CORRESPONDENCE

political choices and divert attention and
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
20. Hansson, A., Brodersen, J., Reventlow, S. & personalized interventions that can opti-
resources from strategies that may be more
effective. Researchers who develop technolo-
gies for preventive medicine should take its
profound challenges seriously—especially
overdiagnosis. To make informed choices
about the future of healthcare, we need stud-
ies that substantiate what we may call action-
able evidence; that is, studies showing changes
in hard endpoints that take seriously the risk
of unintentional harm. In the context of P4
medicine or precision medicine, the balance
between promises and evidence should be
better calibrated.
Editor’s note: This article has been peer-reviewed.
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Project (P100)1 was the first example of gen-
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across a population, following in the foot-
steps of several other groundbreaking efforts
on single individuals2–4. We developed the
logistical and technological framework to
mize wellness and minimize disease risk.
When medical interventions are necessary,
such data (perhaps in the future collected
on a real-time basis using smart technol-
ogy) could identify the optimal timing and
dosage of medication, replacing the current
trial-and-error cycle of dosage versus clini-
cal efficacy. We certainly agree that over-
diagnosis and overtreatment are important
issues when providing medical care. Indeed,
a major goal of personalized medicine is to
reduce unnecessary treatment, which is an
enormous current problem. Of the top ten
most commonly prescribed drugs in the
United States, the most effective benefits only
1 in 4 patients, and the least effective benefits

ACKNOWLEDGMENTS
H.V. wishes to thank L. Getz and I. Hetlevik at
the General Practice Research Unit, Norwegian
University of Science and Technology; this article
builds on his PhD project, which they supervised.
COMPETING INTERESTS
The authors declare no competing interests.
Henrik Vogt1, Sara Green2 & John Broderson3
1Norwegian University of Science and Technology,
Department of Public Health and Nursing,
General Practice Research Unit, Trondheim,
Norway. 2Section for History and Philosophy
of Science, Department of Science Education
& Centre for Medical Science and Technology
Studies, Department of Public Health, University
of Denmark, Copenhagen, Denmark. 3Section
of General Practice & Research Unit for General
Practice, Department of Public Health, University
of Copenhagen, Copenhagen, Denmark.
e-mail: vogt.henrik@gmail.com
1. Green, S. & Vogt, H. Humanamente 30, 105–145
(2016).
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(2017).
4. Butte, A.J. Nat. Biotechnol. 35, 720–721 (2017).
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collect and analyze longitudinal health data
combined with genetic data. We analyzed the
data clouds to generate an initial multi-omic
correlation network across all these domains
(genome, proteome, metabolome, microbi-
ome, clinical laboratory and lifestyle data),
extract communities of related analytes asso-
ciated with physiology and disease, and iden-
tify molecular correlates of polygenic risk.
We also curated actionable information from
these data sets and developed coaching strat-
egies to communicate personalized infor-
mation to individuals, helping to improve
clinical blood biomarkers in our cohort and
observe disease-to-wellness transitions as the
quality of individuals’ health improved.
Vogt et al.5 make several arguments about
the promise and challenges of precision or
P4 (predictive, preventive, personalized
and participatory) medicine, using our
study as a window through which to judge
future applications to clinical medicine.
They acknowledge the P100 as a landmark
study that sets the stage for the US National
Institutes of Health (NIH) All of Us pro-
gram6, but then go on to extrapolate from
our study a future in which evidence-based
medicine is discarded in favor of unproven
claims and unnecessary interventions.
In truth, we have barely begun to densely
phenotype the human body over time and
systematically. It is important to emphasize
that the goals for the P100 study were focused
on discovery rather than clinical practice7.
There is still much to learn about human
biology, including how the combination of
genetics, the microbiome, environment and
lifestyle synergistically influences health
and disease through dynamic changes in
the body, as well as the optimal strategies
for communicating this information to indi-
viduals in a manner that leads to behavior
change. Learning better how to translate
data to actionable possibilities will enhance
only 1 in 25, which has been referred to as
our current state of ‘imprecision medicine’8.
Furthermore, we concur that personalized
approaches for disease prevention must be
guided by good evidence. ‘Scientific wellness’,
a quantitative or data-informed approach
to improving health and avoiding disease,
should be embraced by the medical research
community, with funding allocated to study
it more rigorously.
Vogt et al. state that, in a true ‘n-of-1’ trial,
changes in clinical biomarkers are biased if the
individual knows they are taking an experi-
mental therapy (i.e., the Hawthorne effect).
In the case of a true experimental therapy (for
example, an experimental drug intervention)
this is undoubtedly true. However, as Vogt et al.
remind us, the P100 study focused on action-
able recommendations involving diet, exercise,
stress management, dietary supplements and
physician referral—not experimental therapy.
In fact, personal data collected throughout the
P100 study were explicitly used to motivate
behavior change in each individual. In this
scenario, the Hawthorne effect is a feature, not
a bug. That being said, we do not categorize
the P100 as an ‘n-of-1’ trial, as Vogt et al. sug-
gest. Most of the assays collected throughout
the P100 were not used for coaching or inter-
ventions of any kind. Actionable recommen-
dations were enabled from personal data but
were ultimately derived from evidence-based
guidelines, meta-analyses or clinical trials, and
coaches were licensed allied health profession-
als (registered dietitian nutritionists with expe-
rience in promoting behavior change) working
under the supervision of a physician.
Vogt et al. raise concerns about relying on
surrogate endpoints, rather than morbidity
and mortality endpoints, and mention that
the Inter99 study found no evidence that
lifestyle interventions had an impact on
ischemic heart disease, stroke or mortal-
ity over a 10-year period9. We acknowledge

680 VOLUME 36 NUMBER 8 AUGUST 2018 NATURE BIOTECHNOLOGY


that the P100 study—a pilot study of only
9 months—was too short to observe changes
in hard endpoints, and we are pursuing
much longer follow-up through the Arivale
(Seattle, WA) program on scientific well-
ness, as well as an already-underway 3-year
study for 1000 individuals in the Providence
St. Joseph Health system.
However, the Inter99 study differs from
our long-term approach in several important
features, particularly the rate of follow-up
and intervention, which was heavily weighted
toward the first year in Inter99. After inter-
vention, there were only 3- and 5-year
follow-ups, and mostly for those individu-
als predefined as ‘high risk’. Furthermore,
Inter99 used group-based rather than per-
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
sonalized interventions. Nevertheless, after
the first 5 years the Inter99 authors reported
a significant reduction in smoking preva-
lence, improved dietary habits, sustained
physical activity (among men), decreased
binge drinking and improved self-reported
mental and physical health.
The authors of the Inter99 study partially
attribute the failure to alter morbidity and
mortality endpoints (after 5 additional years
of no contact with participants) to the need
for regular, personalized interventions,
which they described as unfeasible. Thus,
the Inter99 study is not evidence that per-
sonalized lifestyle intervention will never
work, but rather that this particular one-
size-fits-all lifestyle intervention was not
effective at modifying the tested endpoints.
Positive responses to standardized lifestyle
intervention programs have a significant
heritable component10, and some individu-
als may experience adverse responses11.
Nevertheless, standardized lifestyle interven-
tion trials have successfully shown long-term
effects (>10 years) on hard endpoints such as
type 2 diabetes12,13.
We argue that success depends on regular,
personalized follow-up, which is both pos-
sible and scalable today. In the 20 years since
Inter99 began, technological developments
have led to the proliferation of powerful
mobile devices; miniaturization of biomet-
ric measurement technology; powerful new
assays for clinical laboratory tests, proteins
and metabolites; and the rise of social media
as a powerful force in guiding behavior and
behavior change in the 21st century.
The authors’ dismissal of the label pre­
diabetes as one of the “controversies” in pre-
ventive medicine is surprising. The reference
range we used (HbA1c ≥ 5.7%) is defined by
the American Diabetes Association (ADA;
New York) as the cutoff for ‘prediabetes’; the
ADA clearly states individuals in this range
NATURE BIOTECHNOLOGY VOLUME 36 NUMBER 8 AUGUST 2018 681
should be informed of increased risk for
developing diabetes14. We identified 48% of
individuals out-of-range for HbA1c at base-
line, which is consistent with US population
estimates. A recent Journal of the American
Medical Association study estimates that
12–14% of the US adult population have dia-
betes and 37–38% have prediabetes15.
We observed on average a 0.085%
improvement of HbA1c between consecu-
tive blood draws. Taken over three blood
draws, this represents an absolute improve-
ment of 0.17% of HbA1c over half a year for
individuals who began above the predia-
betic cutoff. A recent meta-analysis found
that an 0.16% improvement in HbA1c for
those with prediabetes was associated with
a 1% or more reduction in the annualized
incidence of diabetes16. If this improve-
ment in HbA1c were realized in the current
US adult population with prediabetes17, it
would result in an estimated 880,000 fewer
cases of diabetes per year.
The implication of “overmedicalization”
(for example, in the case of mercury levels)
might be valid had we advised individuals
to undergo a medical intervention, such as
chelation therapy. We adhered to clinical
reference ranges specified by the testing lab-
oratories, and our recommendations were
fairly benign: that individuals with higher
levels of mercury either reduce consump-
tion of mercury-containing fish such as tuna
(a well-known source of organic mercury in
the diet) or, in a few cases, review with their
dentist whether old mercury-containing
amalgam fillings could be replaced with
modern composite resins. We subsequently
observed significant decreases in mercury
levels, which were most pronounced in a
handful of individuals with the most ele-
vated levels. This is not overmedicalization,
nor is the recommendation of a vitamin D
supplement for those with low serum values.
The Endocrine Society (Washington, DC)
estimates 36% of the US population is vita-
min D deficient (<20 ng/mL), with a larger
percentage being vitamin D insufficient
(<30  ng/mL)17. Most of the P100 partici-
pants lived in the US Pacific Northwest, an
area celebrated for its fish consumption and
certainly not celebrated for its sun exposure,
so it is reasonable to assume a higher than
average out-of-range percentage for mer-
cury and vitamin D.
Moreover, we strongly disagree with the
commenters’ characterization that all of the
108 participants were “labeled as in need of
medical attention.” Finding actionable pos-
sibilities to reduce risk factors or improve
nutrition does not imply an individual
CORRESPONDENCE
needs medical attention. Indeed, a major
goal of scientific wellness is to improve each
individual’s health and thus make medical
interventions less necessary. Although we
did make referrals into the medical system
for the unusual example of hemochromato-
sis, our goal is to intervene before such refer-
rals are necessary. It is disconcerting to see
Vogt et al. criticize the P100 for “pathologiza-
tion” of individuals with simple data-driven
lifestyle recommendations while preventable
diseases largely driven by lifestyle choices
are the leading causes of death in the United
States18. Individuals are not consumed with
anxiety upon receiving personal data about
themselves, even concerning serious disease
risk factors19. Many of the P100 participants
said the study had the opposite effect on
them. What the authors decry as pathologi-
zation we see as an important complement to
a medical system largely focused on disease
and treatment rather than prevention20.
Vogt et al. raise an important point on
the issue of compliance and the difficulty
of behavior change. The P100 study and the
Arivale program emphasize relationship-
based coaching assisted by technology and
motivated by data as critical to effective and
persistent behavior change. The example of
low Fitbit compliance in the P100 cohort
illustrates that health monitoring needs
to be adapted to the individual. Not every-
one wants to wear a Fitbit device; many of
the P100 participants already wore other
devices and preferred not to change, and in
2014 there was no simple way to collect data
from different devices through a single inter-
face. Also, cyclists and swimmers complained
that their activity was not measured by the
then-current Fitbit, which only measured
steps. Sleep tracking was a manual process
easily neglected at bedtime. These limitations
are rapidly improving: modern wrist-worn
quantified-self devices now measure activity
as a function of heart rate, sleep tracking is
automated, and technologies such as Apple’s
healthKit and the HumanAPI (https://www.
humanapi.co/) enable integration of multiple
quantified-self devices into a single user-
friendly interface. Moreover, 100% compli-
ance is not required for discovery. Despite
compliance limitations, we recently related
sleep variability (as measured by wrist-worn
Fitbit devices) to body mass index and other
clinical factors for individuals enrolled in the
Arivale program21. We also note that nearly
three-quarters of participants complied with
actionable lifestyle recommendations from
the coach and showed clinical improvements
consistent with sustained lifestyle change.
Simply providing data—whether through
 CORRESPONDENCE
self-tracking devices or genomic reports22—
does not generally motivate people to make
lifestyle change. Health coaching and educa-
tion, however, does drive behavior change,
and coupling coaching with data relevant to
an individual’s health objectives can drive
greater engagement and stronger clinical
outcomes.
Finally, the author(s) described our study
as “a reductionist method defined less by true
integration than by the collection and corre-
lation of diverse, but mostly molecular, data.”
How will “true integration” occur if it does
not begin with gathering and correlating data
from many individuals?
We argue that creating personal, dense,
dynamic data clouds is a cornerstone to
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
enable the preventive medicine of the future.
‘Scientific wellness’ makes data actionable
for individuals and motivates greater partic-
ipation, which in turn enables more discov-
ery. A focus on scientific wellness will also
enable the identification of the earliest tran-
sitions to disease. To help drive this process
forward, we have made the data from the
P100 available to the entire scientific com-
munity via dbGap (phs001363.v1.p1). In the
meantime, we are analyzing data for a much
deeper analysis of the clinical outcomes of
the scientific wellness approach through
the Arivale program, including the impact
of personalized genetic risk profiles and
mobile app-based measures of compliance.
In partnership with the Providence
St. Joseph Healthcare system, in 2017 we
launched an institutional review board
(IRB)-approved clinical trial with the goal
of examining the impact of the scientific
wellness approach on improving individ-
ual health, as well as reducing health care
costs for 1,000 individuals over 3 years. We
have also recently launched another IRB-
approved clinical trial to leverage personal,
dense, dynamic data clouds to determine
how health coaching affects the cognitive
function of older individuals experiencing
cognitive decline, as well as explore transi-
tions in cognitive function over time. The
results from these and other studies23 that
have a more clinical focus than the P100 will
begin to generate the “actionable evidence”
that we are motivated to generate and that
Vogt et al. request.
Editor’s note: This article has been peer-reviewed.
COMPETING INTERESTS
L.H. and N.D.P. are cofounders of Arivale and hold
stock in the company. N.D.P. is on the Arivale Board
of Directors; L.H. is chair and G.S.O. a member of
Arivale’s Scientific Advisory Board. A.T.M. and J.C.L.
are employees of Arivale and have stock options in the
company, as do J.C.E., G.G. and G.S.O.
682 VOLUME 36 NUMBER 8 AUGUST 2018 NATURE BIOTECHNOLOGY
Andrew T Magis1, John C Earls2,
Gustavo Glusman2, Gilbert S Omenn3,
Jennifer C Lovejoy1,2, Nathan D Price1,2
& Leroy Hood1,2,4
1Arivale, Seattle, Washington, USA. 2Institute
for Systems Biology, Seattle, Washington, USA.
3Department of Computational Medicine
and Bioinformatics, University of Michigan,
Ann Arbor, Michigan, USA. 4Providence
St. Joseph Health, Seattle, Washington, USA.
Correspondence should be addressed to N.D.P.
(nathan.price@systemsbiology.org) or L.H.
(lhood@systemsbiology.org).
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6. Collins, F.S. & Varmus, H. N. Engl. J. Med. 372, 793–
795 (2015).
Challenges in modeling the human
gut microbiome
To the Editor: A paper by Magnúsdóttir et al.1
in a previous issue describes the generation of
genome-scale metabolic models (GEMs) for
773  members of the human gut microbiota,
referred to as AGORA. It represents a valuable
contribution to quantitative analyses of how
the many different species of gut microbiota
interact and influence host metabolism. At the
same time, a detailed analysis of the models
described in this work raises several questions.
Evidence is growing that differences in gut
microbiota may have an impact on human
health, including cardiovascular disease2
and type  2 diabetes3–5, but so far no stud-
ies have demonstrated causal relationships.
Mathematical modeling of the gut microbiota
makes it possible to evaluate different hypoth-
eses and thereby gain mechanistic insight into
how the gut microbiota composition affects
host metabolism. GEM analysis is particularly
well suited to this purpose as it is possible to
reconstruct the metabolic networks of gut
symbionts on the basis of genomic informa-
tion and then use constraint-based model-
ing, often referred to as flux balance analysis
(FBA), for simulation of their metabolic func-
tions6. This modeling concept has been vali-
dated for its ability to correctly simulate the
metabolism of colonized bacteria in germ-free
mice7 and its ability to predict how the levels
of key metabolites in fecal water or plasma
are influenced by gut microbiota composi-
tion8. Furthermore, using this concept, com-
putational tools and frameworks have been
7. Hood, L., Lovejoy, J.C. & Price, N.D. BMC Med. 13, 4
(2015).
8. Schork, N.J. Nature 520, 609–611 (2015).
9. Jørgensen, T. et al. Br. Med. J. 348, g3617 (2014).
10. Rice, T. et al. Circulation 105, 1904–1908 (2002).
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developed to allocate metabolic resources to
individual microbes and infer the ecological
interaction, spatial dynamics and community-
level assembly processes9,10.
The paper by Magnúsdóttir et al.1 describes
AGORA, a resource of GEMs for >700  gut
microbes that account for most of the domi-
nant species in the human gut microbiota. Here
we point out several drawbacks associated with
these GEMs as functional models for simulat-
ing metabolic interactions between either gut
symbionts or the gut microbiota and their host.
A quality check of the 773  GEMs in
AGORA suggests that most of the models are
incapable of quantitative predictions with-
out further manual curation and support
from experimental data. We illustrate this by
benchmarking all 773 AGORA GEMs against
70 metabolic models from BiGG11, another
GEM repository.
First, we evaluated the ability of the AGORA
models to predict growth. The COBRA toolbox
was used to calculate the specific growth rate
of the AGORA GEMs using the glpk solver.
Growth in aerobic, microaerobic and anaerobic
conditions was simulated by setting the lower
bound of oxygen exchange reaction to –1,000,
–1 and 0 mmol gDW–1 h–1, respectively (in all
cases, the upper bound for the oxygen exchange
reaction was 0; other exchange bounds were
not altered and were taken from AGORA).
We found that the specific growth rate under
anaerobic conditions varied between 0.004 h–1
and 255 h–1 (Fig. 1a).