tation to semantics and natural language by such means (e.g. Ref. [70]),
and Dirac himself believed that his system was applicable to many as­
pects of human thought (e.g. ref [71]). Philosophers and theoreticians
have explored certain aspects which relate to probabilistic semantics (e.
g. Refs. [72–76]), but there seems to be a significant gap between such
efforts and what is needed for the SW and decision support that em­
braces uncertainty. Prediou and Stuckenschmidt note that there is still as
yet no settled opinion on how to describe probability and render the
Semantic Web probabilistic [77] (again, also see Ref. [7] for review).
Many authors have been of the opinion that a fuzzy logic approach is an
appropriate compromise (e.g. Ref. [78]). In Q-UEL “probabilistic
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Computers in Biology and Medicine 117 (2020) 103621
semantics” essentially means “reasoning using statements about the
world and the probabilities attached to them which are degrees of truth,
certainty, scope, prevalence, reliability, or lack of vagueness of the
statements.” More precisely and pragmatically, a probability is ulti­
mately based on an estimate of the information in a statement, in a
quantitative information-theoretic sense, relevant to drawing a partic­
ular conclusion including identifying common meanings in different
ontologies, or making a particular decision or prediction [32,39,70]. In
principle at least, that is quantifiable by experiments with any method
based on probabilistic semantics by studying its performance on test
data with known outcomes. This latter information-theoretic definition
impacts the former involving “degrees of truth” etc. when the available
evidence is limited and probabilities cannot be assigned so objectively.
Then there are defaults and preferences regarding assignment of pre­
liminary probability values that are characteristic of Q-UEL, one of
which is based on the position that statements are initially assertions
awaiting refutation by contrary evidence in accordance with the work of
the philosopher Popper (see Ref. [70] for discussion, and brief review in
Section 4.4 below). In theory, these preliminary probability values could
still change in special cases or when Q-UEL enters a new knowledge
domain. In the present study it was noted that the probabilities can
sometimes be updated and upgraded in a reasonable way to more
informative values based on prior semi-quantitative knowledge of the
population distribution of mitochondrial DNA and approximate sizes of
populations, as discussed in Results Section 4. Much work with DNA, as
well as in evidence based medicine and public health generally, involves
the notion of probability as a matter of scope and proportion in a similar
way. Any less quantitative or fuzzy logic approach [79] to semantics
involving uncertainty would clearly not be appropriate if applied in such
cases [33].
2. Theory
2.1. Use of Dirac braket notation
For the theoretical basis of Q-UEL and associated Hyperbolic Dirac
Nets, see Refs. [4–7,32–37]. This Theory Section is confined to those
aspects directly applicable to the paper, descriptions required to explain
new features (notably the relationship to the neural net) and to mtDNA
research. The values of the basic Dirac braket forms the basis of the other
entities in the Dirac notation and in Q-UEL. In Q-UEL they are computed
and/or interpreted as follows along with some important equivalents,
for the h-complex case. Note that “complex conjugate” means the
consequence of changing the sign of the imaginary part, as in QM.
< A | B> (braket)
¼ ½ [ P(A|B) þ P(B|A)] þ h ½[ P(A|B) – P(B|A)] (h-complex Hermitian
commutator)
¼ ½ [P(“All B are A00 ) þ P(“All A are B00 )] þ h½ [P(“All B are A00 ) - P(“All B
are A00 )]
¼ P(“Some A are B00 ) þ h½ [P(“All B are A00 ) - P(“All B are A00 )]
¼ Partexistential þ h Partuniversal (interpretation as probabilistic categorical logic)
¼ (½ [ P(A|B) þ P(B|A)] - h½[ P(A|B) – P(B|A)])* (effect of the complex
conjugate)
¼ <B|A>* (effect of the the complex conjugate)
¼ < A | if |B> (braket in preferred sematic triple bra-operator-ket format)
¼ < B | if | A>* (effect of the complex conjugate because if is taken as a
Hermitian operator)
¼ <A Pfwd:¼P(A|B) |B Pbwd:¼P(B|A)> (transmitted/stored Q-UEL tag
format)
B. Robson
¼ <B Pfwd:¼P(B|A) | A Pbwd:¼P(AIB))>* (effect of the complex conjugate)
¼ ιP(A|B) þ ι*P(B|A) (spinor projector form, ι ¼ ½ (1þh) and ι* ¼ ½ (1þh) )
¼ (ι*P(A|B) þ ιP(B|A))* (effect of the complex conjugate)
¼ {P(A|B), P(B|A)} (probability dual, usually used to assign a constant e.g.
{0.91,0.23}) (1)
¼ {P(B|A), P(A|B)}* (effect of the complex conjugate)
In considering interconversion of Q-UEL with other languages it is
often useful to consider the format Pfwd(A|B) simply meaning P(A|B),
but extending that in a natural way, note that Pbwd(B|A) ¼ Pfwd(A|B)
and Pbwd(A|B) ¼ Pfwd(B|A). The sense in which the above remains QM
is discussed in section 5.4, but some operational similarities and dif­
ference should be noted.1
2.2. Vector-matrix algebraic properties and HDN-like neural nets
Vectors and matrices in Dirac notation have been recognized for
some time in Q-UEL as important for probability distributions of medical
measurements, but they also make an important connection with HDN-
like neural nets that have not previously been described. Neural nets
used by the present author and collaborators for comparison purposes
with HDN predictions [36] were essentially standard. A Dirac bra < … |
is a column vector as follows.
<A| ¼ [<A| Ψ 0>, <A|Ψ1>, <A|Ψ2>, ….<A|Ψn>] (2)
Here [<Ψ 0>, <Ψ1>, <Ψ2>, ….<Ψn>] is expressed as a vector of
wave functions, or distribution description of a wave function, or of
probability amplitudes of quantum states generally. The Q-UEL in­
terpretations are of practical value as discussed below. The corre­
sponding ket is the column vector.
|B> ¼ [<Ψ0|B>, <Ψ1|B>, <Ψ2|B>, …..<Ψn|B>]T (3)
The T indicates the row-column transpose. Dirac’s braket can be seen
as the scalar result of an algebraic expression containing vectors: <A|
B> ¼ <A||B> ¼ <A|.|B>. The dot operator is not usually written in
physics, but it is added here for clarity. The above and the following
apply both in Q-UEL and QM. Note that <A| ¼ |A>* (by definition, a bra
is the complex conjugate of a ket), |B>¼<B|* (similarly a ket is the
complex conjugate of a bra), and operator ¼ |A><B| (outer product, a
particular kind of matrix as an operator). While many authors write <A|
¼ |A>y, it seems clear from Dirac’s writings that the < and > delimiters
already provide the transpose, so only the complex conjugate * is
required. As in QM, the most useful Q-UEL operators are Hermitian,
which means that it is unchanged under complex conjugations and
transposition, as implied in the following: < A | operator |B > ¼ <B |
operator | A >* ¼ <B | operator* |A>. It is usually convenient to use a
class of h-complex forms called zipper vectors and matrices in which
1 <Lm | Noverall |L0> ¼ … …< L3 |N2 |L1 >< L2 |N1 |L1 >< L1 |N0 |L0 >(7)
In QM, the spinor projector form also uses h or an equivalent entity that
squares to 1 (e.g. γ5). Many of the other expressions above would be valid for
the i-complex case characteristic of much QM, although then the probability
dual { …,…} is less directly deduced by a recipe for observable probabilities
due to Dirac. It can be shown to remain valid in the h-complex case, but here
the above essentially definitional approach is sufficient. Also in traditional i-
complex QM, one would replace the empirical probabilities by normalized
exponentials of i-complex expressions of what is, in effect an information
measure (it is this which resulting in QM’s characteristic periodic, i.e. wave,
function). The probability values required for Q-UEL can be obtained by data
mining methods that analogously result in information measures of which ex­
ponentials are then taken (see Section 4.5). The use case of mtDNA also makes
relatively easy some probability estimates made using prior semi-quantitative
knowledge as discussed in Results Section 4.
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Computers in Biology and Medicine 117 (2020) 103621
positive and negative imaginary parts alternate, zipper-like [33]. For
example for any real values a, b, c, d, etc.,
|A> ¼[ιa, ι*b, ιc, ι*d, …] (4)
<A| ¼ [ι*a, ιb, ι*c, ιd, …] T
(5)
The wave function or universal quantum state Ψ in Q-UEL with the
distribution Ψ 0, Ψ 1, Ψ 2 in Q-UEL taken as something on which all the
other states and events etc. considered are strongly dependent, and in Q-
UEL in the medical setting that is usefully the age and sex of the patient.
Intriguingly, however, in HDN-like neural nets, the distribution Ψ 0, Ψ 1,
Ψ 2, … in bra and ket vectors then represent the states with unknown
weights to find by optimization, i.e. by the training or learning process.
Neural nets have been fairly extensively used by researchers in bioin­
formatics, probably because they are well suited to handling sequences.
Unfortunately, the introduction of hidden layers of arbitrary states with
weights optimized by feedback to produce best predictions leads to
weights that are poorly understood. To facilitate interoperability at a
deeper level, one wishes to make hybrid, HDN and HDN-like neural nets,
or introduce initial knowledge as weights prior to training, not least for
efficiency, better laying out of the final weights, and avoiding entrap­
ment in local false solutions. HDN-like neural nets are HDNs with
arbitrary nodes in layers, and remain h-complex.
The overall activation function of a hyperbolic neuron is considered
as f (z) ¼ f (x) þ h f(y). As in any Neural net, a set of activation nodes α(0)
0 ,
α(0) (0) (0) (0)
1 , α2 , αn , … α3 , … represents the input layer, say L0, acting on node
say 0 with value α(1)0 in a first hidden layer 1 with a total weight w0,0 α0
(0)
(0) (0) (0) (0)
þ w0,1 α1 þ w0,2 α2 þ w0,3 α3 þ …. þ w0,n αn . There is also a bias
vector say β0 which (in the traditional neural nets) has been used with
the sigmoidal renormalization function f(z) ¼ σ(z) ¼ ez/(ezþ1). In Deep
Learning neural nets each of the layers (including input and output as
special cases) correspond to vectors. Prior to the “firing” of the neurons,
one may write
|Liþ1> ¼ Ci | Li > þ |Bi> (6)
Here |Liþ1> and |Li > correspond to two consecutive layers, and Ci is
the connection matrix, assigning values to the connection between every
node in Li with every node in Liþ1. Bi is a bias or threshold vector cor­
responding to βi above. The relation to the HDN is seen in that the usual
task of parameterizing the values of the vector and matrix elements,
characteristic of neural nets, now becomes one of assigning <Ψ0| Li >,
<Ψ1| Li >, <Ψ2| Li >, ….<Ψn| Li > and <Ψ0| Li >, <Ψ1| Bi >, <Ψ2| Bi >,
….<Ψn| Bi > or functions of them as elements of the vectors and matrix
in order to optimize prediction.
Forming inner products < Liþ1 | Li > is legal, but so that vectors may
correspond to those used in semantic HDN inference nets with a
Hamiltonian relator between bra and ket, the orthogonal case should
apply such that inner products are zero. The form required to overcome
this is < Liþ1 | Ni | Li > using some neural net operator Ni in such a way
that it describes a probability of how the state described by a layer Li
influences the immediate outputs state Liþ1, and vice versa. By a chain of
such expressions a bidirectional net overall may be expressed,
It is however vector elements as <Ψ0| Li >, <Ψ1| Li >, <Ψ2| Li >,
….<Ψn| Li > and <Ψ0| Li >, <Ψ1| Bi >, <Ψ2| Bi >, ….<Ψn| Bi > etc. in
their logarithmic forms (see Section 2.7) that are of direct operational
interest as knowledge elements prior to firing. However, the sigmoid
transformation ez/(ezþ1). that sets the response is by no means the only
choice of conversion of results to the 0 … 1 range. Consistent with the
information theoretic basis discussed below,
|Liþ1> ¼ exp(-(<Li| Ci / /<Li||U> þ <Biþ1|)) (8)
Due to the idempotent property, exp{x, y} ¼ {exp(x), exp(y)} for any
real values x,y. Note the <Li||U> for normalization; here |U> is a unit
B. Robson
vector composed of elements 1.
3. Methods
3.1. System used and overall workflow
It is in large part the role of Q-UEL language in precision medicine
and genomics that is of interest in this study. In general, Q-UEL has the
following roles, to which comment on the importance of the role in the
present project is added.
(i) Represent the “tags” conveying knowledge and logic, rendered as
probabilistic statements whenever possible. They are stored in
the Knowledge Representation Store (KRS). Q-UEL is a system
that “learns through experience” as well as though data mining,
meaning that any Q-UEL generated by any process can be kept as
potentially of interest as knowledge for future use. In the present
project, this was particularly so for see roles (v) and (vii) below.
(ii) Provide the AI particularly by guiding the automatic construction
and evolution of the inference net called the Hyperbolic Dirac
Net. This is one of main uses of Q-UEL tags in the KRS, whether
for semi-manually [32,70] or automatically [35] constructed
HDNs, or for answering multiple choice questions [44]. All had
some use in this study, but DiracSmash was of particular impor­
tance, for structured data mining and automatic odds inference
net construction [35].
(iii) Respond to queries to compute probabilities and odds as risk fac­
tors, PICO etc. for measures in EBM, epidemiology, insurance,
finance. DiracSmash [32] in particular generates not only tags
with tag value attributes for two conditional probabilities that
may for example represent risk factors, but also odds from which
odds ratios (OR) can immediately be constructed. This is impor­
tant here because odds ratios are commonly used in genetic
studies for clinical genomics as described in Results Section 4,
allowing easy comparison of predictions and experimental
studies.
(iv) Represent medical records and messages and other kinds of medical
or other data and information (i.e. written in Q-UEL itself). This
was less important here for medical records: those used were
available in two versions Q-UEL patient record format (e.g.
Ref. [35]), but they were also available as commas separated
value files (essentially spreadsheets) that also could be read
directly by most applications. However, this record and message
representation role of Q-UEL remains important in the present
study not least because Q-UEL-PATIENT-DNA tags had to be
designed and generated.
(v) Act as a ‘hub language” for interoperability, and interconversion
and joining of diverse medical data. After being used to enhance
interoperability by carrying information between Q-UEL appli­
cations and/or the use of the Internet, the Q-UEL tags continued
to represent knowledge of potential more general interest that is
useful to retain in the knowledge representation store (KRS), as in
role (i). Currently, converters play a key role in exchanging in­
formation between Q-UEL and tools on the web, usually via the
HTML underlying the web pages for the tools primarily because
Q-UEL is not widely accepted as an interoperability language at
this time, so there is no internal capability on public servers to
receive process it. Application to a new domain such as genomics
and bioinformatics also requires new converters,
(vi) Act as a programming language. Q-UEL is being developed as a
programming language as was illustrated in a simple way in the
Q-UEL application POPPER [70]. However, in the present study
the Q-UEL application DiracSmash [35] intrinsically managed
most of the programming language features that would be
required for data mining and inference net construction.
7
Computers in Biology and Medicine 117 (2020) 103621
(vii) Provide in single large tags reports such as statistical summaries and
Systematic Review. See Section 4.9, but in the present study use
primarily consisted of querying and directly examining the
XTRACT tags generated in the automated surfing process [45],
rather than semiautomatic generation of systematic review tags
as reports [33]. This more limited use is still typically more
efficient than interactive use of a standard search engine and,
importantly, the knowledge extracted during the surfing process
is preserved in the KRS, again as mentioned in regard to role (i).
Fig. 1 describes the main flows of information from the broad
perspective of the system as an intelligent agent interacting with the
Internet. The distribution into three main conceptual components in this
particular way along with converters is in some part a compromise. If Q-
UEL were widely accepted as a Universal Exchange Language (UEL) as
its name suggests, and used to extend the Internet’s currently emerging
Semantic Web to a probabilistic Thinking Web [7], then (except for
security and privacy concerns which can be overcome by a PCAST
encryption and disaggregation model [41]) one would need to consider
only the human user and the Internet. Of course, human user, local
computation and local files, and access to internet, always make up a
popular three-component option. As it is, Q-UEL is playing the role of an
architectural principle with A.I. flavor as the basis of the local system
(albeit potentially enterprise-wide, and between collaborators). The
local system is then usefully seen as an “artificial brain”, borrowing
some of the concepts of processing, working, short term and long term
memory from neuroscience [45]. From that perspective, the local system
is the inner or mental world and the outer world is the Internet. At least,
this is the model used in the present project, but with an important
caveat. The “brain” is only currently considered as an artificially semi-­
intelligent system in which the human user such as a physician makes up
the rest of the required intelligence by replacing, via an interface, what
neuroscience would consider as “the central executive”, i.e. the au­
thority responsible for the control and regulation of cognitive processes,
taking account of longer term planning, focusing system attention, and
making working memory and long-term memory work together. Later,
some of these tasks may also be automated. Working memory can be
considered as all those tags that have been selected for current HDN
construction, placed on a file called the HDNtags file (e.g. Ref. [35]). For
example, such a file is built by the Hitlist (interdependent factor list) and
Wishlist (independent factor list) by module DiracSmash [35]. Medium
term memory can be considered as all the tags gathered so for in rela­
tionship to a current project, and in simple cases that may be represented
by tags generated or selected on the basis of the Hitlist, which could
result in a number of tags several orders of magnitude larger than those
generated by Hitlist and Wishlist acting together. Long Term memory is
represented by a separate but accessible storage archive; it includes tags
that pass certain curation tests [44].
In the present study, the role of the central “model brain” figure in
Fig. 1 is currently played by the BioIngine, which is more general in
application and has been industrialized for management and mining of
Big Data [32–36,44]. The arrows in this part of Fig. 1 all represent in­
formation transmitted which is represented by Q-UEL, and the MEMORY
is also represented by Q-UEL tags. To be so in the left side of Fig. 1, i.e. on
the INTERNET would, as noted above, require wide acceptance of Q-UEL
as a Universal Exchange Language. Q-UEL could be used in interactions
in the INTERFACE for the PHYSICIAN to the right hand side, but Q-UEL
has as yet no particular advantage here over conventional methods. In
the BioIngine these are usually represented by programs or short scripts
in the SCALA language. The modules that Q-UEL connects in the Bio­
Ingine are also coded in the SCALA language to facilitate distributed
processing of Big Data. However, because the amount of data available
for the current study was small, much work was done in algorithmically
equivalent Perl research code on a laptop. All neural net codes are
research codes in Perl at this time. In each interaction with the Internet,
the request for a particular tool invokes a link to a web page on a server,
B. Robson
Fig. 1. The System used in the Present Project can be considered as Based on Brain Models from Neuroscience. See text and ref [45].
and the data to be submitted to that web page. This is easy to do
manually, although Q-UEL control tags for driving processes can also be
used [32]. It is the design and specification and description of tags
carrying the data component of the above query that is important in the
present study. In the first pass of the outer cycle used for clinical pur­
poses, such tags will typically be Q-UEL-PATIENT-DNA tags (Results
Section 4.1). It is the HTML behind the web page that is directly matched
and edited, not the text in the surface display.
3.2. Data sources
Use was made of the present author’s collection originating in his
earlier genomic and proteomic studies of mtDNA-disease relationships
(e.g. Ref. [39]), but those related to largely monogenic, less common
mitochondrial diseases and the status of the patients to common and
more complex diseases such as of type 2 diabetes (T2D) was not clear.
The data that was mainly used comprised 74 mtDNA sequences relating
to presence, or absence so far of T2D including mtDNA consented for use
and in part from the family TreeDNA data base [23] (which is genea­
logical and by itself provides no data as to health or disease). Whatever
the source, consent is by the persons from whom the original DNA
sample was maintained. Only two full sequences have so far been con­
sented for public view of significant lengths of mtDNA sequence. For
reasons discussed in Results Section 4, interest quickly focused on the
relationship between inherited mutation T3394C and type 2 diabetes
(T2D). Here 8 patents had the T3394C marker and T2D, 30 had the
normal T at that location and T2D, 3 patients had the T3394C marker
and no T2D, and 33 had the normal T at that location and no T2D. The
above may be considered as a “training set”. As a check on both as­
signments and the reasonableness of disease predictions, and to show
interoperability with Web resources with the flavor of similar pre­
dictions, use was also made of MITOMAP [42] with its MITOMASTER
tool. It is a comprehensive on-line resource with curated datasets of
mitochondrial DNA (mtDNA) rearrangements, with circa 10,300 expert
8
Computers in Biology and Medicine 117 (2020) 103621
annotated mitochondrial DNA variants, including circa 580 with dis­
ease, including T2D, information. Of course agreement with MITO­
MASTER by no means assured because many other factors might
influence whether or not a patient is manifesting T2D. A further option is
the use of data and tools in the Mitochondrial Disease Sequence Data
Resource (MSeqDR) Consortium data base in preliminary development,
but useful insight for interpretations can be obtained from such web­
sites, as follows.
3.3. Extraction of knowledge from Internet text
In contrast to use of converters to access tools at specific sites (see
below), XTRACTOR [7,44] can be directed at diverse initial sites
because it was designed for unstructured data mining of the Web (here
meaning of natural language text), as automated surfing and knowledge
harvesting from the Web. It keeps results initially in the form of XTRACT
tags, which it is said to “auto-spawn” explosively as it follows through
surfing on links and reference citations with links. The restriction is that
will not alone enter, for example, DNA sequences. It can enter Google
and Wikipedia queries Wikipedia to start off, and continue to do so itself,
in the surfing process. Most comments made about mitochondria and
mtDNA in the present text, and many references were obtained by this
automated webpage searching approach. There is some associated nat­
ural language processing to represent extracted knowledge in a canon­
ical form which can easily be converted to semantic triples. Example
XTRACT tags and use of MARPLE [44] are described in Results Section
4.6. In practice, in the present study, XTRACTOR use tends to go
hand-in-hand with alignment work to explore patient features in a larger
context.
3.4. Converters for interaction of Q-UEL with bioinformatics websites
At present, interaction with webpages for specific public domain
bioinformatics tools is less smart than in the case of XTRACTOR above
B. Robson
which is controlled by MARPLE, although sufficient for a specification
study. The reason is as follows. “Traditionally” and prior to Q-UEL one
might write a simple converter using regular (match-and-edit) expres­
sions to identify a known string in the webpage HTML < input type ¼
"text” name ¼ "authority” value ¼ "Genomic analyst” SIZE ¼ "3000
MAXSIZE ¼ "50">, and ensure that data is sent to the appropriate link
for the tool upload address by a <FORM METHOD ¼ POST ACTION ¼
“upload script link”> having tested it by e.g. <FORM METHOD ¼ "POST”
ACTION ¼ "mailto:robsonb@ …."> [43]. However, contemporary sites
show considerable diversity that mostly need to be tackled one-by-one.
Not all converters have been completed at this time and so use was
sometimes semi-manual, but it was assured by inspection that the con­
verters were feasible for inputting and/or outputting appropriate tags.
Extraction from the author’s own internal mtDNA collections did not
have this problem since it involved more standardized off-line web
pages intended for clinical genomic analysts based on the author’s
earlier genomic messaging system (GMS) [43] (Q-UEL tags now entirely
replace the original GMS language).
A Q-UEL patient mtDNA tag so generated is discussed as design result
in Section 4.1). In the workflow it is typically followed by alignment of
those sequences (e.g. Section 3.3). In particular, to create a useful per­
manent knowledge package about the mtDNA of a patient that is stored
in the Knowledge Representation Store (KRS) for future use, the patient
mtDNA tag is further reprocessed to a final form using alignment so that
inherited mutations as substitutions of base pairs with respect to a
standard reference sequence are included. For alignment of a DNA or
protein sequence in general, clinical geneticists use well known bioin­
formatics tools such as BLAST [8] ideally followed by ClustalW, for
subsequent detailed alignment of two or more sequences. Consequently,
Q-UEL links to these tools and others such as SIXPACK for translation of
DNA to amino acid sequences were studied, particularly (but not solely)
at https://blast.ncbi.nlm.nih.gov/Blast.cgi, https://www.ebi.ac.uk/, htt
ps://www.expasy.org/resources and https://www.uniprot.org/. Sites
used are quoted in Results Section 4, in context. Tools at Japanese
Institute of Genetics, the Philippine Genome Center, and the Broad
Institute were considered but not used in this study. A Q-UEL application
interface to https://en.wikipedia.org/wiki/List_of_open-source_bioi
nformatics_software was a useful hub access to some lesser known
open source codes, but generally downloading and installing open
source, while a feasible approach in theory, was not done. The author’s
own in-house methods for alignment and HDN-based secondary struc­
ture prediction provided some advantages, but emphasis in this study
was access to tools by other workers and feely accessible public web
sites. However, HDNs used in the preliminary prediction and risk
assessment studies were mostly odds-based HDNs for the dual {predic­
tive odds, likelihood ratio} built using DiracSmash [35]. Some molec­
ular mechanics and dynamics modeling techniques briefly mentioned
briefly mentioned below were own codes because those of the nature
required or preferred were not suitable freely available Web options.
3.5. Prediction of mitochondrial derived peptides
Note that the mitochondrion has a slightly different genetic code that
was commonly used in the present kind of study, but there are also
products of mtDNA genes produced in the cytoplasm by standard genetic
code that may differ slightly and need studying [17]. In theory, despite
the above complication, digital translation of DNA or RNA to a protein
amino acid sequence remains the simplest of the bioinformatics tasks for
the present study because the genetic code is conceptually simple, pre­
cise, well known and easy to code, e.g. ACG codes for threonine, GAA for
glutamate, and so on. However, the problem is that not every translation
as a putative string of amino acid residues is necessarily realized as a
peptide or protein biologically. To use that as a tool for predicting
protein-coding genes as open reading frames (ORFs) requires further
considerations and is somewhat more sophisticated. This sophistication
presents particular difficulties for the present study because of the
9
Computers in Biology and Medicine 117 (2020) 103621
interest in the unexpectedly small Mitochondrial Derived Peptides
(MDPs). Gene-finders have been fine tuned for features of globular
proteins and so may be unsuitable for MDPs. http://www.softberry.
com/berry.phtml is a promising gene-finder website but for free aca­
demic used it allows only a few searches per day, and so less suitable as
an essentially automatically Q-UEL based interaction. Three methods
were used. The first “Simple short ORF” approach is simply elucidation
of all 6 reading frames using the human mitochondrial genetic code, and
looking for DNA sections of a specified length range (typically 63–105
base pairs) starting with a start codon (methionine) and ending with a
stop codon. ORFfinder at www.ncbi.nlm.gov was mainly used in this
case. The second was an in-house tool and was initially the same HDN
prediction technique used for secondary structure prediction in proteins
[4,35] but note that the start and end of a open reading frame is more
crisply defined than the start and end of, say, an α-helix. Subsequently, a
more elaborate form used MDP amino acid sequence features as dis­
cussed below. The third used the HDN-like neural net and the same more
elaborate input data, but this had a greater challenges because prior
knowledge of the above kind cannot be introduced (at least not in the
current algorithm, although an experimental approach under develop­
ment is expected to be able to use that strategy). Both the two last two
tools depended on data mining and training respectively on sets of
similar short peptides from different species or highly homologous
sections to the three currently known types of MDP Humanin, MOTS-c
and SHLP1-6 (Section 4.9), so for example the set would include
MAPRGFSCLLLLTSEIDLPVKR Humanin 1 (human), MAAGGFGCLLLLI­
SEIDL SMRR Humanin-like peptide 7 (Piliocolobus tephrosceles),
MATQGFSCLLLS ISETDLSMKR Humanin-like peptide 4 (Pongo abelii)
and so on.
4. Results
The study obtained several kinds of descriptive and quantitative re­
sults, ranging from Q-UEL tags designed for genomics and bioinfor­
matics through some new techniques in the form of Q-UEL software
applications, up to use of all that in example use cases that in some case
are believed to contain some new scientific information. The following is
a summary guideline. Note that more attention is naturally given to
research than clinical use because clinical use is more rigidly set by set
by well-defined guidelines and clinical pathways. Original research is
more open and less well defined. Note though that the practice of evi­
dence based medicine by physicians also requires that the physician do
some research-like study in regard to patients for which diagnosis and
best therapy is less clear, e.g. using the PICO method [33].
A. Features of Principal Types of Q-UEL tags designed in the study.
#4.1. Designed Patient DNA Tag.
#4.2. Designed Additional and Alternative Alignment Attributes.
#4.3. Example of Designed Knowledge Tag.
#4.4. Assignment of Appropriate Default Probability Values.
#4.5. Assignment of Probability Values Based on Counting.
#4.6. Tags Expressing Translation into Peptide and Protein
Sequences.
B. Studies on the Early Processing of Patient Genomic Data Using Q-
UEL.
#4.7. Initial Clinical and Research Use Case Examples.
#4.8. Studies with Contrived Clinical-Genomic Data ad Conclu­
sions for Real Data.
#4.9. Semi-automated Systematic Review with Associated
Alignment Studies.
C. Clinical Use Cases
#4.10. Prediction Use Case. Example involving Mutation
T3394C.
#4.11. Further Analysis Regarding Type 2 Diabetes and Mito­
chondrial DNA.
D. Research Use Cases
B. Robson
#4.12. Research Use Case. Initial Studies and Observations on
Humanin.
#4.13. Research Use Case. Predicting Other Mitochondrial
Derived Peptides.
#4.14. Research Use Case. Validating Mitochondrial Polypeptide
Products.
#4.15. Research Use Case. Conformational Studies on MDPs.
A further Section 4.16 addresses interoperability and interconversion
with other approaches, with Q-UEL is a role as a potential hub language.
4.1. Designed patient DNA tag
Recall that the primary function of the present study is exploration of
the “special specification” of Q-UEL for clinical genomics and bioinfor­
matics. The Q-UEL-PATIENT-DNA tag shown immediately below is
arguably the most important design and even the data used for original
biomedical research will comprise an archive of such in the near future.
A large part of the sequence has been removed for brevity in this paper,
and also the SNiPs/genomic biomarkers in the protein coding region, as
indicated by the ellipsis ‘ … ’ used twice below. That is, the ellipses were
not in the tag as used. The DNA sequence was in actuality of length
16,571 base pairs covering several pages of representation (3 pages of
Arial font size 8). Large Q-UEL tags of this size are optional and not
unusual uotside of genomics, e.g. a more traditional patient medical
record broken down into attributes, usually displayed oneper line and
playing the role of multiple tags and interspersed text in XML.
The following features should be noted.
(i) Source Code Attribute and Program Language. In the tag name
considered as a special case of an attribute usually concerned
with provenance, it is indicated that the tag was generated from
converters (interacting with web pages) using software written in
the Perl language. Q-UEL algorithms have been investigated in
Mathematica, Python, and Q-UEL itself. In particular SCALA is
used in the BioIngine for Big Data analytics. Perl is used here in its
original role as “Pattern Extraction and Report Language”, and
remains a favored approach for converters and related software.
(i) Used and Purpose Attributes. These attributes relate to provenance
regarding the tag’s position as a chunk of information in the
workflow. The ‘used’ attribute value https://www.ebi.ac.uk/
Tools/msa/muscle/is provenance and describes the web page
that was used generate the tag. The ‘purpose’ attribute in the tag
relates to its actual or intended subsequent use. If it is
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Computers in Biology and Medicine 117 (2020) 103621
automatically to access the web page, however, it requires an
extension to include the Q-UEL application that accesses the
HTML code underlying the web page.
(ii) Privacy and Security Features. Regarding the importance of pri­
vacy and security in genomics, note that in two cases in the above
example, the string “DNA: ¼ ‘human mitochondrial chromo­
some’ ¼ ” and “’match code’:¼(match: ¼ 0, difference: ¼ 1) ¼ “,
the simple equals sign ‘ ¼ ’ is used. When Q-UEL applications
encrypt values after the rightmost ‘: ¼ ’ in a branch of an attri­
bute, this is encrypted and the attribute as a whole is subjected to
PCAST disaggregation [41].
(iii) List of Variants with Respect to Reference DNA. Note strings
C16189T etc., in the above example tag in Section 3.1 above. It
means that in the patient a T has replaced an original C at that
locus 16189 in the reference sequence. The reference sequence
most currently used is the revised CRS is designated as rCRS,
deposited in the GenBank NCBI database under accession number
NC_012920. Such variants may be available in source data but are
readily generated by alignment given a reference sequence.
Though these can be computed from other information on the
tag, they contain the kind of biomarker information familiar to
clinical and research genomicists, and save a great deal of time if
this information would otherwise need to be computed for many
tags.
(iv) Match code. This is usually used for neural net input but there are
other applications. A binary match/no match comparison is
typically made with the comparison with standard human
mtDNA Cambridge Reference Sequence (rCRS). The ellipsis “ …”
missing out a large section of sequence in the above tag is only for
brevity here. The match code could be deduced from the list of
the above biomarkers if complete (knowing the reference
sequence), but again having it ready saves a great deal of time in
processing large numbers of tags. There is the implication, but no
guarantee, that the reference sequence is the “normal” or
“healthy” case, and no guarantee that the substitution contributes
to a significant disease state, and an ambiguity, since a substi­
tution of any one base pair could be by any three others. None­
theless purines (A,G) to purines and pyrimidines to pyrimidines
(C,T), called “transitions” are approximately twice as common as
purine-to-pyrimidine or vice versa. In protein coding regions,
B. Robson
amino acid physicochemical properties tend to be conserved. The
loss of the more detailed molecular description is not expected to
have great impact on average, in the current state of the art.
When and where it does start to become important, the tags
almost always contain the DNA sequence. If there are concerns
about neutrals substitutions in a protein coding sequence, then it
is likely best to use a one letter code amino acid sequence in any
event, or a binary coding of that in which the 0s and 1s relate
meaningfully to amino acid properties [43].
By reference to DNA, such representations represent a focus on mo­
lecular ethnicity which is arguably fairer that terms such as “Hispanic”,
“Oriental” and “African” and certainly far more relevant to assessment
of disease risks and application of pharmacogenomics for most effective
treatment [1]. The present study is intended to be extensible to all pa­
tient DNA, i.e. including that in the nucleus, so the following example
non-mitochondrial DNA attribute, also illustrating some other options
for tag content, may be noted.
4.2. Design of additional and alternative alignment attributes
Note the ‘modified for replacements’ attribute in the example above,
which is clearly one way of representing condensed representation of an
alignment between two DNA sequences. Alignments are not only
important for determining the patients genomic biomarkers as “inheri­
ted mutations”, actually the difference with respect to a standard
reference DNA, but for comparison of DNA and proteins sequences of
patients, and even with other species, for research purposes. The
“problem” is that there are a variety of alternative and more accepted
ways to represent alignments that bioinformatics researchers like, and
one of these may be the user’s favorite. Hence it was decided that the
special specification should allow various alternative alignment attri­
butes to be optionally used, for example:
Note that part of the choice relates to various summarizing match
codes such as ‘CLUSTALW match code’ above. The following example
uses the binary match code, prominent in the present study, as the
summary of a specified alignment suitable for, for example, predictions
by neural nets.
4.3. Example of designed knowledge tag
The following a Q-UEL knowledge tag relating to genomics that was
stored in the Knowledge Representation store (KRS) at the start of this
study.
The inclusion of a relationship operator is preferred, here ‘is asso­
ciated with’, which is symmetrical and implies that the Pfwd and Pbwd
values are the same. Since the tag is an assertion with some definitional
character, the probability values are reasonably both 1. Pfwd and Pbwd
are not required to be shown because this is the Q-UEL default (see
below). Note here that one speaks of a single probability for a tag if Pfwd
and Pbwd are the same value, following the rule for duals that {x, x} ¼ x.
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Computers in Biology and Medicine 117 (2020) 103621
4.4. Assignment of appropriate default probability values
A default value of 1 is assumed for Pfwd if not specified, and similarly
for Pbwd (and also for assoc). This was the case in the Q-UEL-PATIENT-
DNA tag above. A finding of the present study was that there is no need
to override the above initial default for uses in genomics. The choice of 1
reflects or implies a parameter setting prior ¼ 0 as discussed in Section
4.5. This default is called the primary default. The particular choice of 1
essentially expresses an initial state actual or elected ignorance or
irrelevance, which may seem counterintuitive. However, it is in accor­
dance with Popper’s principle of assertion and refutation, information
theory that states I(X) ¼ -logP(X) (so P(X) ¼ 1 for I(X) ¼ 0, consistency
with Bayes’ rule, and the fact that if a piece of knowledge as a Q-UEL tag
is unknown or omitted from a purely multiplicative inference net, it is as
if present with probability 1 [7,32–39]. The default 1 also follows from
Eqn. (9) below for the use of data mining in the limiting case of having
no data to mine, if prior ¼ 0 is set. The most useful choice of subsequent
probability assignments reflects the fact that the mtDNA may not be
unique to the specified person. Secondary defaults or values are proba­
bility values that do not yet reflect a specific statistical or data mining
study, or other kind of approach involving counting, but do reflect
common sense and some prior knowledge. It may change the default of 1
depending on the case. Consider the simplified braket < patient:¼Alice |
mtDNA > relating patient Alice to a specified mtDNA sequence. If Alice
and mtDNA are both identified without error and misinterpretation, and
Alice has no close living relatives, then the mtDNA uniquely identifies
her and the imaginary part, i.e. ½ [P(Alice | mtDNA) - P(mtDNA | Alice)]
vanishes and P(Alice | mtDNA) ¼ P(mtDNA | Alice) ¼ 1. That is, the
probability dual is {1,1} ¼ 1. If Alice has a twin and no other siblings or
close relatives and we do not know which the mtDNA comes from, P
(Alice | mtDNA) ¼ 0.5 and P(mtDNA | Alice) ¼ 1, i.e. the dual {0.5,1}; the
real part ½ [P(Alice | mtDNA) þ P(mtDNA | Alice)] is then 0.75 and the
imaginary part ½[P(Alice | mtDNA) - P(mtDNA | Alice)] is 0.5. Sec­
ondary defaults extend this to introduce the effect of a sample size N even
if it is possible to establish a specific count, i.e. something is seen so
many times out of N by data analytics. In a forensic case of a Agatha
Christie style murder mystery in a stately home, for example,
Pfwd:¼P(person in Alice’s line of maternal descent in family’s stately home |
mtDNA) ¼ ~1
Pfwd:¼P(person in Alice’s family’s stately home | mtDNA) ¼ 0.1 (a very rough
estimate)
3
Pfwd:¼P(anyone in England | mtDMA) ¼ 1.9 x10
3
Pfwd:¼P(anyone in United Kingdom | mtDMA) ¼ 1.5x10
Pfwd:¼P(anyone in Europe | mtDMA) ¼ 1.35 x10 4
5
Pfwd:¼P(anyone in World | mtDMA) ¼ 1.3 x10
Some indication should of course be given as to what population the
number corresponds. Typically this is done in the tag name attribute, i.e.
in the annotation attached to the tag name. The following attribute is
B. Robson
said to represent an independent attribute or to reside in an independent
context because its specification as a set of data and any selection from it
is subject to user’s choice.
Compare the following referred to as a dependent attribute that resides
in a dependent context because, operationally at least, all automatically
emerges as a result of data analysis outside or partly outside user control,
importantly including the metadata name (here “County”).
4.5. Assignment of probability values based on structured data mining
Tertiary assignments are not defaults, but represent objective proba­
bility values estimated from observations and counts by data mining or
other data analytic techniques. There are nonetheless choices to be made
for any new domain, and some require consideration of fairly subtle
aspects. They include choices that are impacted by the above consid­
eration of prior probabilities, as follows. Data may be sparse, and
inevitably it is also the case for probabilities containing many factors
(attributes) even in Big Data. What really matters is the information
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Computers in Biology and Medicine 117 (2020) 103621
content because, as in a court of law, inference collated from a large
number of items of weak evidence could overthrow a decision that is
made without it. The theory of expected information based on Bayesian
principles was still found to be a satisfactory approach. It was originally
developed for bioinformatics [37]) although it has been further devel­
oped for use in Q-UEL and HDN calculations (e.g. Ref. [32]). An example
would be mtDNA found at a crime scene and then thought of as intro­
duced to the data base, e.g. as follows.
PðmtDNA j AliceÞ
¼ e ζðs ¼ 1; nðmtDNA; databaseÞ þ nðmtDNA; sourceÞÞ ζðs ¼ 1; nðdatabaseÞ nðmtDNA; sourceÞÞ
(9)
Whatever the approach, in Q-UEL it usually involves the partially
summated zeta function ζ(s, n) ¼ 1 þ 2 sþ 3 s þ … þ n-s with the
parameter s usually being set at s ¼ 1, or a closely related z function
[32]. Probabilities converge to classical values for ample data, i.e. P(A|
B) → n(A, B)/n(B) where n is the number of observations as n(A|B) in­
creases. As the amount of knowledge approaches zero, it is affected by
B. Robson
any prior knowledge. Prior knowledge can be included by considering or
computing virtual frequencies of occurrence and adding that to any actual
counts n [32,37–40]. The required frequencies are readily calculated in
conjunction with the sample size N to give the prior probability that is
wanted. The virtual frequency added represent the value called “prior”,
and it was found that a choice of prior ¼ 0 is also suitable for genomics,
consistent with Section 4.4. Details of the sample and the calculation and
comparisons, including the choice of prior values are usually given on a
tag as an aspect of provenance. The following kind of data mining output
tag was already available in Q-UEL and was readily adapted to genomics
[32].
This tag was produced in the present study but, because the amount
of mtDNA-disease data was small, it used the kind of contrived input
data discussed in Section 4.8, but in this case from a socioeconomic
health study [36] appropriate to inclusion of disease prevalence. Here
the sample size (500) was useful as not too small but also not too large,
so illustrating the above points as to the relationships classical and zeta
probability estimates: note that the values are approaching each other
within approximately 4–5%. It is important that a simple specification of
prior:¼0 on the tag means that all the virtual frequencies are 0, that this
is uniformly applied to calculation of all probabilities, and that this
overrides any other choices in the flow of information that led to this tag.
It indicates the conclusion of a further choice that had to be made
because, theoretically, the secondary defaults of Section 4.5 are prior
probabilities, and one might expect that they would be introduced
(retained) as added virtual frequencies. While it remains an option, it is
not done in the genomics case. Largely this is because in evidence based
medicine, the probabilities estimated are usually considered as pro­
portions form an actual sample, used to indicate prevalence, incidence
and risk. They have a formal definition based on counting, and they are
not expected to contain some kind of Bayesian prior belief. Note also
that the uniform application of prior ¼ 0 for the virtual frequencies
behind all probabilities essentially relates to what is commonly called a
Dirichlet prior density, although the standard choice in probability theory
actually corresponds to a negative virtual frequency, of 1 [37]. How­
ever, this choice justified by Dirichlet theory is somewhat undesirable
from an evidence based medicine perspective and counterintuitive from
an information theory perspective [37–40]. In the present genomics
study it would imply a blurring of the distinction between zero and one
occurrences, the latter being an important distinction because it means
that the possibility is existentially qualified, i.e. that the event is possible,
which implies a rather large leap of belief from not knowing if it is
possible.
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4.6. Tags expressing translation into peptide and protein sequences
When a gene codes for a protein, initial estimates of severity of effect
on the protein helps establish probabilities that it is responsible for a
disease suspected to be associated with changes to the protein. This is
because not all bases lead to an amino acid change, and not all amino
acid changes will have drastic effect. Tables and diagrams of conserva­
tive and non-conservative substitutions from which probabilities can be
derived are given in Ref. [2] and most protein textbooks. In the present
study, amino acid sequences derived from the open reading frames
(ORFS) are classified as coding for polypeptides as follows, “oligopep­
tides” (2–20 amino acids), “peptide-miniproteins” (from 21 to an
adjustable number, usually set at 35), and otherwise as “proteins”. The
standard IUPAC one-letter code for amino acids is used. With the
adjustable parameter set arbitrarily large, an example is as follows.
The patient’s open reading frame identified above has 100% identity
with NADH (ubiquinone) dehydrogenase subunit 5 [Homo sapiens]
Sequence ID: AAK17360.1 (mitochondrial) at blast.ncbi.nlm.nih.gov
data base when queried on the blast.ncbi.nlm.nih.gov (i.e. queried by
BLAST). There is a commonly cited sequence at https://www.uniprot.or
g/uniprot/Q9B1R0 that at blast.ncbi.nlm.nih.gov matches 100% to
NADH dehydrogenase subunit 5 [Homo sapiens] Sequence ID:
ASS29244.1 (mitochondrial). With respect to AAK17360.1 above,
however, it shows an N-terminal (leading end) MLVQLQMKV extension
and a C-terminal (finishing end) MTYSPEQSQLQYMHQQTMFNQ
deletion.
4.7. Initial clinical and research use case examples
Having generated a Q-UEL-PATIENT tag (Section 4.1), the next step
is generation of a tag describing the disease associations and risks that
those mutations may represent for the patient. The Q-UEL-DIRAC­
MINER-KMETHOD-3-FACTOR–CHF–SURVEY tag in Section 4.5 above is
such an example, but it relates to various populations, not a specific
patient. Various public web tools now exist to facilitate that step, so here
Q-UEL plays a more passive interoperability role by interacting with the
HTML underlying the webpage for the tool via its converters. However,
this also forms the basis of a more elaborate study in which one may be
able to attach improved probabilities to the mtDNA-disease relation­
ships, apply it to a larger body of patients, and possibly discover now
significant mtDNA-disease relationships in that process. For example,
using the MITOMASTER tool from that resource at https://www.
mitomap.org/foswiki/bin/view/MITOMASTER/WebHome, and trans­
ferring the mtDNA for patient 75229 with type 2 diabetes (T2D) in
FASTA format, returned a web page indicating “LHON/Diabetes/CPT
B. Robson
deficiency/high altitude adaptation” (recall LHON as Leber’s hereditary
optic neuropathy), as indicated by the presence of T3394C. The page.
www.mitomap.org/foswiki/bin/view
/MITOMAP/ClinicalPhenotypes1#Abbreviations.
displays clinical phenotypes (non-LHON) associated with mtDNA
polypeptide gene mutations reported in the literature that could be
automatically inserted into host sequences for test purposes.
Appropriate tags similar to that shown in Section 4.5 can be applied
to individual patients by use of DiracMiner, and they will then have
similar form to the tag example shown there. In the present study,
however, DiracSmash was predominantly used for assessing probabili­
ties and risks for individual patients. It generates tags for odds HDN
construction (hence the additional odds attributes Ofwd and Obwd - see
below). The process of generating associations is usually much faster
with DiracSmash (hence the name “Smash”), so these tags are used
immediately for inference net construction, and not stored long term or
transmitted over the Internet. Typically, therefore, the option is taken
for generating simplest possible appearance sufficient for the inference
task and any required curation, uncluttered by web management and
provenance detail.
< ‘type 2 diabetes’: ¼ ’Y’ Pfwd: ¼ 0.40 Ofwd: ¼ 0.67 | if | ‘genomic
biomarker’: ¼ mtDNA.T3394C and ‘age(years)’: ¼ ’gt650 and Gender: ¼ ’M’
and Obesity: ¼ ’Y’ Pbwd: ¼ 0.03 Obwd: ¼ 1.19 >
For a female over 65, the 0.4 becomes a 0.3 probability. As the
amount of data is relatively small, such tags as directly generated above
may be also may be seen as initial guidelines and be curated and refined.
Probabilities in particular may be adjusted by interaction with a human
expert aided by use of XTRACTOR to obtain supporting information on
the Web. Such study shows that the Pbwd is reasonably be much lower
than Pfwd is because many potentially causative mutations are found in
the type 2 diabetic groups. For example, C1310T, A1438G, A3243G,
A8348G, C8393T, C8478T, T8551C, T14577C, and T14709C are known
or suspected to be implicated. Literature studies with XTRACTOR indi­
cated that T3394C alone showed only mild defect in glucose-stimulated
insulin secretion, but hyperglycemia appears when strengthened by
factors as age and obesity. Even Pfwd, however, is low compared with
that for e.g. sickle cell anemia and cystic fibrosis mutations from both
parents that guarantee severe disease, and LHON in which three mtDNA
mutations have probabilities of 0.80–95 for having the disease.
Although other mutations along with the T3394C variant can also lead
to LHON with a high probability, these mutations were not in the private
collection. For T2D, there is some indication that there are fewer other
potential serious disease risks, if any, as for patient 75229. In contrast an
example non-diabetic patient 4640 carried another LHON/Insulin
Resistance/possible adaptive high altitude variant T4218C at rCRS
reference position 4216 as T4216C, a variant for vomiting syndrome
with migraine, a variant for PD protective factor/longevity/altered cell
pH/metabolic syndrome/breast cancer risk/LS risk/ADHD/cognitive
decline/SCA2 age of onset, and variant for LHON/Increased MS risk/
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Computers in Biology and Medicine 117 (2020) 103621
higher frequency in PD-ADS. Nonetheless this patient carried A10398G
(rCRS position) associated with longevity shows that not all variants are
“bad news” and many of the above disorders may emerge simply dis­
eases that tend to occur in old age. A fuller data mining of a larger data
set is expected to be able to test these ideas.
4.8. Studies with contrived clinical-genomic data and conclusions for real
data
While a great deal of tag design and specification can be done with a
small preliminary amount of data, tests on larger amounts are important
for some use cases. Tests on large contrived data are sufficient for tag
design, but they also revealed some important principles about trends
and relationships between values that are not necessarily obvious
(Table 1). The medical data record is real, and the genomic feature can
be real, but the joining is artificial; however it uses an adjustable rela­
tionship factor X as described below rather than random. Preliminary
prediction and risk assessment studies used real medical record data
(first 100,000 records, then repeated for 500,000 and 667,000 for
appreciation of convergence) and adding a hypothetical mutation called
“heart attack variant” HAV, entered along with ‘Year of birth’:­
¼<’19810 , ‘Gender’: ¼ as a requirement for the interdependent neces­
sary factors specified in a “Hitlist” (a logical AND list).
Such constructed models can be described in generalized statements
which allow preliminary probability assignments. If the presence of the
genomic biomarker is assigned at random to records except that and
fraction a with the variant have congestive heart failure (CHF) and 1-a
do not, then value X ¼ a/(1-a) is a multiplicative adjustment factor to
values indicated with X in Table 1. The actual numbers in Table 1
represent a study in which X ¼ 1. Values in italic bold font are of
broadest clinical interest, conditional on the mutation, age, and male for
all the available data used. These are useful for disease-variant associ­
ation studies. In the absence of ability to evaluate full probabilities,
multiplying by X for a variant will give estimates of odds. In Table 1, to
explore CHF in response to other serious conditions, the HDN was built
as described in Methods Section 3.1. That includes use of a query list
called “Wishlist” (in this case of diseases better called “Shortlist”) of
strong individually sufficient independent factors. Recall that it is a
logical inclusive OR list for building block tag selection, but a logical
RAND or randomly associated AND list as far as HDN results are con­
cerned, so setting the prediction model defined in terms of the in­
dependencies (for estimating probabilities with many factors, all
inference nets such as Bayes Nets assume certain independencies). For
studies on type 2 diabetes (T2D) below, that independency was not
assumed. It comprised ‘Pulmonary circulation disorder’: ¼ ’Y’, ‘Renal
failure’: ¼ ’Y’, ‘Diabetes complicated’: ¼ ’Y’, ‘Valvular disease’: ¼ ’Y’.
These are generally held to be amongst the comoborbities or antecedents
of CHF.
The overall approach is a perturbation method since the odds condi­
tional on the Hitlist of interdependent factors alone (see Methods Sec­
tion 3.1) could be computed exactly, providing a correction factor for
B. Robson Computers in Biology and Medicine 117 (2020) 103621

Table 1
Steps in the DiracSmash HDN calculation of predictive odds and likelihood ratios.
Step in DiracSmash calculation (Prior Odds forward Odds backward h-complex real of h-complex imaginary LINEARITY CHECK - Slope of vector
odds calculation is called step [0]) (predictive odds), (likelihood ratio), HDN part to be part of hDN to be from (0,0) to this (real part,
Hitlist – e.g. demographic factors 100K records Perl 100K records Perl plotted as ½ [Odds plotted part as ½ [Odds imaginary part) in h-complex space.
Wishlist – e.g. clinical factors. PrO ¼ code, 500K code, 500K fwd þ odds bwd ], bwd - odds fwd ] E.g. 0.9260/0.7268 ¼ 1.2741 (first
0.1163 (100K records Perl code), ProO ¼ records Scala records Scala 100K records Perl 100K records Perl code, row)
0.0731 (500 K records, Scala code), PrO ¼ code, code, code, 500K records 500K records Scala
0.0424 (667 K records Perl code) 667K records Perl 667K records Perl Scala code, code,
code. code. 667K records Perl 667K records Perl code.
code.

[1] Exact result for inter-dependent factors 0.1992 X 1.6529 X 0.9260 X 0.7268 X 1.2741
(Hitlist) 0.1064 X 1.4552 X 0.7808 X 0.6744 X 1.1578
0.0622 X 1.4671 X 0.7646 X 0.7024 X 1.0886
[2] HDN result for inter-dependent factors 0.7409 X 6.3700 X 4.1742 X 3.5554 X 1.1740
(Hitlist) 0.5685 X 7.7798 X 4.1741 X 3.6056 X 1.1577
0.5668 X 13.3791 X 6.9729 X 6.4061 X 1.0885
[3] HDN result for inter-dependent þ 1.4143 X 12.1601 X 7.5150 X 5.3792 X 1.3970
independent factors (Hitlist þ Wishlist) 1.0188 X 13.9421 X 7.4804 X 6.4616 X 1.1630
1.3219 X 31.2030 X 16.2624 X 12.8123 X 1.2693
[4] HDN result for inter-dependent þ 0.3669 X 3.1553 X 1.7611 X 1.3942 X 1.2632
independent factors corrected by 0.1907 X 2.6077 X 1.2992 X 1.2080 X 1.0755
perturbation method 0.1145 X 3.4216 X 1.7681 X 1.6535 X 1.0693

the full calculation. Because the factors of interest were rather sparse in
the data and because of approximations made, and because the Wishlist
factors represented a severe perturbation, it would be more correct to
say that the likelihood ratio overall lay between 3.4216 X and 31.2030 X
in Table 1, a considerable spread in this case, but importantly both
predicting CHF as ‘yes’ by being considerably greater than 1 in each
case. DiracSmash partly overcomes difficulties in this kind of result by
generating simplified models from these results and optimizing their
accuracy, sensitivity and specificity using ROC methods [35]. In this
case, 90% accuracy, 68% specificity, and 92% specificity were obtained
for the 667,000 records. Table 1 shows that the slope of the “vector”, the
value in the final column in Table 1, does not vary greatly, and that is
typically be so even if X is not independent of the prediction target, here
CHF. In this case the slope is determined largely by the prior odds for
congestive heart disorder, e.g. 0.0731 for 100,000 records and 0.0424
for 667,000 records, its real part ½ [1þPrO)] divided by imaginary part
½ [1-PrO] giving 1.1579 for 100,000 records and 0.9858 for 667,000.
This kind of near-independence provides a general check on any such
kind of calculation, which is useful because several assumptions are
made even in using completely real data, including the perturbation
method along with estimated probabilities based on zeta function for
667,000 records. Note that medical records and particular hospital re­
cords are subject to Berkson bias in that they highlight sick people; the
prevalence of CHF in the US in recent decades would put the odds at
around 0.01. Finally, note that the ratio between the values (e.g. 2.6077
X) calculated on the above independency assumption and as obtained by
data mining (say 3.5492) value is of interest in its own right as a measure
of interdependency between X and the other factors.
4.9. Semi-automated systematic review with associated alignment studies
A first step in setting out on a more elaborate genomic research
study, or to help a physician with a more complex clinical case in accord
with the dictates of evidence based medicine [1,33], is systematic review
of available knowledge such as published scientific literature [33].
MARPLE that can, in response to the multiple choice answers in turn,

15
B. Robson
autosurf and spawn XTRACT knowledge tags [45] produced the
following when executed in the multiple choice answer medical
licensing examination mode. While direct queries are also possible in a
single run, multiple choice questions are a convenient way to get the
probability distribution over number of some suspected possibilities (the
option list could be of much greater length), e.g. as follows.
Equal probabilities for several options (here, C, D, E) are indicative of
the fact that knowledge tags concerning the medical effects of inherited
mutations are currently sparse in the Knowledge Representation store
KRS. It is extensions of the present pilot study that will correct, refine
and greatly extend that knowledge. However, the state of the KRS as it is
at the stage of the study already supported the initial interest in type 2
diabetes T2D, demonstrated that MARPLE input and output can be
inserted into the current Q-UEL tag-based workflow, and initiated pre­
diction studies discussed below. The XTRACTOR component [46] that
underlies MARPLE can also be used directly as an efficient means of
detecting relevant web pages and extracting content for semi-automated
systematic review [33], and the knowledge tags from this enrich the
KRS. In the studies on humanin, for example, the following tag was
obtained.
The initial zero in e.g. [0https://en.wikipedia.org/wiki/Micropepti
de] indicates that the uniform resource locater is a direct link in the
text. If it had been a number 1,2,3, etc., this would related to references
(if present) of that number below text in the Web page, if they too have
links. The natural language text or structured text in other format is
parsed, and sometimes automatically restructured, to facilitate decom­
position into several semantic triple subject-relationship-object or linear
semantic multiple (LSM) forms [44]. Some studies were carried out on
situations that could give rise to tissue stress to which mitochondria can
respond with signaling by MDPs, for example,
XTRACTOR was able to uncover a good deal of information about
T3394C because it has well studied for being associated with Leber’s
hereditary optic neuropathy, carnitine palmitoyltransferase deficiency,
and Altzheimer’s and Parkinson disease, amongst others. However, it
appears to require another mutation such as A3397G to also be found for
these more serious diseases to occur. To understand that kind of logic of
gene expression in disease, and explore how mutations expressed as
amino acid changes in the same protein can interact in particularly
complex ways (sometimes reinforcing and sometimes compensating
each other’s effects on protein function) it is necessary to work a lot with
DNA and particularly protein sequences. It was found useful to develop
means of extracting DNA and particularly amino acid residue sequences
from text. One particular popular format (FASTA) used a delimiter
starting ‘>‘. It was re-rendered as &gt to prevent interference with Q-
UEL tag delimiters.
XTRACTOR produced XTRACT tags showing that most of the rele­
vant studies by other authors involved type 2 diabetic patients, or sub­
jects living at high altitude, or both. Haplotype CEE15319 includes
northeastern Indian populations with T2D, ANA92115 is derived from
part of a study enriched pathogenic mutations in Tibetan highlanders. In
the case of ADI79705, after the Last Glacial Maximum approximately
26500 to 19000 years ago, improved climate allowed humans to re-
colonize the high latitude regions, and the ADI79705 sequence corre­
sponds to the M9a0 b haplogroup that is relatively concentrated in Tibet.
16
Computers in Biology and Medicine 117 (2020) 103621
European and US patients the T3394C marker presumably reflect
ancient origins of the maternal line of decent in North Eastern India and
Tibet. T3394C lies in the protein product of the mtND1 gene coding for
NADH dehydrogenase subunit 1 (ND1) subunit 1 in Complex I of the
mitochondrial electron transport chain, and translates to an H (histi­
dine) at amino acid residue position 30. Replacing the H by Y (tyrosine)
in a query sequence, which corresponds to the amino acid residue at that
position in the Cambridge reference sequence such that one may refer to
a Y30H mutation, there was a 100% match with NADH dehydrogenase
subunit 1 [Homo sapiens] Sequence ID: ACA80576.3. That and related
sequences with tyrosine at that locus tend to reflect studies on DNA
phylogeny ultimately in Eastern and Western Slavs. This tyrosine to
histidine substitution would not be considered a highly conservative one
due to the uncharged nature of tyrosine and the partial charge (due to
the pK ionization value) of the histidine. Tags including alignment of
DNA combined with its translation as an amino sequence are useful in
the KRS, but can be complex to examine visually. In comparing two
patients in the present study with and without T2D in the home data
base used in the present study, as shown in standard interface display,
the following initial part of the gene for subunit 1 shows mutation
T3394C (the underlined and bold H in the second row, as the 30th amino
acid residue in the protein).
Note the start of the gene with respect to above base pair numbering
as corresponding to 3304 in the Cambridge reference sequence rCRS.
The use of the term “norm” is to indicate that we might think of this as
the “normal” mtDNA although of course this would be a misleading
practice. As a cross-check, the above sequence for the patient with T2D
and the T3394C marker has a 99% 318/319 residue match NADH de­
hydrogenase subunit 1 [Homo sapiens] Sequence ID: ACA80576.3,
which matches the rest of the sequence but retains the original Y
(tyrosine) at position 30. Some extended studies were carried out. There
are a large number of 99% matches e.g. 291/292 for partial sequences
that include the same Y to H mutation. There is bias inherent, however,
in the publicly available sequences reflecting researcher’s interests,
notably in the high altitude mutation.
4.10. Prediction use case. Example involving mutation T3394C
No inherited mutations in the patient mtDNA data used have as yet
been successful in predicting type 2 diabetes (T2D), with the important
exception that use of mtDNA data for subunit 1 of the dehydrogenase did
predict that disease. Nuclear DNA may of course play a more important
role in other cases. By “computer experiments” making various sub­
stitutions including decoys, and by the studies described in Section 4.6,
T3394C was early identified as the principal natural “clue” to the pre­
diction method, e.g. contained most of the information, which was the
origin of the focus on T3394C in the present studies.
There is certainly still value in first using the simple approach of the
more traditional genomic medicine which looks at the association be­
tween single genomic biomarkers and diseases, as opposed to precision
medicine that considers other mutations and whole sequences (see
Section 1.5). A priori, as is the case for many inherited diseases, even a
single marker can turn out to be a strong signal. For this purpose, clinical
genomics researchers have recently tended to report odds ratios. Family
B. Robson
studies by other workers have shown that patients with G3316A and
T3394C for T2D have an odds ratio 5.2 and 3.2 compared to the sample
taken from the same social and environmental background [49]. The 74
patient data set used in the present study as gave an odds ratio of 2.93 for
the association between T3394C and T2D.
In general there was qualitative agreement such a sample odds ratio
(SOR) as a likelihood ratio computed from the data itself, as was done to
obtain the above values, and diagnostic odds ratio (DOR) as a measure of
the effectiveness of a diagnostic test or prediction. The DOR is defined as
the ratio of the odds of the test being positive if the subject has a disease
relative to the odds of the test being positive if the subject does not have
the disease. For example, an HDN (a) computes a SOR from the proba­
bilities deduced from the sample HDN, and also (b) predicts say disease
or not disease if the likelihood ratio is greater than 1 or less respectively
(subject to so-called ROC tuning or optimization by a kind of decision
constant [32]), from which the DOR can be computed. The DOR is the
only option for a neural net, because it does not itself compute odds or
probabilities intrinsically but uses arbitrarily dispersed weights. Simply
predicting T2D or not T2D from the presence or absence of the marker
reduces prediction to a simple evidence based medicine calculation, and
SOR and DOR correspond. The more interesting study is the effect of
including further information is a more complex multifactor calculation,
which is discussed shortly below. Even for the above simpler case,
however, one may obtain some better indication of predictive capability
by distinguishing a training set used to obtain the SOR from the test set
used to obtain the DOR, and in the case of small data, by the technique of
“jackknifing”, i.e. simply omitting each patient used for prediction in
each use of the training set. Leaving the example use case patient 75229
17
Computers in Biology and Medicine 117 (2020) 103621
in the “training set” (meaning here the data-mined set) gave predictive
odds of 2.67 and likelihood ratio of 1.53, and taking the patient out of
the “training set” as a test case gave 2.33 and 1.34 respectively. The fact
that the likelihood ratios (and indeed in this case all these numbers) are
greater than 1, combined with the fact that the T3394C marker is pre­
sent, are all that are needed to predict T2D for that patient on this simple
likelihood basis. The above gives 0.70–0.75 for sensitivity depending on
whether the test patient is or is not removed from the training set, and
similarly a specificity of 0.5–0.55. The former is promising but the latter
is essentially indicative of a random relationship, at least in the present
case. It highlights the importance of obtaining other information that
would help exclude T2D.
In the present study, testing the effect of inclusion of more factors
could, of course, only be a test that there are no further significant
factors in the available mtDNA data that had T2D information. After
high-dimensional (multifactor) unsupervised data mining by Dir­
acSmash, a similar odds ratio of 2.8 was obtained, an important finding
if only because one would expect it to increase if there were other
positively impacting factors in the available mtDNA with T2D infor­
mation. Using MITOMASTER as the test set (see Methods Section 3.1),
an odds ratio of 2.5 for the HDN and 3.0 for the HDN-like neural net was
obtained for predicting T2D from T3394C. Although this supports the
above, it is a consistency check at best. It assumes that insulin resistance
is interpreted only as a risk factor for T2D, i.e. not observed T2D per se,
and metabolic syndrome was not considered as necessarily T2D per se,
and “diabetes” which could be T1D was considered as T2D, then the
predictive agreement is expressible as 2.5. For example, Patient 16325
with T3394C had T2D and was predicted as LHON/Diabetes/CPT
B. Robson
deficiency/high altitude adaptation.
The HDN-like neural net using the final results with the training set
as test set gave a DOR of 3.4 and similar results have been obtained for a
variety of methods of condensing the input sequence information.
Because these studies are very preliminary as far as correctness of pre­
dictions and the genomic basis of T2D are concerned, it is the ability of
Q-UEL to deliver and the neural net to receive appropriate input for
genomics and bioinformatics, and not least the efficiency of the method,
which are perhaps of greatest interest. The project included studies to
compare the efficiency of different approaches including the stacking of
information believed more important toward the front of the input
strings presented to the neural net and training on progressively longer
input strings [5]. The learning (training) time for neural nets took
typically 3 h on an older Lenovo E430 with i3-2350 M CPU at 2.3 GHz
but that depended on a variety of number of nodes and layers explored
with slight modifications and on different machines, which will be
described elsewhere. More importantly, the time persistently took about
two thirds to half that required by the corresponding more standard
purely real-valued neural net. While that result is certainly useful and
promising, it is disappointing in that something like a four-fold speeding
was expected. It may be that the slight modifications made to try and
enhance performance in an otherwise more standard neural net [5] are
inappropriate when also used for the h-complex neural net (see Dis­
cussion Section 5.3).
4.11. Further analysis regarding Type 2 diabetes and mitochondrial DNA
Amongst those accepted mtDNA mutations known or believed in the
literature to be associated with T2D, and found in Web literature with
the benefit of XTRACTOR, are C1310T, A1382C, G1438A, A1202G,
A3252G, A3256T, A3264C, A3271C, T3290C, C3303T, G3316A,
T3394C, T4216C, A8296G, A8344G, G11778A, C12258A, T14577C,
T14709C (though these may occur in non-diabetics). Two of these,
G3316A, T3394C, occur in the mtDNA ND1 gene. Some researchers
identify T4216C (Y304H) as a T2D risk. A few more mutations were also
found by XTRACTOR in the literature as potentially related to T2D (e.g.
Y30H, Y43C, I273V). The following fairly common mutations poten­
tially concerned with T2D are worthy of note as being in the vicinity of,
but not within, the mtDNA ND1 gene: A3252G, A3256T, A3264C,
A3271C, T3290C, C3303T. Common natural variants in the amino acid
sequence of the mtDNA ND1 gene product exemplified below that are
not necessarily associated with T2D or a serious disease state (though a
few have been indicated as disease-related), are A4T Y30C M31T M31V
A52T T87A T168A S205P E214K Y255C Y277C L285P L288P Y302H
(sometimes reported as Y304H). None of the mutations mentioned in
this paragraph showed as strong predictors in the current study, and nor
did any other amino acid residues in the sequence, although one might
for example expect that the neural net approach would be influenced in
some way by the rest of the sequence. The full sequence for the above
diabetic patient 75229 is as follows, in which these natural variants are
underlined and in bold.
The reason for little predictive power of the HDN and HDN-like
Neural net or T2D, apart from that inherent in the T3394C (Y30H)
marker is ultimately due to the small sample of patient sources which
was also likely biased by the kinds of research and medical interests that
gave rise to them. Such small numbers are not unusual in some kinds of
medical research but once predictive results are in one can see that the
sample is somewhat atypical (unrepresentative) of what one might
18
Computers in Biology and Medicine 117 (2020) 103621
expect from the knowledge gathered by XTRACTOR. The study did not
strongly pick up the known G3316A (A4T) and T4216C (Y304H)
markers for T2D because the majority of subjects in the data available
for the study did not have T2D also had these markers. In the example
case of the two patients with mtDNA ND1 gene used in the alignment
earlier above, the TD2 patient did not have the latter accepted mutation
but the non-diabetic patient did.
In the case of the T4216C (Y304H) the MITOMAP tool MITOMASTER
identified 144 references at the time of the present study but only 3
appeared to focus in depth on T2D, perhaps suggesting that the evidence
is considered rather weak by the scientific community as a general as­
sociation between this marker and diabetes. In addition to the above,
there was rather little variation in the above gene sequence within the
data that were actually available. As noted above, the sequence for the
example patient with T2D and the T3394C marker has an exact match
using BLAST with mtDNA ND1 gene sequence ID: ACA80576.3 except
for the T3394C (Y30H) mutation and the above-mentioned T4216C
(Y304H) mutation. A large number of BLAST matches at the 99% level
represent partial sequences that include the same Y to H mutation.
4.12. Research use case. Initial studies and observations on humanin
Certain types of basic research are not so sensitive to having only a
small data base of DNA sequences. Even a single sequence can be
informative. As noted in Section 1.10 and elsewhere, several small
mitochondrial derived peptides (MDPs) are currently suspected to exist
as unusually small protein products of genes and several are being
discovered (e.g. Refs. [19,20]), the first discovered being humanin. The
humanin gene is located at region starting 2633 in the Cambridge
reference (rCRS) and encodes a 24 amino acid peptide. The nucleotide
bases of the Humanin gene also have the separate function of being a
part of the ribosomal RNA 16S molecule, as noted in the XTRACT tag in
Section 3.5. With the adjustable parameter set to 21–35 to focus on small
open reading frames (sORFs) for potential MDPs, and in the first
example requesting a richer report on the clinical and genomic feature,
is as follows.
Humanin falls by definition into the peptide-miniprotein class of
particular interest here, that are primarily responsible for signaling be­
tween the mitochondria and the host cell cytosol. As the above tag in­
dicates, the reference sequence of active humanin in standard IUPAC
one-letter code is MAPRGFSCLLLLTSEIDLPVKRRA [20], though the
last three residues are the C-terminal are expressed only in the cyto­
plasmic genetic code translation of the exported mitochondrial mRNA,
and omitted in the mitochondrial translation. These C-terminal residues
are accepted as non-essential because both 21 and 24-amino acid long
peptides have indistinguishable intracellular and extracellular effects. In
the course of the studies for the present paper using methods [6,43,44],
described in Section 3.2, the following were amongst those humanin
sequences found.
MAPRGFSCLLLLTSEIDLPVKRRA* - most quoted humanin sequence
on the web.
MAPRGFSCLLLLTSEIDLPVKRRA* - next most quoted humanin
sequence on the web.
MAPRGFSCLLLLTSEIDLPVK* - Revised Cambridge Reference
Sequence (rCRS) of the Human Mitochondrial DNA (Genbank
NC_012920.1) mitochondrial genetic code translation.
MAPRGFSCLLLLTSEIDLPVKRRA* - Revised Cambridge Reference
Sequence (rCRS),standard cytoplasmic translation.
B. Robson
The following were found from the present study as mtDNA tags.
MAPRGFSCLLLLTSEIDLPVK* - patient 66115 mitochondrial genetic
code translation.
MAPRGFSCLLLLTSEIDLPVK* - patient 75229 mitochondrial genetic
code translation.
MAPRGFSCLLLLTSEIDLPVKRRA* - patient 66115 cytoplasmic
translation.
MAPRGFSCLLLLTSEIDLPVKRRA* - patient 75229 cytoplasmic
translation.
It is known that the humanin sequence is quite well conserved: only
about one in some 200 patients have a humanin mtDNA sequence
affected by mutations. Whether those that are so affected have medical
consequences is an area research interest in the present studies. It de­
pends on what one considers as the ORF. For example, patient 75229 has
type 2 diabetes T2D , and hypertension, and patient 66115 has no T2D,
and no hypertension. The DNA sequence for was identical in both these
cases, but with the interesting exception of the cytoplasmic stop codon,
and corresponding to the above translation as follows.
The asterisk * is the stop codon. The first line is the sequence as
translated in the mitochondrion. The second line is the sequence as
translated in the cyotoplasm. The three DNA sequences are from the
mtDNA of patient 66115, the second from patient 75229, and the third
from the Cambridge reference sequence. Patient 66115 has a single
accepted mutation with respect to the other sequences, a G replacing an
A (A2760G), but both TAA and TGA are stop codons in human cyto­
plasmic translation. This kind of mutation would typically be considered
as degenerate by having no effect, but that is not entirely clear because
there may be as yet unknown control mechanisms associated with the
gene terminus.
19
Computers in Biology and Medicine 117 (2020) 103621
4.13. Research use case. Predicting Other mitochondrial derived peptides
There are three types of MDP known at the time of writing, each
classified and named after the following by their homology with
representative members, humanin, MOTS-c (mitochondrial open
reading frame 12S rRNA-c), and mebers of the ‘ORF8:2953:3054 SHLP1-
related 1–6 group (Small Humanin-like Peptides 1–6). The best known
members are as follows.
MAPRGFSCLLLLTSEIDLPVK - humanin.
MRWQEMGYIFYPRKLR - MOTS-c.
MCHWAGGASNTGDARGDVFGKQAG - SHLP1.
MGVKFFTLSTRFFPSVQRAVPLWTNS – SHLP2.
MLGYNFSSFPCGTISIAPGFNFYRLYFIWVNGLAKVVW - SHLP3.
MLEVMFLVNRRGKICRVPFTFFNLSL - SHLP4.
MYCSEVGFCSEVAPTEIFNAGLVV - SHLP5.
MLDQDIPMVQPLLKVRLFND - SHLP6.
Humanin was found in all the patients in the present data albeit with
the exception of the variation stop code mutation above. Human vari­
ants are known, e.g. P3A, S7A, C8A, L9A, L12A, T13A, and S14A and
P19A are known, but because humanin has important functions such as
protecting neuronal cells variations may have fairly serious conse­
quences. The recently discovered MOTS-c was also found and is used in
the more detailed work-though later below, also noting that variants of
less serious consequence are known. In predicting the more varied
SHLP1-6 MDPs in particular, there appear to be more mutations with (a)
no guarantee that mutations will lead to the standard reference MDP
being predicted, and (b) where found it is often not be predicted with
exactly the same ORF as the standard reference MDP. However, they are
left in as predictions because, a priori, that ORF could be the reading
B. Robson
frame in that patient, possibly event with more than one translation. For
example:
The current standard view is at least some 3000 proteins and pep­
tides are directly involved with the human mitochondrion, though the
majority of those known are not coded there. It is conceivable that the
order of MDPs that are at least occasionally exist might on balance be of
the order of, say, 500–1000 as follows, even if many turn out to have
similar (redundant) functions (which are useful clues to drug designers).
In theory, with three reading frames on each strand of mtDNA, there is
the capacity for perhaps 3000 or more peptides of MDP size encoded in
mtDNA. This is a statement based on the length of the DNA, not the
likely open reading frames, although it becomes more reasonable if we
include biologically active peptides produced by cleavage of larger
polypeptides, which is the better known usual case, or allow for occa­
sional use of starting codons that do not also code for methionine.
Focusing only on the ORFs (standard and small), we might expect an
upper limit of some 660 based on the percentage of methionine found in
human mitochondrial proteins at 6% (rather higher than the rest of the
human organism at about 1.8%), but exceptions to the starting codon
also coding for methionine are indeed known and might, a priori, be
more abundant for a new class of recently discovered entities such as
MDPs. It is known that the tRNA specific for methionine (tRNAmet) of
human mitochondria contains a formyl-cytosine at the wobble position
of the anticodon to facilitate its binding to RNA’s AUG, but also AUA,
and there are instances known of AUU. Ignoring the last presumed rarer
case, a direct count of ATG and ATA and their anticodons indicates there
are still enough starting codons for over 1000 reading frames. There are
85 that satisfy small open reading frame requirements as found in this
study, as given in Appendix 1. There the original dates of the finding are
kept for provenance, but best matches change: see the comments in
Conclusions Section 6.3. Even they do not include several possible
overlaps and are favored genes by present methods which may none­
theless be taken indicators of locations of one or more overlapping MDP
genes. The potential problem for predicting MDPs as new polypeptide
products from mtDNA is that oligopeptides less than about 35 amino
acid residues in length, and certainly of 20 or less, are not traditionally
thought of capable of being compact globular structures and will lack the
amino acid residue sequence features characteristic of that. Short pep­
tides are usually presumed to exist in a flexible random coil in aqueous
solution, i.e. a statistical-mechanical distribution of many conforma­
tions. While biologically active peptides of short lengths are certainly
well known, they are indirectly gene products, being derived by cleav­
age of larger proteins. Short polypeptides that cannot be globular and
are directly gene products would have been missed by smart gene finder
algorithms in the past.
In the first MDP gene prediction method in Methods Section 3.3 the
simple reasonable presumption is that any predicted polypeptide as a
20
Computers in Biology and Medicine 117 (2020) 103621
direct gene product of circa 12 amino acids or more is actually made
(though it might be switched off in many cells and at many times) until
proven otherwise The new terminology in discovering short polypeptide
gene products is to locate additional sORFs (short open reading frames)
in the mtDNA. MOTS-c peptide was amongst those predicted in this
study and turned out to be a recently discovered MDP [20] of 16 amino
acids in length, and biologically active. MOTS-c is of considerable cur­
rent interest because it has dramatic effects on obesity and insulin
resistance [47]. The presence of an ORF is recognized as exemplified in
the following patient comparison of MOTS-c genes (underlined).
The gene sequence underlined has the following reading frame.
The corresponding Q-UEL tag for this MDP as found in the KRS is.
Using the BLAST tool at https://blast.ncbi.nlm.nih.gov/Blast.cgi, it is
identified as known and specifically as named MOTS-c by the following
BLAST report: RecName: Full ¼ Mitochondrial-derived peptide MOTS-c;
AltName: Full ¼ Mitochondrial open reading frame of the 12S rRNA-c
[Homo sapiens]. There is 100% match. Variants also occur in MOTS-c.
For example, a variant of AAA as CAA that replaces the K by Q, com­
mon in the Asian population, and it has been postulated as a explanation
for the high longevity of Japanese people [20,47]:
In addition to the known MDPs above, 85 further candidate MDPs
were identified, almost all unknown or unproven as protein products.
For example.
At the time of the study up to October 1 2019, no significantly similar
sequences for the above were found by the BLAST routine at https://bla
st.ncbi.nlm.nih.gov/Blast.cgi. Thus far, the prediction methods used to
predict MDP genes (Methods Section 3.3) rather remarkably produced
the same MDPs. The reason, it is suspected, is that human and MOTS-c in
the data had amino acid sequences conserved throughout while the
SHLP1-6 group was diverse. Evidently, the start and stop codons stood
out as the dominant clues in predictions. There is no evidence at the time
of the study to reject any of the 85 new proposals. Despite being entered
earlier into the KRS (march 2018), they are still expected to be valid as
the essential features of the potential ORFs have not changed in the data.
However, as described also in Conclusions Section 6.3, there is frequent
appearance of new sequences to compare. That also depends on the data
base searched and scoring systems. A best BLAST match in October 1
2019 for the above was a hypothetical protein from bacterium Lachno­
clostridium phytofermentans with a SHLP1 match of 67.74%, and on
December 22 2019 putative proline-rich receptor-like protein kinase of
Arabidopsis thaliana, a small flowering plant, was found at https://www.
ebi.ac.uk/Tools/services/web/using database UniProtKB/Swiss-Prot
(the manually annotated section of UniProtKB) with a similar match
but higher bit-based score. The most interesting hits are of course for
B. Robson
vertebrates, and once found as an actual known MDP, e.g.
MLESMSTMGFTTSMLD and QDIMVQPLLKVRLFND, the best match
found naturally almost always stays as such. Even so, if similar se­
quences found are not experimentally identified MDPs, they can repre­
sent intriguing matches with sections in globular proteins, e.g.
Here the segment from above NFIFWR-YALLTVTPQLTHYF matches
fairly suggestively with NFIAWRLFPLLTLTPQLVLYF of RNA (N(6)-L-
threonylcarbamoyladenosine(37)-C(2))-methylthiotransferase MtaB
[Chloroflexi bacterium]. Although many such matches might be consid­
ered coincidental, they are of increased significance when both from a
vertebrate, and particularly a human, mtDNA. The relatively small size
of the mitochondrial genome increases somewhat the probability of
common origin of similar short sequences within it, perhaps not least
because MDPs are short. That means that there is in effect a significant
Bayesian prior probability that there may be some evolutionary common
origin. Humanin itself MAPFHFWVPEVTQGTPLTSGLLLLTWQ matches
with a section MAPRGF——————————SCLLLLTSE of ORF37:
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4472:5515 NADH dehydrogenase (oxidoreductase) subunit 2. Many of
the 85 additional predicted MDPs and some other less likely proposals
for MDPs suggestively match with other DNA sources of prokaryotic
origin, bacteria or even chloroplast proteins, but sometimes with similar
function to mitochondrial proteins, recalling the likely prokaryotic
origin of mitochondria and chloroplasts. The predicted MDP of
sequenceMSSSKPHLSPP WLSSPDEATS has a 76% match with section
MASSKP-LSPPSLSSP–ATS (ATP synthase subunit b’ in the chloroplast of
flowering plant Morus notabilis), and secondly a 72% match with section
EGTKQSAWTQAHTFYFTP (NADH dehydrogenase subunit 4 of Rhino­
gobius cliffordpopei, a ray-finned fish). In many such cases the sequence
resolution is obscure and strengthening the case for a meaningful match
with prior belief seems unreasonable.
4.14. Research use case. Validating mitochondrial polypeptide products
Validation of a protein means that the protein product of the
B. Robson
suspected gene has actually been observed in some way, and ideally by
its extraction and characterization. A failure so far to see the protein is
not definitive of nonexistence because expression may be in some way
“switched off”, and peptides may be short lived when expressed. Vali­
dation of the predicted MDPs is nonetheless obviously important, and
while experimental studies on mDPs are still in early stages, the
following approach has been shown to be interoperable with the Q-UEL
system. By “polypeptide” here is meant large globular proteins as well as
small polypeptide (often called oligopeptide) products. The current Q-
UEL system was used to search available text and more structured re­
sources on the web to find evidence that any of the above putative MDPs
are actually produced by the mitochondrion. Unfortunately, none of the
952 tags capturing this knowledge have related to the above predicted
MDPs, but that might simply suggest that the appropriate experimental
evidence, for or against each peptide, is not yet available. Either way,
the approach remains of more general interest. There is a significant
challenge in experimental verification of which proteins are real and
truly of mitochondrial origin. The inner mitochondrial membrane alone
contains more than 150 different proteins and smaller polypeptides that
are intrinsic to it. In practice, the assignment of many proteins as
physically associated with mitochondria is a matter of degree. That is
because many proteins coded in the nucleus bind to the mitochondrion
more weakly than others. Many are imported by the mitochondrion, and
many are associated only in cases of cell stress or disease. All this varies
in tissues and species: some 600–700 distinct types of protein are found
in a typical example experimental study on cardiac mitochondria, while
in rat mitochondria, close to 1000 types of proteins have been reported.
The top few tags of the 952 collated proteins and peptides, believed
by researchers to be present within the mitochondrion or at least tran­
siently with its membrane (whether coded there or not), are shown
below. This data extracted into and intermediate file Vali­
datedMitoProteins.txt derived from a standard data base at http://lifese
rv.bgu.ac.il/wb/jeichler/MPA/(as indicated on the tag in the “source”
attribute). The reason for the interim file ValidatedMitoProteins.txt is as
follows. Normally knowledge is extracted directly from HTML on web
pages in the form of Q-UEL XTRACT tags [43,44], which are subse­
quently processed into standard Q-UEL knowledge tags in the knowl­
edge representation store. In the present case, the interim file preserves
original source content essentially verbatim after relative simple
tidying. It retains the information should the source web site be down,
and can be curated, annotated, and extended if required, and is finally
converted to standard Q-UEL tag knowledge format.
Note also.
The use of such tags in workflow includes the following. XTRACTOR
was triggered by the superoxide dismutase entry and generated a
number of XTRACT tags, e.g. as follows.
It is the tetrameric manganese superoxide dismutase or SOD2 protein
product that is usually considered as mitochondrial, and consequently a
copper-zinc based superoxide dismutase associated with the mitochon­
drion seem surprising. However, XTRACTOR also found that the copper-
zinc SOD1 is partially localized in the mitochondrial matrix, consistent
with the source list of validated proteins.
A second example of a validated protein tag is as follows.
It is only fairly recently that researchers provided the first demon­
stration that Rad51, which repairs double stranded breaks in DNA, is
also operative in the mitochondrion. In the following further example, a
phospholipase A2 like protein is known to localize in the mitochondria
in, for example, fungi, but not in humans. However, enhanced
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Computers in Biology and Medicine 117 (2020) 103621
phospholipase A2 enzymatic activity is found in cytosolic, microsomal
and mitochondrial fractions after stresses such as renal ischemia, and
calcium-independent phospholipase A2 localizes in and protects rat
mitochondria during exposure to staurosporine, a potent inhibitor of
phospholipid/calcium-dependent protein kinase inhibitor involved in
aptoptosis (“cell suicide”).
In the following example, a progesterone receptor in the mitochon­
drion seems unlikely, but truncated progesterone receptor (PR-M) lo­
calizes to the mitochondrion and controls cellular respiration.
Regarding the following, the human p53 protein is a nuclear gene
mutated in approximately 50% of human cancers, but it is known to
involved with p53-mediated mitochondria-dependent apoptosis.
Other examples, some expected and others less so, are as follows.
Recall that in each case, it does not necessarily mean that the pro­
teins are actually mtDNA products. A match with an ORF in mtDNA and
evidence of physical existence of the product is required.
4.15. Research use case. Conformational studies on MDPs
As a basis for design of modified peptides and more traditional small
molecule “tablet” drugs, one wishes to know more about the three
dimensional structure of the MDPS, and ideally that structure when the
MDP binds to its protein receptor target. A final drug candidate is then a
small molecule with a similar van der Waal’s and electrostatic binding
surface of the MDP, including corresponding polar/nonpolar features. In
the absence of an experimental X-ray structure for the complex, re­
searchers would wish to do conformational energy or molecular dy­
namics computations [2] for MDPs and analogues bound to the target
receptor. Features of the structure of general mitochondrial import re­
ceptor TOM20 that binds to MDP-like peptides is known, but the targets
for biological response to most MDPs do not appear to be known at the
time of writing. Again in the spirit of using Q-UEL approach with con­
verters to interact with public freely bioinformatics tools web pages in
the present study, secondary structure prediction HDN-based methods
already developed in Q-UEL tag context by the present author [35] were
not used, but GOR4, a version of the GOR method first developed as the
information theoretic approach [2,37] by the present author, is avail­
able on a server (https://npsa-prabi.ibcp.fr/cgi-bin/secpred_gor4.pl),
and was used. There was also employment of the author’s molecular
mechanics and molecular dynamics tools (e.g. Ref. [2], and see Section
6.1 below). All these peptide and protein structure prediction methods
were in good accord with each other, so use of GOR4 below illustrates
the findings well. This is not least because, modeled in vacuo or in a
purely water environment, an MDP molecule has not one fixed structure
although each amino acid residue predominently “wobbles around” a
conformational preference for its backbone and sidechain angles. There
is also relevant experimental data (e.g. Ref. [46]). In aqueous solution it
is known from experiments that turn-like structures involving residues
G5-L10 and G15-L18 indicating nascent helix nascent helix, and in less
polar environments it forms a helix spanning G5-L18 (e.g. ref [46).
Noting the characteristic tetra-leucine LLLL core of humanin, and the
strong helix forming tendency of that sequence in globular proteins [2],
an α-helix content or at least tendency to it (that might be realized on
binding to the receptor) is not too surprising.
Sequences homologous to humanin in known proteins that might
give clues as to the corresponding MDP conformations include a section
of NADH dehydrogenase subunit 2, MAPFHFWV­
PEVTQGTPLTSGLLLLTWQ, of which TPLTSGLLLLTWQKL APISI
B. Robson Computers in Biology and Medicine 117 (2020) 103621

23
B. Robson
constitutes an experimentally verified membrane spanning region (res­
idues 122–142) which is helix rich. The GOR secondary structure pre­
diction tool at https://npsa-prabi.ibcp.fr/cgi-bin/secpred_gor4.pl
predicts a primarily coil structure for the humanin free in solution
(consistent with observation in aqueous solution) and for all the 85
predicted MDPs (Appendix), and most often the overall CECEC motif of
coil - extended chain – coil – extended chain – coil, including for
humanin. That is, there is notably no h (helix) predicted, but only the
coil (c) and extended structure (e). For humanin and
TPLTSGLLLLTWQKLAPISIMY,shown along with the alignment, the
prediction is.
The CECEC motif might suggest the e-sections pairing to form a
hairpin pleated sheet, but this is not the experimental evidence [46].
Leucine L is a strong a-helix former so the helical conformation on
binding to a target is expected, of which nonpolar solvents are models
(albeit lacking specificity). For a peptide in isolation of covalent or
binding attachment to a larger sequence, it takes the 12 residue
LLLLLLLLLLLL to predict helix content: ccchhhhhhhhc, using the GOR4
method used at the above site. A strong initiator and terminate
“capping” amino acid residue can strengthen a helix but predictions still
require a minimum of 11 leucine residues ELLLLLLLLLLLK to generate
ccchhhhhhceec. This would be of weak relevance alone, but the above is
all reasonably consistent with experimental data for similar circa 12
–residue peptides in aqueous or weakly nonpolar solution (e.g. Ref. [2]).
But none of the 85 predicted MDPs generated were found to contain
even LLL, and several like the example in the last tag above are rich in
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Computers in Biology and Medicine 117 (2020) 103621
helix-breaking amino acids, notably the very strong helix-breaker pro­
line P. The other well-verified MDP is MOTS-c, MRWQEMGYIFYPRKLR,
which contains few α-helix forming residues, but gives a predicted sec­
ondary structure picture ccccccceeeecceec similar to that of humanin.
Similarly, those predicted MDPs with more extensive proline and other
helix-breaker content give a reminiscent CECCEC picture near the
C-terminal end, but are primarily coil. For example,
MLPSYKPQSTSSLPSPFPTASTAQHFL yields cccccccccccccccccccccee­
ceec. It is unlikely that polypeptides so rich in α-helix breakers such as
proline (P) and serine (S) will adopt an α-helical conformation at the
receptor. Several predicted as MDPs do contain a reasonably helix
forming run of amino acid residues such as ALLI. However, in such cases
there is often a detectable similarity to humanin and the prediction still
favors the CECEC motif.
The LLLL and LLL pattern in proteins with homologous sections may
not be purely to do with preferred conformation. By having what may
seem a simple hydrophobic sidechain, leucine plays a number of sur­
prisingly important roles in recognition, especially in the immune sys­
tem. According to knowledge harvested by xTRACTOR, the calmodulin-
B. Robson
binding tetra-leucine LLLL motif of KCNE4 is responsible for association
with Kv1.3. The voltage-dependent potassium channel Kv1.3 regulates
leukocyte proliferation, activation, and apoptosis, and Kv1.3 function is
central for the immune system response. Tri-leucine LLL motifs are
involved in the mechanism of internalization of Inteleukin-13-bound
Interleukin-13Rα2. Di-leucine LL motifs are known to be involved in
trans Golgi sorting, lysosomal targeting, and internalization of a number
of proteins. The insulin receptor contains four di-leucine pairs in its
cytoplasmic domain.
4.16. Some studies on interoperability in precision medicine
While the above studies are of interest as the basis of a local system
architecture (Notably the BioIngine), Q-UEL was also originally pro­
posed as an interoperability and hub language [7]. Consequently, it is of
interest how it might also share DNA and bioinformatics information by
translation back and forth between other languages or systems in which
a language is the key theme. Simpler to achieve, but still useful goals, are
simply as to whether Q-UEL can capture some of the knowledge held in
other languages, or be expressed in ways that are readily stored in Big
Data Base systems.
4.16.1. Clinical pathways
PROforma [79,80] was developed at Cancer Research UK and can
receive new information and is also developed for genetic risk assess­
ment, so it is easy to represent essential genomic features, but it but has
to the author’s knowledge no special facilities (keywords etc.) for bio­
informatics results. PROforma is an action-oriented language for clinical
pathways. Its task model has generic task and four task types: plan,
decision, action and enquiry. These have been readily rendered as
Q-UEL attributes in a large Q-UEL-PROFORMA tag for thyroid disorders
kindly given by PROforma’s developer Professor John Fox at Oxford
University. The original PROforma file of 10377 lines (586.9 kilobytes)
became the Q-UEL-PROFORMA tag comprised a file of 8472 lines (550.5
bytes). No criticism of PROforma is implied here; the differences are
primarily due to different ways of representing the ontological structure,
the layout of that, and use of aesthetic line spacing. On the negative side
for Q-UEL, Q-UEL applications will not of course (as yet) respond to the
items as a PROforma applications do. They will, however, acquire some
of the knowledge that PROforma captured about clinical pathways, and
in return help analyze (and potentially extend) the relations between the
various issue-to-response aspects represented in PROforma.
4.16.2. Data base languages
Some studies have concerned re-expressing Q-UEL tags generated by
structured data mining [32,35], including actual or contrived DNA se­
quences, as data base languages. Recall (Section 1.3) that while Q-UEL is
quite distinct from the ingenious but now obsolete database language
QUEL [13], there are some common principles. Currently in Q-UEL,
Knowledge Representation Stores composed of millions of Q-UEL tags
can be easily managed and searched by regular expression methods,
particularly those using match-and edit heterogeneous automata [41]
which also have an affinity to Q-UEL and can be rendered as such.
Originally developed to handle chemical formula which themselves
imply complex graph structures [41], they are even more efficient for
DNA, RNA, protein, and other structures that are purely linear. However
the ability to have Q-UEL content expressed and stored using other more
standard data bases and public data base languages is of great interest.
There are circa 20 types of semantic graph data base appropriate for use
with Q-UEL of which GRAKN [83] is a promising newcomer. Like the
obsolete QUEL, GRAKN also rests on semantic graphs and tuple calculus
developed by Codd, inventor of the relational data base [13]. Semantic
graphs focus on edges as relationships and are more efficient on
traversing the edge (chaining through many relationships. There are no
special problems found for genomics and DNA representation because
like Q-UEL, Graph data bases such as ref [83] are general can and have
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Computers in Biology and Medicine 117 (2020) 103621
readily accommodated DNA sequences etc. However, there are differ­
ences if the user is to handle probabilistic aspects of ontological matters.
In conversion of Q-UEL to GRAKN language, a frame or schema (e.g.
Ref. [82]) on such a data base approaches corresponds to a class of
simple Q-UEL tag Q-UEL tag of form < subject attribute Pfwd: ¼ x | if |
object attribute Pbwd: ¼ y > without values yet assigned. If the schema is
to be treated like a variable to which a probability is assigned, this can be
done for two related schema, one with Pfwd(A|B) and one with Pbwd(A|
B), but if the system is to be used generally beyond Q-UEL’s interests it
seems desirable to have in, addition, corresponding schemas for Pbwd
(B|A) and Pfwd(BIA). This is because the data base system does not
know that Pfwd(A|B) ¼ Pbwd(B|A) and Pbwd(A|B) ¼ Pfwd(B|A).
4.16.3. Medical records and messaging
Some preliminary findings may be described in relation to genomic
information in languages for representing clinical records and clinical
messaging. DiracMiner [32] optionally generates medical records in
simple Q-UEL whenever it mines a medical record or messaging file
which is expressed in CSV (comma separated value) format [32]. A main
theme of systems for communicating DNA sequences such as the
Genomic Messaging System Language GMSL [43] are not amenable to
CSV rendering in that way, but GMSL is instead concerned with anno­
tation, data and executables that can be embedded at the appropriate
points in the sequence of characters for the DNA itself, and this poses no
problem for DNA sequences in the attributes in Q-UEL. However, at
present embedded data will simply appear as annotation and Q-UEL will
not automatically respond to embedded executable codes, though they
could be downloaded and executed as programs. Interconversion be­
tween Q-UEL and XML [9] is straightforward because Q-UEL can be
considered as an XML extension. It is harder in the Q-UEL to XML di­
rection, particularly if the user exploits the Q-UEL option of more
elaborate attribute structures expressing ontologies. XML attributes
must be created to hold the Q-UEL relationship expressions (or it can be
embedded between XML tags), and in XML only logical AND is a plau­
sible interpretation between attributes, but DNA in attributes poses no
additional problems. For several digital patient record and medical
messaging languages, some useful degree of interconversion with Q-UEL
is possible with converters [7], but again carrying DNA information
causes no additional problems. To carry genomic content from
XML-based HL7 to Q-UEL Version 3 in a way that would be agreeable to
most stakeholders is facilitated because HL7 has been extended to
accommodate the standard terminology Genetic Variation Model [7].
Also GMS notation [43] can provide an alternative approach to the
above (see Chapter 5 of ref [1]).
5. Discussion
5.1. Implications for precision medicine
These preliminary studies demonstrate that Q-UEL can be extended
from more traditional medicine to precision medicine with genomic
content. With the structures of new tags required now specified, it is now
possible to move on to diverse, more advanced, studies, especially pre­
dictions by HDNs and HDN-like neural nets based on larger data. The
deeper examination of the proposed MDPs as a basis for novel phar­
maceuticals will be of particular interest to the author and collaborators.
However, a question of interest to the scientific community is whether
Q-UEL, or at least its core features such as the HDN, provides significant
advantages over other approaches. The answer in other medical do­
mains has been asserted to be yes, based on a variety of arguments and
use case studies described in the published papers, probably the most
central of which relate to the demonstrable advantages of the HDN [4–6]
over the Bayes Net and similar probabilistic inference net methods. As
HDN provides the theory of Q-UEL and Q-UEL provides the building
blocks and means of HDN construction, they are considered inseparable,
at least in the author’s strategy. It remains, however, that most of the
B. Robson
observations made in the present study are also potentially important,
not just for Q-UEL, but for any proposed interoperability, ontology or
probabilistic semantics language working with genomics. It is as yet
unclear whether one can reasonably say that there are fundamental
advantages in using Q-UEL in the genomics and bioinformatics domain if
one addresses that domain alone, but inclusion of knowledge from ge­
nomics should be seen as part of the Q-UEL vision for a thinking web for
medicine as a whole [7].
5.2. Biomedical findings in the present study
Predictions by Bayes Nets, HDNs and neural nets arguably can
generate new knowledge at least in the sense that the diagnosis or
prediction of, say, a disease for a patient may be unexpected or unsure.
Somewhat similarly new knowledge can also potentially generated from
XTRACT tags by probabilistic deductive reasoning by some Q-UEL ap­
plications [44,70]. As far as biomedical knowledge is concerned, how­
ever, predictions of relationships between genomic biomarker (variant,
inherited mutation) T3394C and type 2 diabetes were tests of method­
ology but did not produce knowledge new to science. It is amongst
several mutations in NADH Ubiquinone Oxidoreductase that have also
been of interest to researchers for some time (e.g. Refs. [49–52]). In
contrast, some of the MDPs proposed and listed in the Appendix might
turn yet out to be real and previously unknown to science. In many case,
the question of whether a finding by Q-UEL is discovery or rediscovery is
not so clear. A reviewer suggested that a key findings discussion might
be helpful to appreciate findings of the kind “XTRACTOR also found that
the copper-zinc SOD1 is partially localized in the mitochondrial matrix
… " (Section 4.14). Most often, XTRACTOR is used to aid the kind of
research that a researcher should do in an initial review of the literature
[33], or that a physician should do according to the practices of evidence
based medicine [33,44]. As far as can be ascertained for the present
study, none of the insight provided by XTRACT tags represented
knowledge new to science, with a possible exception discussed below.
One may still ask if at least the user’s examination of the collective as­
sembly of XTRACT tags suggested new ideas. This is arguably the case in
preliminary study and explorative side studies. XTRACTOR was useful
for explorative study in certain cases such as when one XTRACT tag
mentions a genomic biomarker associated with a list of diseases, and
another XTRACT mentions another mutation with another list, when the
disease lists overlap extensively. This provided useful insights and may
as yet lead to new knowledge. To approach this more automatically,
MARPLE/HDNstudent that uses XTRACTOR can be used in a slightly
different way to link, say, biomarkers in a “question” with different
biomarkers in candidate “answers” by automatically finding XTRACT or
other Q-UEL tags that illustrate such overlap [44]. However, experience
with this suggests the value of modified forms of such software to make
the most of the underlying algorithmic features in genomics and bioin­
formatics, as will be reported elsewhere.
One line of investigative study using XTRACTOR that may have
helped discover something of a more general biomedical nature is as
follows. Note first that T3394C is already accepted by authorities as
likely a possible example of a founder mutation, i.e. a mutation that has
survived natural selection by conferring an advantage, probably at some
stage in prehistory, for example the ability to hunt in a state of starva­
tion, and to function well at high altitude. These ideas have been well
explored by others (e.g. Ref. [51]). Also known is that risk for metabolic
syndrome including T2D has been shown to be reduced at high altitude
[52]. But because the mutation occurs in a protein involved in NADH:
ubiquinone oxidoreduction which reduces ubiquinone to ubiquinol to
carry electrons in the electron transport chain, and because statin drugs
inhibit mevalonate synthesis and hence also ubiquinone (coenzyme Q)
production, the present author is exploring the possibility that diabetes
type 2 might be triggered by use of statins such as Lipitor. If so, a po­
tential simple therapy to the effects of T3394C is use of oral supplements
of coenzyme Q, fairly readily available in pharmacies and health food
26
Computers in Biology and Medicine 117 (2020) 103621
shops. No previous discussion of that matter was found that specified
T3394C and statins at the time of writing, but popular dietary websites
do commonly list coenzyme Q as a supplement for a plethora of diseases
including diabetes, so the extent of any novelty is at this time unclear.
Such cases argue in favor of the XTRACTOR approach for biomedical
research: the extent to which knowledge is new or is well known is not
always well defined, and a matter of degree.
5.3. Hyperbolic neural networks
The present work introduced HDN-like neural nets (of course any
advantage shown is unlikely to be limited to genomics). Again, the work
is preliminary, but more conclusions can be drawn as to their likely
prospects than one might expect because, as noted in the Introduction
and Theory Section 2.2, the useful relation to Dirac’s quantum me­
chanics (and hence consistency with Q-UEL) may be new information
but the use of an h-complex neural net is not new (e.g. Refs. [31,57–62]).
In early HDN and Q-UEL papers this work was missed because HDN
origins came from a different direction [54] and because of the huge
variety of names and guises for h that occur in the literature [6]. It was
quickly realized that it added credibility to the HDN as an predictive
method even though the HDN is different and novel. The distinction
between neural nets and inference nets like the Bayes Net is that neural
nets are said to work “bottom up” by calibrating weights to bring output
and observation into agreement, while Bayes Nets and HDNs work top
down by pre-assigning weights as probabilities based on prior knowl­
edge. The “only” but important common feature of HDNs and h-complex
neural nets, is in the attraction of using h-complex values aþhb. They
contain information that models twice the dimensionality of corre­
sponding real values. As shown as early as 1993, that means that the
decision boundary of a complex-valued neuron consists of two hyper­
surfaces and divides a decision region into four equal sections [61]. An
h-complex neural net can solve the XOR problem, i.e. can learn to
respond to a pattern containing X or Y but not both, in a single neuron
[62]. From this one may expect that any given number of nodes will do a
more efficient job than the same number using weights that are real
values. As discussed in Results, replacing the real values in the neural net
by h-complex values, effectively pairs of numbers only reduced learning
time by between a third and a half when from the above one might
expect more, and a possible reason that our neural nets, while essentially
standard, did incorporate some features that may have been counter­
productive in the h-complex case [5]. Notably modifications included
particular ways of using prior probabilities and of starting with expected
important features ranked toward the beginning of the record as input,
and then progressively lengthening the binary representation from the
beginning [5]. This is being explored. The previous studies [31,57–62]
did not seek to make any significant link to QM, and this may be more
important than first appears because the attempt to do so within the
Q-UEL framework appears insightful and might promise significant ad­
vances. Previously, Q-UEL sought to represent the universal quantum
state or wave function Ψ by an empirically chosen, useful feature, with
which diverse medical data had a strong association. This was typically
gender combined with age or age group. Now the principal difference
between the HDN and the HDN-like neural net is that Ψ, which repre­
sents the weights, is found by optimization, i.e. by learning. The main
effort regarding neural nets in the present paper was to show their
relationship with the HDN and Q-UEL, to describe that relationship in
terms of Dirac notation, and to lay a basis for Q-UEL delivering prior
knowledge to neural net algorithms. The importance of this is to make
learning more efficient, avoid entrapment in local optima, and lead to a
more meaningful dispersal of weight across the nodes that can be related
to probability. Proof that his is the case awaits results of studies
currently being initiated. For the present, the binary 0/1 “match code”
proved to help efficiency by significantly reducing the size of input, in
contrast with training on whole DNA sequences. Although the ‘1’ could
be any one of three possible bases out of AGCT, certain transitions are
B. Robson
favored, and the indication that there is a difference and potentially a
defect seem sufficient information for an initial study.
5.4. Is Q-UEL quantum mechanics?
It is not usual for the author and collaborators to use the word
“quantum” in the title of a paper. It has seemed somewhat brash to do so,
and in the past the term has often been inappropriately applied by others
in the literature outside of physics. Even the use of the Q declared as
“Quantum” in Q-UEL was simply intended to reflect the use of Dirac
notation and mathematics of theoretical physics for broader use, as
Dirac suspected would be possible (e.g. Ref. [71]). It is simply the
effectiveness in applications in medicine (and potentially other disci­
plines outside of physics) that ultimately matters. However, Dirac’s
system as developed for QM continues relentlessly to provide guidelines,
insights, and useful tools, of which the HDN-like neural net introduced
in this study, at least with further development, may emerge as an
example. Even if seen as an h-complex neural net without starting from
preassigned probabilities as planned, this now intellectually links
Q-UEL, the HDN and probabilistic semantics to the neural net and Deep
learning domains. It is this kind of development that facilitates the
interoperability both between ontologies and between probability the­
ories [7] to which Q-UEL aspires.
Our approach may reasonably be considered as QM seen more
broadly, but that still seems within QM as Dirac saw it. The present
author found h by considering what aspects of Dirac’s system would lead
to classical probability results [54], first defining a special multiplica­
tion operator @ for i-complex numbers. Like many others since Cockle
[55,56], Dirac had also rediscovered h, but it is not at first obvious
because he used it primarily not as a new imaginary number but in the
form of matrices (γ matrices) and linear operators (e.g. σ). Dirac’s
γ0 (γtime) and spinor projectors are notably already representations of
h-complex values, as are ι and ι* in Q-UEL (Eqn. (1)), written as ½ (1þ
γ5) and ½ (1- γ5) in physics. Here γ5 has the same hyperbolic property
γ5γ5 ¼ þ1. There are several flavors of h as well as i, γ5 ¼ -iγ0 γ1γ2 γ3.
Here γ1γ2 γ3 relating to space are flavors of i. Dirac’s probability am­
plitudes of brakets etc. can this be both h and i complex overall: exp(hi
x) ¼ exp(-ih x) ¼ cos(x) þ hi sin(x) is still periodic, a wave function,
although a purely h-complex exponential is a hyperbolic one: exp(h x)
¼ cosh(x) þ h sinh(x). The Q-UEL system could also be described as the
result of a Lorentz rotation i → h of Schro €dinger’s i-complex wave me­
chanics, arguably relating to “collapse of the wave function”, i.e. it be­
comes classical [54]. For example, < p| x> for momentum p ¼ mx and
position x leads to a term in exp(-mx2/t ћ) for mass m, distance x, time t
and Planck’s reduced constant ћ, which is a normal (Gaussian) distri­
bution resembling diffusion. Q-UEL does not illustrate quantization, at
least not extensively, but that arises with the wave properties respon­
sible for “quantum weirdness”. Eigenvalues as a result of
Halmitonian-like operators do have their analogues in Q-UEL, but this is
for future discussion by relating to expected experimental values other
than probabilities, but note that eignenvalues of h as þ1 and 1 (and 1
and 0 for the spinor projectors) determine the two values in the prob­
ability dual of Q-UEL as eigensolutions. The key questions are whether
we still inherit the full machinery of QM, and whether we find that
useful. The argument is that it allows the Bidirectional General Graph for
inference, and a probabilistic semantics closely related to natural lan­
guage. Some features that appear different in such practical applications
are also found in certain important situations QM.
Subject-verb-relationships follow bra-operator-ket rules but are always
related to probabilities; nonetheless this is permissible for any mea­
surements based on 0, 1 outcomes and projection and related operators
in QM. Probably the major unfamiliar step in putting the results of
Dirac’s system to use is in forming Hermitian matrices and related
vectors with purely h-complex elements, but at least one approach, by
zipper vectors and corresponding matrices [33] (see also Eqns (9) and
(10) above) is straightforward. In general, theoretical physics still
27
Computers in Biology and Medicine 117 (2020) 103621
remains the guideline for Q-UEL.
6. Conclusions
6.1. General observations
Q-UEL can be readily formulated for the genomics and bioinfor­
matics domains without departing from its general specification, but
some new attributes with rather different features were required in
order to carry DNA and protein sequences. Since Q-UEL tags were
designed to be read by medical services if much of the IT infrastructure
breaks down in a disaster, as well for ease of development and main­
tenance [7], sequence and alignments also needed to be displayed
appropriately. It is likely that analogous findings will apply to any
interoperability or reasoning language, including for a future Thinking
Web [7] beyond the Semantic Web [9] that is currently being developed.
On the one hand, the above conclusions, while important to establish,
are not surprising, and the changes required the current repertoire of
Q-UEL tags are not dramatic. On the other hand, the features and their
uses are numerous and fairly complex and require some bioinformatics
experience, so their documentation with associated observations should
be useful to workers interested in knowledge management systems in
medicine. There may of course be future refinement or corrections, and
the present study is the first pass at the special specification of Q-UEL in
the genomics and bioinformatics domain. Of broader interest are new
algorithms or software applications that use the tags and in the present
case that primarily means the HDN-like neural net, and also any findings
or predictions of the kind discussed in Section 5.2 and regarding MDPs in
Section 6.3 below which may have novel, and ultimately testable, as­
pects. Once biomedical research is chosen as a use case, it raises the
question of which discoveries may actually be novel. In Discussion
Section 4 it was noted that it is not always an easy question, and a matter
of degree (at least not without very deep analysis of the kind that oc­
cupies the patent office [88]). One approach, which is readily auto­
mated, is to consider whether on using all the associated items from data
mining as a query to Medline produces few or many hits: few hits suggest
novelty [89]. Also, the publications represented by those few hits can
also suggest biomedical and population health mechanisms and pro­
cesses discovered by researchers that justify and explain the associations
[89]. In the present study, however, for those findings that appeared to
be particularly interesting, evidence of discovery was either very clear,
or notably absent at time of writing. See Section 6.3 for a special
comment on this in regard to proposed new MDPs.
6.2. Interoperability, discovery, extensibility and future work
The developer of an interoperability language faces a dichotomy,
seeking to promote the scientific and technical advantages, and hoping
for new discoveries, but at the same time arguing that it can accom­
modate well, and ideally make equally good use of, many alternative
approaches by other workers. Nevertheless, whatever is included, one
might seek to argue that the whole is greater than the sum of the parts
embraced. In that, two points arise. The first is that while the HDN and
Q-UEL may appear unusual and special, that approach is taken because
the use of the h-complex number enhances interoperability: it leads to a
broader approach that includes Bayes Nets and other technologies as
variously subgraphs and subsets. Consequently, Q-UEL embraces these
established approaches well and can serve them just as well. The second
is somewhat converse to the above, being that maintaining consistency
with the broader, fundamental principles for at least some of the tools
added, rather than simply just plugging in established software, may
also be important. For example, the introduction of the HDN-like neural
net extends the Q-UEL/HDN idea and provides a deeper useful rela­
tionship to Q-UEL probability theory. Future efforts will include using Q-
UEL to introduce prior knowledge into compatible h-complex neural
nets [57–62]) prior to training, alongside linking precision medicine to
B. Robson
current Q-UEL efforts in regard to tissue biobanks [34], and linking
medical data to modeling peptides and proteins [2,81,87] as a path to
drug discovery [81] as discussed below in Section 6.3. Research into
MDPs and identification of potential new MDPs may represent basic
drug discovery for a new class of pharmaceutical candidates. Another
next step in the Q-UEL project will be to link related computational drug
candidate selection methods and techniques for modeling the proteins
with which they interact and their mode of interaction with them (e.g.
Ref. [81]). Another future step of great interest will be the examination
of mtDNA sequences from many patients to see what inherited muta­
tions are found in MDPs and how these might relate to health and dis­
ease, but it is intriguing that this could in principle yield suggestive
results even prior to the above validation.
As also regards future work, one may ask how extensible other fea­
tures in the present paper may be outside genomics and bioinformatics,
and whether they are worth progressing for more general use. Many are
obviously specific to those domains, but some may also be specific while
seeming more general. For example, while HDN-like nets are likely to be
generally useful, the use as input of binary 0/1 assignment with (say) the
1 represents any change from a standard reference, may be more
restricted. There may be concerns about that approach even within ge­
nomics (these can easily be addressed in various ways, e.g. see Results
Section 4.1), but the idea seems reasonable because one is usually
initially simply testing whether any mutation matters, i.e. if that
observed in a patient or donor is a suspect for causing or helping cause a
disease. Outside genomics, however, the specific nature of any kind of
difference may matter much more at the outset. Despite that, exploring
various ways of presenting only the most relevant features to neural nets
will be of obvious general interest.
6.3. The mitochondrial derived peptides
Of dominant interest in the present research use cases were the
potentially new mitochondrial signaling factors (the MDPs). The fact
that they are peptides holds great promise for drug discovery and design.
That is because the ability to synthesize and even design active, quite
large peptides and proteins that are wholly or partly composed of D-
amino acids has been feasible for some years [82–86], as a first step to
achieving oral tablets. Various prediction methods were used here, but
many MDPS might be found by changing standard criteria, particularly
to allow shorter length, for the open reading frame (ORF). The emphasis
has been on the use of Q-UEL, or a language like it, to facilitate such
work. Nonetheless, it remains that some may be discoveries because
these were not found in the literature by the author at the time of
writing. Also most did not have amino acid sequence matches at that
time to peptides on public data bases that were immediately identifiable
as actual or potential MDPs. Indeed, most matches (but not all) are
unlikely evolutionary relatives as discussed in Results Section 4.13. Best
matches can of course change. Q-UEL-ORF-PROTEIN tags in the sup­
plementary data Appendix 1 carry best sequence match information at
the time of the 2018 study, this being their prper provenance within
Q-UEL, and there have been no drastic revisions, but best matches
change frequently. For example, the putative MDP MAACLMLVPFDRG
DLEGELTGTGMLACVILL originally found a partial match with a K
(þ)-transporting ATPase subunit F of Lechevalieria aerocolonigenes, a
bacterium, and the original dates are retained as provenance, but as of
12/22/2019 a complete match was found, except for isoleucine I in
place of the initial methionine M, with Hypothetical protein CIN­
CED_3A015187 in Cinara cedri, an insect (a conifer aphid), using
BLASTP at https://blast.ncbi.nlm.nih.gov/Blast.cg. See also Results
Section 4.13. Ideally, of course, one should first be assured that the
predicted MDPs actually do exist. It is to that end that the list of pre­
dictions of potential MDPs is given in the Appendix, for interested re­
searchers to consider and find published, or even provide, experimental
validation.
28
Computers in Biology and Medicine 117 (2020) 103621
6.4. The general importance of the mitochondrial DNA choice
Mitochondrial DNA was chosen for initial genomics studies because
of its relative simplicity in terms of small size and because many patients
are having their mtDNA sequenced because of genealogical interests, but
mtDNA is no “poor cousin” of the DNA in the cell nucleus. It is important
in its own right because of its fundamental relation to metabolism and
major diseases. Efforts to collate access to worldwide mtDNA data
shoulds benefit the community through forensic science as well as
through medical genetics [90]. New techniques based on in vitro
fertilization (IVF), emerged in the past few years and have the potential
to prevent the transmission of serious mtDNA diseases via mitochondrial
donation [91], and this also hints at direct engineering of mtDNA to
avoid disease, alleviate subclinical issues, and enhance robust health
and promote longevity. These are all sweeping claims for such a small
part of human DNA, but they are by no means unique to the present
author. Currently, possibly no other sections of human DNA compressed
into so few base pairs have so much diverse impact on human health and
affairs, providing interesting and timely tests cases for development of
systems for management and productive use of biomedical knowledge.
Declaration of competing interest
This paper is provided to the community to promote the more gen­
eral applications of the thinking of Professor Paul A. M. Dirac to human
and animal medicine in accordance with the charter of The Dirac
Foundation, to emphasize the advantages and simplicity of the basic
form of the Hyperbolic Dirac Net, to encourage its use, and to propose at
least some of the principles of the associated Q-UEL, a universal ex­
change language for medicine, as a basis for a standard for interopera­
bility. These mathematical and engineering principles are used, amongst
many others in an integrated way, in the algorithms and internal
architectural features of the BioIngine.com, a distributed system
developed by Ingine Inc. DE for the mining of, and inference from, Very
Big Data for commercial purposes.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.compbiomed.2020.103621.
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30
Computers in Biology and Medicine 117 (2020) 103621
Barry Robson BSc(Hons) PhD DSc, Professor Emeritus Medicine
(Evidence Based Medicine, Epidemiology & Biostatistics) was
five years as Chief Scientific Officer IBM Global Healthcare,
Pharmaceutical, and Life Sciences and, prior to that, six years as
the Strategic Advisor at IBM Global Research Headquarters (T.
J. Watson Research Centre). For those 11 years he held the
prestigious title of IBM Distinguished Engineer. According to
Barry’s two page biography written by journalist Brendan
Horton in Nature (389,418–420, 1997), Barry was a pioneer in
bioinformatics, protein modelling, and computer-aided drug
design. He is the recipient of several honours including the
Asklepios Award for Outstanding Vision in Science and Tech­
nology at the Future of Health Technology Congress at M.I.T. in
2002. He has helped start up several other companies or di­
visions in the UK and USA. Barry continues as CEO of The Dirac
Foundation in the UK, and Distinguished Scientist (Admin.) at
the University of Wisconsin-Stout Department of Mathematics,
Statistics, and Computer Science. He is also cofounder of Ingine
Inc., Delaware USA, a medical A.I. company. While continuing
to work for, and then collaborate with IBM, he was also Uni­
versity Research Director and Professor of EBM, Biostatistics
and Epidemiology at St. Matthew’s University School of Med­
icine which he helped established in its earlier days in the
Cayman Islands. Barry also holds a Harvard-Macy Course Cer­
tification in the Business of Medical Education. Immediately
prior to joining IBM in 1998, he was hired as Principal Scientist
at MDL Information Systems in California to help put together
the technology for the multimillion sale of a bioinformatics
system to the holding company forming Craig Venter’s Celera
Genomics that produced the first draft of the human genome.
Prior to that, he was CSO of Gryphon Sciences (later Gryphon
Pharmaceuticals) in South San Francisco, California, a bio-
nanotechnology ultrastructural chemistry start-up largely held
and then acquired by SmithKline Beecham. Before moving to
the US, Barry was the scientific founder of Proteus International
plc in the UK, designing and leading the development of the
PROMETHEUS Expert System and its underlying GLOBAL
Expert System, bioinformatics and simulation language for
drug, vaccine, and diagnostic discovery. It sold for the equiv­
alent of $9.4 million to the pharmaceutical industry in the mid-
1990s. At Proteus, he also led the team that used the above
Expert System to invent and patent several diagnostics and
vaccines including the Mad Cow disease diagnostic subse­
quently marketed worldwide by Abbott. He has over 300 sci­
entific publications in Nature, Science, J. Mol. Biol.
Biochemical J., including some 50 patents and two books: “The
Engines of Hippocrates. From the Dawn of Medicine to Medical
and Pharmaceutical Informatics” Robson and Baek, 2009,
Wiley, 600 pages)” and “Introduction to Proteins and Protein
Engineering” (B. Robson and J. Garnier, 1984, 1988, Elsevier,
700 pages). He has contributed to several reports to govern­
ments (EU, US, Denmark) including Panels of the National
Innovation Initiative for “Innovate America” published by The
Council on Competitiveness, Washington D.C. (2004) as a
whitepaper to the President of the United States. He was also an
advisor in relation to a major scientific computer-aided drug
design collaboration and network for Peter Feinstein Consul­
tants between work between US scientists and the Russian
Science City Arzamas. He has a Harvard-Macy certificate in the
business of medical education. For some five years, Barry was a
Nature “News and Views” Correspondent on biomolecules. He
was Visiting Scholar Stanford University School of Medicine
1997–1998, Professorial Lecturer Mount Sinai NYC during part
of his period at IBM Corporation, and held visiting positions and
professorships in INRA and U. Paris-Sud France, and a Tech­
nical University of Copenhagen under Sir Rodney Cotterill, as
well a postdoctoral position at Oxford (Wolfson College) under
Sir David Phillips while Lecturer and Reader in Biochemistry at
the University of Manchester.