Module 011 – Emerging Technology in Medicine

This module contains the following topics:

1. Genomic Sequencing and the Emerging Medical Practice
2. The Digitization of Health Records

Genomic sequencing
The development of massively parallel sequencing (or next-generation sequencing) has
facilitated a rapid implementation of genomic sequencing in clinical medicine. Genomic
sequencing (GS) is now an essential tool for evaluating rare disorders, identifying
therapeutic targets in neoplasms, and screening for prenatal aneuploidy. Emerging
applications, such as GS for preconception carrier screening and predisposition screening
in healthy individuals, are being explored in research settings and utilized by members of
the public eager to incorporate genomic information into their health management. The
rapid pace of adoption has created challenges for all stakeholders in clinical GS, from
standardizing variant interpretation approaches in clinical molecular laboratories to
ensuring that nongeneticist clinicians are prepared for new types of clinical information.
Clinical GS faces a pivotal moment, as the vast potential of new quantities and types of data
enable further clinical innovation and complicated implementation questions continue to
be resolved.

Current and emerging clinical applications of GS

Diagnostic sequencing
To date, the diagnosis of rare Mendelian disease has been the primary clinical
application of sequencing the genomes of individual patients. Thousands of
pathogenic mutations identified through GS have been reported in recent years, and
novel gene-disease associations are proliferating. Early reports on clinical GS
demonstrated that identification of a causative mutation through GS can help to
formulate a treatment plan and in other cases offer new opportunities for
reproductive planning, as in the first publication reporting a successful diagnosis via
GS, which resulted in effective management for a severe autoimmune illness in a
young boy. Diagnostic GS is indicated for the detection of diagnostic genetic variants
in patients with suspected monogenic disorders after known single -gene candidates
have been eliminated from consideration or when a multigene testing panel has not
yielded a diagnosis. The vast majority of diagnostic GS to date has been performed in
children. However, patients can be of any age and presentations of Mendelian
disorders in adulthood are probably underrecognized.
The breadth of possible results from GS requires that thorough counseling and
evaluation be performed before ordering GS to ensure proper interpretation of
genomic variants, as well as careful clinical contextualization of the results. This
process should include gathering detailed family history information, systematically
evaluating the patient's and/or family's phenotype, reviewing medical literature and
databases for possible overlap with known syndromes or implicated biochemical
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pathways, and obtaining informed consent. Individuals who consent to clinical GS
should be aware that they may learn about disease risks that may also affect their
relatives.
Whereas many clinical molecular laboratories in academic medical centers and
commercial laboratories now offer exome sequencing, Baylor College of Medicine
and the University of California Los Angeles (UCLA) in the United States have
reported on the largest number of clinical sequencing cases and have estimated that
they find a causative mutation in 25% to 26% of cases overall, with lower diagnostic
rates for adults than for children. Of solved cases, a surprising percentage (4.6%)
appear to result from blended phenotypes of two separate Mendelian disorders, each
associated with distinct pathogenic variants. The combined impact of two distinct
Mendelian disease variants often leads to a hybrid phenotype that appears unique
and challenging to diagnose.
The application of GS to rare disease has understandably been of intense research
interest. In the United States, several National Institutes of Health (NIH) gra nt
programs, including the Clinical Sequencing Exploratory Research (CSER)
Consortium, the Centers for Mendelian Genomics, and the Undiagnosed Diseases
Program and Network, have been funded to investigate the application of GS to the
diagnosis of rare diseases. The scope of these efforts is broad and includes
establishing technical standards for GS and interpretative pipelines (i.e., variant
filtration algorithms and interpretation protocols), developing and implementing
reporting mechanisms, and evaluating the clinical, behavioral, legal, and ethical
impacts of GS on clinical practice.
Emerging application: preconception carrier screening
Although targeted carrier screening is well established (e.g., focused carrier
screening for conditions such as Gaucher, Tay-Sachs, and Canavan disease in
individuals of Ashkenazi Jewish descent), genomic technologies offer the opportunity
for broader, more comprehensive screening. Preconception screening for carrier
variants associated with rare, recessive disorders has been increasingly available in
recent years via targeted multiplex genotyping that screens for known mutations in
dozens of genes. These tests do not necessarily detect extremely rare or novel
genetic variants that an unaffected individual may carry, and therefore a “residual
risk” of being a carrier remains after negative testing.
Several companies now offer GS for preconception screening. GS affords the
opportunity to go beyond a selected subset of recessive disorders to evaluate and
report on genes associated with extremely rare recessive conditions. Preliminary
data from the MedSeq Project, which reports results on carrier variants in any gene
associated with known autosomal recessive disorders, suggest that approximately
90% of individuals in the general population are carriers for at least one recessive
disorder and that most carry two to four carrier variants. Due to imperfect coverage
of some genes and the low sensitivity of GS for certain types of genetic variation
(reviewed below), a negative result on GS does not eliminate the post-test
probability of being a carrier, though it generally improves upon the existing residual
risk of mutation panel-based approaches.
 Discovering that reproductive partners are each carrier for a severe recessive
condition enables preimplantation genetic diagnosis (PGD). PGD allows for testing of
embryos for a specific genetic variant (or variants, in the case of recessive diseases).
Embryos lacking the targeted genetic variants are then implanted, preventing
transmission of the genetic disease to offspring. PGD is a complicated and
controversial topic both technically and ethically, and has been reviewed thoroughly
elsewhere.
Emerging application: genetic predisposition screening
Several research studies and personal genomics companies have begun to report a
broad range of predispositional Mendelian variants to individuals. The general goal
of these initiatives is to provide genetically informed predictions of disease risk and
medication safety and efficacy, thereby enabling participants to make personalized
decisions for disease prevention. Although preliminary data has not demonstrated
significant risk of harm, benefits have not been systematically evaluated, and many
experts and professional organizations call for caution before adopting GS for
generally healthy individuals. To this end, the PeopleSeq (Personal Genome
Sequencing Outcomes) Consortium has been formed as the first systematic large -
scale longitudinal study of outcomes of predisposition sequencing and will seek to
collect short- and long-term data on participants in GS projects.
Monogenic variants for Mendelian syndromes that confer a significant risk for a
condition, such as the breast cancer susceptibility gene 1 and 2 (BRCA1/2) variants
associated with breast and ovarian cancer, may be revealed in GS of persons without
a personal or family history. In current clinical practice, these findings are discovered
secondary to diagnostic sequencing and are routinely reported for selected genes
believed to be clinically actionable. However, in predisposition screening, these
variants are a primary finding. Using strict variant-filtering criteria and all genes
associated with human disease, the MedSeq Project identified a monogenic variant in
21 out of 100 participants. Identification of these variants has enabled MedSeq
physicians to perform deep phenotyping (targeted medical examination and
assessment for manifestations of the associated conditions) of asymptomatic
individuals with monogenic variants.
GS can identify common genetic variants that have been associated with risk for
complex phenotypes, such as coronary artery disease and type 2 diabetes, in
genome-wide association studies (GWAS). Millions of individuals have undergone
genotyping for such variants via direct-to-consumer services such as 23andMe,
which have utilized chip arrays that identify genotypes at specific single-nucleotide
polymorphisms (SNPs). Because many variants identified in GWAS reside outside of
exons (protein-coding regions of the genome), such SNPs would not be detectable by
exome sequencing. Therefore, with regard to utilizing GS to identify these variants,
wholegenome sequencing, instead of exome sequencing, is required. Despite the
availability of relevant data from GS and the broad reporting of common disease
risks by personal genomic testing companies, there is limited evidence for the clinical
validity or utility of risk assessments from common genetic variation. GWAS variants
account for a small proportion of variability in the risk of multifactorial phenotypes,
known as the “missing heritability” problem (ie, other as yet unidentified genetic
factors or interactions between genetic variants must contribute to the heritability of
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 diseases). Additionally, risk-assessment methodologies to combine multiple variants
remain in flux, and reclassification of individuals from higher risk to average or lower
risk is expected to occur in most phenotypes as additional data accrue . Nevertheless,
some studies have shown that individuals make positive lifestyle changes and
become more engaged in their care after receiving such risk predictions .
Utilizing known associations between genetic variants and blood group and antigen
subtypes, GS can be used to predict clinically relevant hematological data, such as
blood group and platelet antigen types. Antigen subgroup status has potential
relevance for individuals who require multiple transfusions secondary to a chronic
medical condition, as well as for identifying potential donors who have rare blood
group antigens. The analytical algorithms have been developed and validated as part
of the MedSeq Project.
Finally, GS is a powerful tool to screen for multiple pharmacogenomic variants
simultaneously, creating the opportunity for personalized medication selectio n and
dosing regimens based on an individual's genotype or haplotype (group of genes
inherited together). Pharmacogenomic data offer the opportunity for querying
genomic data at the point of care as patients are prescribed medications for the first
time and new associations among drugs, genetic variants, and dosing requirements
or side effect risks are discovered and validated. The topic of pharmacogenomics will
be explored more comprehensively in two companion articles in this special issue.

The Digitization of Health Records

In medicine, the first information technology wave to hit the art and science of
healing was the digitization of medical files, now known as electronic health records
(EHRs). The data contained in EHRs in combination with other sources have the
potential to transform medical practice by leveraging data, technologies, and
healthcare delivery to improve the overall efficiency and quality of care at a
reasonable cost.
The widespread adoption of EHRs has generated large sets of data. The cr eative
merging of datasets collected from patients and physicians could be a viable avenue
to strengthen healthcare delivery. These massive datasets are currently understood
as a byproduct of medical practice instead of utilizable assets that could play pivotal
roles in patient care. Currently, for instance, most EHRs collect quantitative,
qualitative, and transactional data, all of which could be collated, analyzed, and
presented using sophisticated procedures and techniques that are now available to
make use of text-based documents containing disparate and unstructured data.
The purposeful use of data is not a mystery to medical practice. Since their humble
beginnings, evidence-based undertakings have been grounded in the principle that
questions answered through the scientific method were superior to anecdotes,
expert opinion, panels, and testimonials. In terms of acknowledging the value of data
and information in guiding a rational and logical decision-making process, medicine
has been at the forefront of adapting to modernity. However, physicians, nurses, and
healthcare facilities have been slow to embrace the newest methods to fully use the
data contained in EHRs. Let us examine four hidden benefits of EHRs.
 EHRs may augment the attainment of new knowledge through the automated and
systematic analysis of unstructured data by applying advanced computational
techniques that enable comprehensive data collection. The acquisition of structured
data to answer emerging clinical questions is onerous. Narrow and a utomatic
searches within EHRs using natural language processing (NLP) may be a less
expensive alternative. In fact, a 2011 study suggests that the automated identification
of postoperative complications within electronic medical records using NLP is far
superior to patient safety indicators linked to discharge coding. EHRs may assist in
the dissemination of new knowledge. As clinical practice evolves to incorporate the
latest evidence and facts guiding medical care, physicians encounter the daunting
task of sorting through large volumes of information to craft adequate and safe
treatment options for patients with diverse chronic illnesses. Tinkering with EHRs
can generate on-screen dashboards that can guide medical care decisions. Physicians
could receive pop-up messages informing them about clinical presentation,
diagnostic work, and therapeutic choices made by clinicians facing similar case
profiles. It appears that data-driven healthcare decision-support tools aid the
standardization of care and result in cost savings.
EHRs may help to blend medical practice with personalized clinical initiatives by
facilitating opportunities to utilize analytical methods and techniques that can
holistically integrate biology-based interdisciplinary fields of study (e.g.,
metabolomics, phenomics) with EHR datasets to streamline genomics research and
create a rich culture of cooperation.
EHRs may empower patients to play more active roles in caring for their health by
directly delivering information to these individuals. Patients not only can know
specific details about their health parameters and illnesses but also can present
medical records to other healthcare professionals when needed. The benefits of this
approach are twofold: information can be readily accessed without filling out forms
or having to interview patients with long questionnaires, and traditional health -
related data can be linked to other details associated with personal data, such as diet,
education, exercise, habits, hobbies, income, and military service.
There will surely be problems along the way. Current EHR systems and health
information exchange platforms are diverse and fragmented and have limited
interoperability. Privacy issues will very likely emerge as a concern, especially for the
protection of confidential information. Ultimately, interconnections between
technology and medicine are inevitable, which explains why medical informatics
plays a central role in healthcare.
An article by Palgon added the benefits of electronic health records:
In the early 1960s, when most hospitals and health systems were steeped in paper, a
handful of highly progressive healthcare providers embarked on a journey to
implement a computer-based patient record. Envisioning the benefits of electronic
health records to reduce, or even eliminate, paper in medical record keeping for
healthcare providers of all sizes and specialties, their bold steps forever changed the
way clinicians gather, document and review patient information.

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In 1972, the first electronic medical record system emerged, only to be shunned by
physicians due to its high cost. It was mainly used by government hospitals and few
forward thinking institutions.
Fast forward to 2017, and the benefits of electronic health records (EHR) are widely
recognized among healthcare providers. In fact, 98 percent of all hospitals now
demonstrate meaningful use and have adopted an EHR. On the ambulatory side,
the global EHR market expects 5.8% growth by 2021, growth that is fueled by
government mandates, the need to reduce costs and growing consumer demands to
enhance healthcare quality and delivery.
Growing Value for Providers, Patients
Despite growing use of electronic health records, the healthcare industry is nowhere
close to realizing the full benefits of the digitized record. While most providers
acknowledge the benefits and vision for the future, the growing pains created by
varying standards and the challenges of data exchange due to different electronic
formats remain a hurdle.
EHRs deliver advantages to healthcare providers and patients by enabling better
collection, storage and sharing of health information for the purpose of coordinated
care delivery. Electronic data storage and retrieval reduces the risk of lost patient
records and test results and offers more secure access over their paper predecessors,
which easily could be left on a desk and viewed by anyone walking by. This can be a
very important advantage and in better alignment with HIPAA compliance
requirements.
Another benefit of EHR technology is that it supports greater accuracy in records, as
healthcare providers are prompted to complete required data fields, use standard
terminology and check predefined boxes, not to mention the fact that the EHR has
purged the patient record of illegible physician notes. One specific benefit of
electronic health record technology is the speed in which clinicians can gain access to
critical test results and progress notes, eliminating delays in treatment caused by
missing data. Finally, electronic health records support enhanced patient safety by
collecting more complete data and providing secure access throughout the care
continuum.
On the other hand, electronic health records are not without their own challenges.
One of the biggest and perhaps most visible risks of electronic health records is data
security, as brought to light by the recent WannaCry ransomware cyber attack which
affected16 National Health Service hospitals in the UK. This massive hack effectively
took the hospitals offline, forcing suspension of services. In this attack, as in previous
ones, cyber criminals disrupted care and business operations by making personal
and clinical data contained in the electronic health records unavailable at the point of
care.
The negative impacts of cyber attacks are two-fold: risk to patient care and safety
and risk to patients’ financial health as other personal information is exposed to
unauthorized individuals with malicious intent. While data is potentially more secure
inside the four walls of the health system, the ability to share data to those who need
it to deliver care beyond those walls also offers the risk of unintended information
 exchange on a mass scale. Therefore, health systems need a comprehensive approach
to data security that includes all aspects of their operations, including the EHR.
Efficiency Supports Better Care
The benefits of electronic medical records are spread between healthcare providers
and patients and support the ultimate goal of effective exchange of data
(information) between providers caring for the same patient. In addition, electronic
health records can help physicians practice more efficiently by saving time with
electronic prescription, lab and imaging ordering and faster test result transactions.
The end goal is improved patient care and outcomes through better health and
disease management.
Enabling data integration into a single electronic medical record or single view, EHRs
make data accessible for the right person at the right time in the care delivery
process. But on a broader scale, health systems, like Accountable Care Organizations
(ACO) and highly integrated delivery systems that embrace EHR technology, are able
to integrate, aggregate and harmonize data across specialties, multiple EHRs in acute
and ambulatory settings, and financial, operational and claims data sources. This
allows providers to effectively collaborate and establish appropriate metrics to
support the overarching goal of coordinated, high quality care.
Hidden Data Provides Insight
While the benefits of electronic health records to store, manage and exchange patient
information are enormous, the advantages of using the EHR as a data source to
provide insight beyond individual patient care are immeasurable. However, a recent
survey showed that we still have ways to go. The survey noted that only 31 percent
of healthcare providers use their EHR analytics capabilities while another third
utilized a combination of the EHR capabilities and an outside vendor to analyze data.
Demonstrating the underutilization of this important aspect of the EHR, 11 percent
of respondents said they didn’t analyze EHR data at all.
For the greater patient (or population) good, health systems more than ever need to
understand and utilize the comprehensive set of data that the EHR can provide,
especially in combination with other EHRs and other data sources. ACOs know that
this integrated approach to data management and exchange can improve care. They
understand the benefits of using the collective data in electronic health records to
analyze specific patient populations, distinguish risk factors, identify trends in
disease treatment and predict future outcomes, all of which improve patient care,
outcomes and the cost of care.
To unlock this hidden benefit of the EHR, healthcare organizations need a flexible
and scalable platform that allows management and integration of complex data
across and, in some cases, beyond the enterprise. In many organizations, internal IT
resources do not have the time or ability to manage the increasing volume and
integration complexities of new and expanding sources of data. Choo sing cloud-
based technologies and a trusted partner to supplement internal IT resources helps
create a comprehensive data set in a secure and compliant manner.
The success of data management can be measured by the quality of the business
decisions and outcomes that are derived from the data. This requires moving beyond

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 simple data collection to a strategy and tools that are designed to improve data
integration, data exchange, and overall data management along with care and
business outcomes. A good place to start is analyzing the data that exists in the EHR
and leveraging that data for continual improvement.

References and Supplementary Materials

Online Supplementary Reading Materials
1. Genomic sequencing in clinical practice: applications, challenges, and o pportunities;
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5067147/; November 9, 2017
2. Future Opportunities for Genome Sequencing and Beyond: A Planning Worksho[ for
the National Genome Research Institute;
https://www.genome.gov/27559219/future-opportunities-for-genome-sequencing-
and-beyond/; November 9, 2017
3. Deploying whole genome sequencing in clinical practice and public health: Meeting
the challenge one bin at a time;
https://www.nature.com/gim/journal/v13/n6/full/gim9201182a.html; November 9,
2017
4. Electronic health records: beyond the digitization of medical files;
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752637/; November 9, 2017
5. Digitizing Delivers: The Benefits of Electronic Health Records;
https://www.liaison.com/blog/2017/05/19/digitizing-delivers-benefits-electronic-
health-records-ehr/; November 9, 2017
6. The Digitization of Medical Records; https://rctom.hbs.org/submission/the-
digitization-of-medical-records/; November 9, 2017
7. Digitizing Healthcare: Why Having an Electronic Medical Record Matter s;
http://possiblehealth.org/blog/electronic-medical-record/; November 9, 2017