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Repurposing large datasets for exposomic discovery in disease
1. Repurposing large datasets to dissect
exposomic (and genomic) contributions in
health and disease
Chirag J Patel
Joslin Diabetes Center
03/10/16
chirag@hms.harvard.edu
@chiragjp
www.chiragjpgroup.org
2. P = G + EType 2 Diabetes
Cancer
Alzheimer’s
Gene expression
Phenotype Genome
Variants
Environment
Infectious agents
Nutrients
Pollutants
Drugs
3. We are great at G investigation!
over 2400
Genome-wide Association Studies (GWAS)
https://www.ebi.ac.uk/gwas/
G
4. Nothing comparable to elucidate E influence!
E: ???
We lack high-throughput methods
and data to discover new E in P…
7. σ2
G
σ2P
H2 =
Heritability (H2) is the range of phenotypic
variability attributed to genetic variability in a
population
Indicator of the proportion of phenotypic
differences attributed to G.
8. Eye color
Hair curliness
Type-1 diabetes
Height
Schizophrenia
Epilepsy
Graves' disease
Celiac disease
Polycystic ovary syndrome
Attention deficit hyperactivity disorder
Bipolar disorder
Obesity
Alzheimer's disease
Anorexia nervosa
Psoriasis
Bone mineral density
Menarche, age at
Nicotine dependence
Sexual orientation
Alcoholism
Lupus
Rheumatoid arthritis
Crohn's disease
Migraine
Thyroid cancer
Autism
Blood pressure, diastolic
Body mass index
Depression
Coronary artery disease
Insomnia
Menopause, age at
Heart disease
Prostate cancer
QT interval
Breast cancer
Ovarian cancer
Hangover
Stroke
Asthma
Blood pressure, systolic
Hypertension
Osteoarthritis
Parkinson's disease
Longevity
Type-2 diabetes
Gallstone disease
Testicular cancer
Cervical cancer
Sciatica
Bladder cancer
Colon cancer
Lung cancer
Leukemia
Stomach cancer
0 25 50 75 100
Heritability: Var(G)/Var(Phenotype) Source: SNPedia.com
G estimates for burdensome diseases are low and variable:
massive opportunity for high-throughput E discovery
Type 2 Diabetes
Heart Disease
Autism (50%???)
9. Eye color
Hair curliness
Type-1 diabetes
Height
Schizophrenia
Epilepsy
Graves' disease
Celiac disease
Polycystic ovary syndrome
Attention deficit hyperactivity disorder
Bipolar disorder
Obesity
Alzheimer's disease
Anorexia nervosa
Psoriasis
Bone mineral density
Menarche, age at
Nicotine dependence
Sexual orientation
Alcoholism
Lupus
Rheumatoid arthritis
Crohn's disease
Migraine
Thyroid cancer
Autism
Blood pressure, diastolic
Body mass index
Depression
Coronary artery disease
Insomnia
Menopause, age at
Heart disease
Prostate cancer
QT interval
Breast cancer
Ovarian cancer
Hangover
Stroke
Asthma
Blood pressure, systolic
Hypertension
Osteoarthritis
Parkinson's disease
Longevity
Type-2 diabetes
Gallstone disease
Testicular cancer
Cervical cancer
Sciatica
Bladder cancer
Colon cancer
Lung cancer
Leukemia
Stomach cancer
0 25 50 75 100
Heritability: Var(G)/Var(Phenotype) Source: SNPedia.com
G estimates for complex traits are low and variable:
massive opportunity for high-throughput E discovery
σ2
E : Exposome!
10. It took a new paradigm of GWAS for discovery:
Human Genome Project to GWAS
Sequencing of the genome
2001
HapMap project:
http://hapmap.ncbi.nlm.nih.gov/
Characterize common variation
2001-current day
High-throughput variant
assay
< $99 for ~1M variants
Measurement tools
~2003 (ongoing)
ARTICLES
Genome-wide association study of 14,000
cases of seven common diseases and
3,000 shared controls
The Wellcome Trust Case Control Consortium*
There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the
identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip
500K Mapping Array Set) undertaken in the British population, which has examined ,2,000 individuals for each of 7 major
diseases and a shared set of ,3,000 controls. Case-control comparisons identified 24 independent association signals at
P , 5 3 1027
: 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn’s disease, 3 in rheumatoid arthritis, 7 in type 1
diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these
signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found
compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a
25 27
Vol 447|7 June 2007|doi:10.1038/nature05911
WTCCC, Nature, 2008.
Comprehensive, high-throughput analyses
GWAS
11. Explaining the other 50%:
A big data-driven paradigm for robust discovery of E in
disease via EWAS and the exposome
what to measure? how to measure?
PERSPECTIVES
Xenobiotics
Inflammation
Preexisting disease
Lipid peroxidation
Oxidative stress
Gut flora
Internal
chemical
environment
Externalenvironment
ExposomeRADIATION
DIET
POLLUTION
INFECTIONS
DRUGS
LIFE-STYLE
STRESS
Reactive electrophiles
Metals
Endocrine disrupters
Immune modulators
Receptor-binding proteins
itical entity for disease eti-
ogy (7). Recent discussion
as focused on whether and
ow to implement this vision
8). Although fully charac-
rizing human exposomes
daunting, strategies can be
eveloped for getting “snap-
hots” of critical portions of
person’s exposome during
ifferent stages of life. At
ne extreme is a “bottom-up”
rategy in which all chemi-
als in each external source
f a subject’s exposome are
easured at each time point.
lthoughthisapproachwould
ave the advantage of relat-
g important exposures to
e air, water, or diet, it would
quire enormous effort and
ould miss essential compo-
ents of the internal chemi-
al environment due to such
actors as gender, obesity,
flammation, and stress. By
ontrast, a “top-down” strat-
gy would measure all chem-
als (or products of their
ownstream processing or
ffects, so-called read-outs
r signatures) in a subject’s
ood. This would require
nly a single blood specimen
each time point and would relate directly ruptors and can be measured through serum
some (telomere) length in
peripheral blood mono-
nuclear cells responded
to chronic psychological
stress, possibly mediated
by the production of reac-
tive oxygen species (15).
Characterizing the
exposome represents a tech-
nological challenge like that of
thehumangenomeproject,which
began when DNA sequencing
was in its infancy (16). Analyti-
cal systems are needed to pro-
cess small amounts of blood from
thousands of subjects. Assays
should be multiplexed for mea-
suring many chemicals in each
class of interest. Tandem mass
spectrometry, gene and protein
chips, and microfluidic systems
offer the means to do this. Plat-
forms for high-throughput assays
shouldleadtoeconomiesofscale,
again like those experienced by
the human genome project. And
because exposome technologies
would provide feedback for thera-
peuticinterventionsandpersonal-
ized medicine, they should moti-
vate the development of commer-
cial devices for screening impor-
tant environmental exposures in
blood samples.
With successful characterization of both
Characterizing the exposome. The exposome represents
the combined exposures from all sources that reach the
internal chemical environment. Toxicologically important
classes of exposome chemicals are shown. Signatures and
biomarkers can detect these agents in blood or serum.
onOctober21,2010www.sciencemag.orgrom
“A more comprehensive view of
environmental exposure is
needed ... to discover major
causes of diseases...”
how to analyze in relation to health?
Wild, 2005
Rappaport and Smith, 2010, 2011
Buck-Louis and Sundaram 2012
Miller and Jones, 2014
Patel CJ and Ioannidis JPAI, 2014
12. Connecting E with Disease:
Missing the “System” of Exposures?
E+ E-
diseased
non-
diseased
?
Exposed to many things, but do not assess the multiplicity.
Fragmented literature of associations.
Challenge to discover E associated with disease.
14. Gold standard for breadth of human exposure information:
National Health and Nutrition Examination Survey1
since the 1960s
now biannual: 1999 onwards
10,000 participants per survey
The sample for the survey is selected to represent
the U.S. population of all ages. To produce reli-
able statistics, NHANES over-samples persons 60
and older, African Americans, and Hispanics.
Since the United States has experienced dramatic
growth in the number of older people during this
century, the aging population has major impli-
cations for health care needs, public policy, and
research priorities. NCHS is working with public
health agencies to increase the knowledge of the
health status of older Americans. NHANES has a
primary role in this endeavor.
All participants visit the physician. Dietary inter-
views and body measurements are included for
everyone. All but the very young have a blood
sample taken and will have a dental screening.
Depending upon the age of the participant, the
rest of the examination includes tests and proce-
dures to assess the various aspects of health listed
above. In general, the older the individual, the
more extensive the examination.
Survey Operations
Health interviews are conducted in respondents’
homes. Health measurements are performed in
specially-designed and equipped mobile centers,
which travel to locations throughout the country.
The study team consists of a physician, medical
and health technicians, as well as dietary and health
interviewers. Many of the study staff are
bilingual (English/Spanish).
An advanced computer system using high-
end servers, desktop PCs, and wide-area
networking collect and process all of the
NHANES data, nearly eliminating the need
for paper forms and manual coding operations.
This system allows interviewers to use note-
book computers with electronic pens. The staff
at the mobile center can automatically transmit
data into data bases through such devices as
digital scales and stadiometers. Touch-sensi-
tive computer screens let respondents enter
their own responses to certain sensitive ques-
tions in complete privacy. Survey information
is available to NCHS staff within 24 hours of
collection, which enhances the capability of
collecting quality data and increases the speed
with which results are released to the public.
In each location, local health and government
officials are notified of the upcoming survey.
Households in the study area receive a letter
from the NCHS Director to introduce the
survey. Local media may feature stories about
the survey.
NHANES is designed to facilitate and en-
courage participation. Transportation is provided
to and from the mobile center if necessary.
Participants receive compensation and a report
of medical findings is given to each participant.
All information collected in the survey is kept
strictly confidential. Privacy is protected by
public laws.
Uses of the Data
Information from NHANES is made available
through an extensive series of publications and
articles in scientific and technical journals. For
data users and researchers throughout the world,
survey data are available on the internet and on
easy-to-use CD-ROMs.
Research organizations, universities, health
care providers, and educators benefit from
survey information. Primary data users are
federal agencies that collaborated in the de-
sign and development of the survey. The
National Institutes of Health, the Food and
Drug Administration, and CDC are among the
agencies that rely upon NHANES to provide
data essential for the implementation and
evaluation of program activities. The U.S.
Department of Agriculture and NCHS coop-
erate in planning and reporting dietary and
nutrition information from the survey.
NHANES’ partnership with the U.S. Environ-
mental Protection Agency allows continued
study of the many important environmental
influences on our health.
• Physical fitness and physical functioning
• Reproductive history and sexual behavior
• Respiratory disease (asthma, chronic bron-
chitis, emphysema)
• Sexually transmitted diseases
• Vision
1 http://www.cdc.gov/nchs/nhanes.htm
>250 exposures (serum + urine)
GWAS chip
>85 quantitative clinical traits
(e.g., serum glucose, lipids, body
mass index)
Death index linkage (cause of
death)
15. Gold standard for breadth of exposure & behavior data:
National Health and Nutrition Examination Survey
Nutrients and Vitamins
vitamin D, carotenes
Infectious Agents
hepatitis, HIV, Staph. aureus
Plastics and consumables
phthalates, bisphenol A
Physical Activity
e.g., stepsPesticides and pollutants
atrazine; cadmium; hydrocarbons
Drugs
statins; aspirin
17. EWAS in HDL-C:
17 Validated Factors
FDR < 5%
carotenes
cotinine
heavy metals
organochlorine pesticides
Int J Epidem. 2012
hydrocarbons
log10(HDL-C)
adjusted for BMI, SES, ethnicity, age, age2, sex
N=1000-3000
E
Vitamins
DCBA
minerals
1-5 mg/dL
R2 ~ 15%
18. EWAS in Triglycerides and LDL-C
22 factors
organochlorine pesticides
polychlorinated biphenyls
carotenoids
vitamin E
vitamin A
8 factors
carotenoids
vitamin E
vitamin A
Int J Epidem. 2012.
1-15 mg/dL
R2 ~ 15, 2%
20. Persistent pollutants and endocrine disruptors:
How are these factors linked with these diseases?
•organochlorine pesticides
•polychlorinated biphenyls
•dibenzofurans
•dioxins
•found all over the world
•persist in food chain
Porta et al, Environ Int 2008
•heart disease,
•T2D/insulin resistance
Porta et al, Lancet, 2006
Lee et al, Diabetes Care, 2006
Lee et al, Diabetologia, 2007
Everett et al, Environ Res, 2010
Lind et al, EHP, 2011
(Korea, Japan, Europe)
Biological mechanisms remain elusive...
capacitors
adhesives
21. What E are associated with all-cause mortality and
telomere length?
22. How does it work?:
Searching for exposures and behaviors associated with all-
cause mortality.
NHANES: 1999-2004
National Death Index linked mortality
246 behaviors and exposures (serum/urine/self-report)
NHANES: 1999-2001
N=330 to 6008 (26 to 655 deaths)
~5.5 years of followup
Cox proportional hazards
baseline exposure and time to death
False discovery rate < 5%
NHANES: 2003-2004
N=177 to 3258 (20-202 deaths)
~2.8 years of followup
p < 0.05
Int J Epidem. 2013
24. Adjusted Hazard Ratio
-log10(pvalue)
0.4 0.6 0.8 1.0 1.2 1.4 1.6 2.0 2.4 2.8
02468
1
2
3
4
5
67
1 Physical Activity
2 Does anyone smoke in home?
3 Cadmium
4 Cadmium, urine
5 Past smoker
6 Current smoker
7 trans-lycopene
(11) 1
2
3 4
5 6
78
9
10 1112
13 14
1516
1 age (10 year increment)
2 SES_1
3 male
4 SES_0
5 black
6 SES_2
7 SES_3
8 education_hs
9 other_eth
10 mexican
11 occupation_blue_semi
12 education_less_hs
13 occupation_never
14 occupation_blue_high
15 occupation_white_semi
16 other_hispanic
(69)
EWAS (re)-identifies factors associated with all-cause mortality:
Volcano plot of 200 associations
age (10 years)
income (quintile 2)
income (quintile 1)
male
black income (quintile 3)
any one smoke in home?
Multivariate cox (age, sex, income, education, race/ethnicity, occupation [in red])
serum and urine cadmium
[1 SD]
past smoker?
current smoker?serum lycopene
[1SD]
physical activity
[low, moderate, high activity]*
*derived from METs per activity and categorized by Health.gov guidelines
R2 ~ 2%
25. 452 associations in Telomere Length:
Polychlorinated biphenyls associated with longer telomeres?!
IJE, in press
0
1
2
3
4
−0.2 −0.1 0.0 0.1 0.2
effect size
−log10(pvalue)
PCBs
FDR<5%
Trunk Fat
Alk. PhosCRP
Cadmium
Cadmium (urine)cigs per day
retinyl stearate
R2 ~ 1%
VO2 Maxpulse rate
shorter telomeres longer telomeres
adjusted by age, age2, race, poverty, education, occupation
median N=3000; N range: 300-7000
26. Studying the Elusive Environment in Large Scale
Itispossiblethatmorethan50%ofcomplexdiseaserisk
isattributedtodifferencesinanindividual’senvironment.1
Airpollution,smoking,anddietaredocumentedenviron-
mental factors affecting health, yet these factors are but
a fraction of the “exposome,” the totality of the exposure
loadoccurringthroughoutaperson’slifetime.1
Investigat-
ing one or a handful of exposures at a time has led to a
highly fragmented literature of epidemiologic associa-
tions. Much of that literature is not reproducible, and se-
lectivereportingmaybeamajorreasonforthelackofre-
producibility. A new model is required to discover
environmental exposures associated with disease while
mitigating possibilities of selective reporting.
Toremedythelackofreproducibilityandconcernsof
validity, multiple personal exposures can be assessed si-
multaneously in terms of their association with a condi-
tion or disease of interest; the strongest associations can
then be tentatively validated in independent data sets
(eg, as done in references 2 and 3).2,3
The main advan-
tages of this process include the ability to search the list
ofexposuresandadjustformultiplicitysystematicallyand
reportalltheprobedassociationsinsteadofonlythemost
significant results. The term “environment-wide associa-
tion studies” (EWAS) has been used to describe this ap-
proach (an analogy to genome-wide association stud-
ies).Forexample,Wangetal4
screenedmorethan2000
chemicalsinserumtodiscoverendogenousexposuresas-
sociated with risk for cardiovascular disease.
Therearenotablehurdlesinanalyzing“big”environ-
mental data. These same problems affect epidemiology
of1-risk-factor-at-a-time,butinEWAStheirprevalencebe-
comes more clearly manifest at large scale. When study-
the EWAS vantage point, intervening on β-carotene
(Figure, D) seems a futile exercise given its complex rela-
tionship with other nutrients and pollutants.
Giventhiscomplexity,howcanstudiesofenvironmen-
talriskmoveforward?First,EWASanalysesshouldbeap-
pliedtomultipledatasets,andconsistencycanbeformally
examinedforallassessedcorrelations.Second,thetempo-
ral relationship between exposure and changes in health
parametersmayofferhelpfulhintsaboutwhichofthesig-
nalsaremorethansimplecorrelations.Third,standardized
adjustedanalyses,inwhichadjustmentsareperformedsys-
tematicallyandinthesamewayacrossmultipledatasets,
may also help. This is in stark contrast with the current
model,wherebymostepidemiologicstudiesusesingledata
setswithoutreplicationaswellasnon–time-dependentas-
sessments,andreportedadjustmentsaremarkedlydiffer-
entacrossreportsanddatasets,eventhoseperformedby
thesameteam(differentapproachesincreasevaliditybut
mustbereconciledandassimilated).
However, eventually for most environmental cor-
relates,theremaybeunsurpassabledifficultyestablish-
ing potential causal inferences based on observational
data alone. Factors that seem protective may some-
times be tested in randomized trials. The complexity of
the multiple correlations also highlights the challenge
thatinterveningtomodify1putativeriskfactoralsomay
inadvertently affect multiple other correlated factors.
Even when a seemingly simple intervention is tested in
randomizedtrials(affectingasingleriskfactoramongthe
manycorrelations),theinterventionisnotreallysimple.
In essence what is tested are multiple perturbations of
factors correlated with the one targeted for interven-
VIEWPOINT
Chirag J. Patel, PhD
Center for Biomedical
Informatics, Harvard
Medical School,
Boston, Massachusetts.
John P. A. Ioannidis,
MD, DSc
Stanford Prevention
Research Center,
Department of Health
Research and Policy,
Department of
Medicine, Stanford
University School of
Medicine, Stanford,
California, Department
of Statistics, Stanford
University School of
Humanities and
Sciences, Stanford,
California, and
Meta-Research
Innovation Center at
Stanford (METRICS),
Stanford, California.
Opinion
JAMA, 2014
JECH, 2014
Proc Symp Biocomp, 2015
How can we study the elusive environment in larger scale for
biomedical discovery?
Studying the Elusive Environment in Large Scale
Itispossiblethatmorethan50%ofcomplexdiseaserisk
isattributedtodifferencesinanindividual’senvironment.1
Airpollution,smoking,anddietaredocumentedenviron-
mental factors affecting health, yet these factors are but
a fraction of the “exposome,” the totality of the exposure
loadoccurringthroughoutaperson’slifetime.1
Investigat-
ing one or a handful of exposures at a time has led to a
highly fragmented literature of epidemiologic associa-
tions. Much of that literature is not reproducible, and se-
lectivereportingmaybeamajorreasonforthelackofre-
producibility. A new model is required to discover
environmental exposures associated with disease while
mitigating possibilities of selective reporting.
Toremedythelackofreproducibilityandconcernsof
validity, multiple personal exposures can be assessed si-
multaneously in terms of their association with a condi-
tion or disease of interest; the strongest associations can
then be tentatively validated in independent data sets
(eg, as done in references 2 and 3).2,3
The main advan-
tages of this process include the ability to search the list
ofexposuresandadjustformultiplicitysystematicallyand
reportalltheprobedassociationsinsteadofonlythemost
significant results. The term “environment-wide associa-
tion studies” (EWAS) has been used to describe this ap-
the EWAS vantage point, intervening on β-carotene
(Figure, D) seems a futile exercise given its complex rela-
tionship with other nutrients and pollutants.
Giventhiscomplexity,howcanstudiesofenvironmen-
talriskmoveforward?First,EWASanalysesshouldbeap-
pliedtomultipledatasets,andconsistencycanbeformally
examinedforallassessedcorrelations.Second,thetempo-
ral relationship between exposure and changes in health
parametersmayofferhelpfulhintsaboutwhichofthesig-
nalsaremorethansimplecorrelations.Third,standardized
adjustedanalyses,inwhichadjustmentsareperformedsys-
tematicallyandinthesamewayacrossmultipledatasets
may also help. This is in stark contrast with the current
model,wherebymostepidemiologicstudiesusesingledata
setswithoutreplicationaswellasnon–time-dependentas-
sessments,andreportedadjustmentsaremarkedlydiffer-
entacrossreportsanddatasets,eventhoseperformedby
thesameteam(differentapproachesincreasevaliditybut
mustbereconciledandassimilated).
However, eventually for most environmental cor-
relates,theremaybeunsurpassabledifficultyestablish-
ing potential causal inferences based on observationa
data alone. Factors that seem protective may some-
times be tested in randomized trials. The complexity of
VIEWPOINT
Chirag J. Patel, PhD
Center for Biomedical
Informatics, Harvard
Medical School,
Boston, Massachusetts.
John P. A. Ioannidis,
MD, DSc
Stanford Prevention
Research Center,
Department of Health
Research and Policy,
Department of
Medicine, Stanford
University School of
Medicine, Stanford,
California, Department
of Statistics, Stanford
University School of
Humanities and
Sciences, Stanford,
California, and
Meta-Research
Innovation Center at
Stanford (METRICS),
Stanford, California.
Opinion
High-throughputascertainmentofendogenousindicatorsofen-
vironmentalexposurethatmayreflecttheexposomeincreasinglyat-
tractattention,andtheirperformanceneedstobecarefullyevaluated.
These include chemical detection of indicators of exposure through
metabolomics, proteomics, and biosensors.7
Eventually, patterns of
US federally funded gene expression experiment data be d
itedinpublicrepositoriessuchastheGeneExpressionOmnibu
repositoryhasbeeninstrumentalindevelopmentoftechnolo
measurement of gene expression, data standardization, and
ofdatafordiscovery.JustaswiththeGeneExpressionOmnib
Figure. Correlation Interdependency Globes for 4 Environmental Exposures (Cotinine, Mercury, Cadmium, Trans-β-Carotene) in National Healt
Nutrition Examination Survey (NHANES) Participants, 2003-2004
A Serum cotinine B Serum total mercury C Serum cadmium D Serum trans-β-carotene
37 Total correlations 42 Total correlations 68 Total correlations 68 Total correlations
Negative correlation Positive correl
Infectious
agents
Pollutants
Nutrients
and vitamins
Demographic
attributes
Eachcorrelationinterdependencyglobeincludes317environmentalexposures
representedbythenodesaroundtheperipheryoftheglobe.Pairwisecorrelations
aredepictedbyedges(lines)betweenthenodeofinterest(arrowhead)andother
nodes.Correlationswithabsolutevaluesexceeding0.2areshown(stronge
Thesizeofeachnodeisproportionaltothenumberofedgesforanode,and
thicknessofeachedgeindicatesthemagnitudeofthecorrelation.
Opinion Viewpoint
•bioinformatics to connect exposome with phenome
•new ‘omics technologies to measure the exposome
•dense correlations
•reverse causality
•confounding
•(longitudinal) publicly available data
27. Interdependencies of the exposome:
Correlation globes paint a complex view of exposure
Red: positive ρ
Blue: negative ρ
thickness: |ρ|
for each pair of E:
Spearman ρ
(575 factors: 81,937 correlations)
permuted data to produce
“null ρ”
sought replication in > 1
cohort
Pac Symp Biocomput. 2015
JECH. 2015
28. Red: positive ρ
Blue: negative ρ
thickness: |ρ|
for each pair of E:
Spearman ρ
(575 factors: 81,937 correlations)
Interdependencies of the exposome:
Correlation globes paint a complex view of exposure
permuted data to produce
“null ρ”
sought replication in > 1
cohort
Pac Symp Biocomput. 2015
JECH. 2015
Effective number of
variables:
500 (10% decrease)
29. Telomere Length All-cause mortality
http://bit.ly/globebrowse
Interdependencies of the exposome:
Telomeres vs. all-cause mortality
30. Studying the Elusive Environment in Large Scale
Itispossiblethatmorethan50%ofcomplexdiseaserisk
isattributedtodifferencesinanindividual’senvironment.1
Airpollution,smoking,anddietaredocumentedenviron-
mental factors affecting health, yet these factors are but
a fraction of the “exposome,” the totality of the exposure
loadoccurringthroughoutaperson’slifetime.1
Investigat-
ing one or a handful of exposures at a time has led to a
highly fragmented literature of epidemiologic associa-
tions. Much of that literature is not reproducible, and se-
lectivereportingmaybeamajorreasonforthelackofre-
producibility. A new model is required to discover
environmental exposures associated with disease while
mitigating possibilities of selective reporting.
Toremedythelackofreproducibilityandconcernsof
validity, multiple personal exposures can be assessed si-
multaneously in terms of their association with a condi-
tion or disease of interest; the strongest associations can
then be tentatively validated in independent data sets
(eg, as done in references 2 and 3).2,3
The main advan-
tages of this process include the ability to search the list
ofexposuresandadjustformultiplicitysystematicallyand
reportalltheprobedassociationsinsteadofonlythemost
significant results. The term “environment-wide associa-
tion studies” (EWAS) has been used to describe this ap-
proach (an analogy to genome-wide association stud-
ies).Forexample,Wangetal4
screenedmorethan2000
chemicalsinserumtodiscoverendogenousexposuresas-
sociated with risk for cardiovascular disease.
Therearenotablehurdlesinanalyzing“big”environ-
mental data. These same problems affect epidemiology
of1-risk-factor-at-a-time,butinEWAStheirprevalencebe-
comes more clearly manifest at large scale. When study-
the EWAS vantage point, intervening on β-carotene
(Figure, D) seems a futile exercise given its complex rela-
tionship with other nutrients and pollutants.
Giventhiscomplexity,howcanstudiesofenvironmen-
talriskmoveforward?First,EWASanalysesshouldbeap-
pliedtomultipledatasets,andconsistencycanbeformally
examinedforallassessedcorrelations.Second,thetempo-
ral relationship between exposure and changes in health
parametersmayofferhelpfulhintsaboutwhichofthesig-
nalsaremorethansimplecorrelations.Third,standardized
adjustedanalyses,inwhichadjustmentsareperformedsys-
tematicallyandinthesamewayacrossmultipledatasets,
may also help. This is in stark contrast with the current
model,wherebymostepidemiologicstudiesusesingledata
setswithoutreplicationaswellasnon–time-dependentas-
sessments,andreportedadjustmentsaremarkedlydiffer-
entacrossreportsanddatasets,eventhoseperformedby
thesameteam(differentapproachesincreasevaliditybut
mustbereconciledandassimilated).
However, eventually for most environmental cor-
relates,theremaybeunsurpassabledifficultyestablish-
ing potential causal inferences based on observational
data alone. Factors that seem protective may some-
times be tested in randomized trials. The complexity of
the multiple correlations also highlights the challenge
thatinterveningtomodify1putativeriskfactoralsomay
inadvertently affect multiple other correlated factors.
Even when a seemingly simple intervention is tested in
randomizedtrials(affectingasingleriskfactoramongthe
manycorrelations),theinterventionisnotreallysimple.
In essence what is tested are multiple perturbations of
factors correlated with the one targeted for interven-
VIEWPOINT
Chirag J. Patel, PhD
Center for Biomedical
Informatics, Harvard
Medical School,
Boston, Massachusetts.
John P. A. Ioannidis,
MD, DSc
Stanford Prevention
Research Center,
Department of Health
Research and Policy,
Department of
Medicine, Stanford
University School of
Medicine, Stanford,
California, Department
of Statistics, Stanford
University School of
Humanities and
Sciences, Stanford,
California, and
Meta-Research
Innovation Center at
Stanford (METRICS),
Stanford, California.
Opinion
JAMA, 2014
JECH, 2014
Proc Symp Biocomp, 2015
How can we study the elusive environment in larger scale for
biomedical discovery?
Studying the Elusive Environment in Large Scale
Itispossiblethatmorethan50%ofcomplexdiseaserisk
isattributedtodifferencesinanindividual’senvironment.1
Airpollution,smoking,anddietaredocumentedenviron-
mental factors affecting health, yet these factors are but
a fraction of the “exposome,” the totality of the exposure
loadoccurringthroughoutaperson’slifetime.1
Investigat-
ing one or a handful of exposures at a time has led to a
highly fragmented literature of epidemiologic associa-
tions. Much of that literature is not reproducible, and se-
lectivereportingmaybeamajorreasonforthelackofre-
producibility. A new model is required to discover
environmental exposures associated with disease while
mitigating possibilities of selective reporting.
Toremedythelackofreproducibilityandconcernsof
validity, multiple personal exposures can be assessed si-
multaneously in terms of their association with a condi-
tion or disease of interest; the strongest associations can
then be tentatively validated in independent data sets
(eg, as done in references 2 and 3).2,3
The main advan-
tages of this process include the ability to search the list
ofexposuresandadjustformultiplicitysystematicallyand
reportalltheprobedassociationsinsteadofonlythemost
significant results. The term “environment-wide associa-
tion studies” (EWAS) has been used to describe this ap-
the EWAS vantage point, intervening on β-carotene
(Figure, D) seems a futile exercise given its complex rela-
tionship with other nutrients and pollutants.
Giventhiscomplexity,howcanstudiesofenvironmen-
talriskmoveforward?First,EWASanalysesshouldbeap-
pliedtomultipledatasets,andconsistencycanbeformally
examinedforallassessedcorrelations.Second,thetempo-
ral relationship between exposure and changes in health
parametersmayofferhelpfulhintsaboutwhichofthesig-
nalsaremorethansimplecorrelations.Third,standardized
adjustedanalyses,inwhichadjustmentsareperformedsys-
tematicallyandinthesamewayacrossmultipledatasets
may also help. This is in stark contrast with the current
model,wherebymostepidemiologicstudiesusesingledata
setswithoutreplicationaswellasnon–time-dependentas-
sessments,andreportedadjustmentsaremarkedlydiffer-
entacrossreportsanddatasets,eventhoseperformedby
thesameteam(differentapproachesincreasevaliditybut
mustbereconciledandassimilated).
However, eventually for most environmental cor-
relates,theremaybeunsurpassabledifficultyestablish-
ing potential causal inferences based on observationa
data alone. Factors that seem protective may some-
times be tested in randomized trials. The complexity of
VIEWPOINT
Chirag J. Patel, PhD
Center for Biomedical
Informatics, Harvard
Medical School,
Boston, Massachusetts.
John P. A. Ioannidis,
MD, DSc
Stanford Prevention
Research Center,
Department of Health
Research and Policy,
Department of
Medicine, Stanford
University School of
Medicine, Stanford,
California, Department
of Statistics, Stanford
University School of
Humanities and
Sciences, Stanford,
California, and
Meta-Research
Innovation Center at
Stanford (METRICS),
Stanford, California.
Opinion
High-throughputascertainmentofendogenousindicatorsofen-
vironmentalexposurethatmayreflecttheexposomeincreasinglyat-
tractattention,andtheirperformanceneedstobecarefullyevaluated.
These include chemical detection of indicators of exposure through
metabolomics, proteomics, and biosensors.7
Eventually, patterns of
US federally funded gene expression experiment data be d
itedinpublicrepositoriessuchastheGeneExpressionOmnibu
repositoryhasbeeninstrumentalindevelopmentoftechnolo
measurement of gene expression, data standardization, and
ofdatafordiscovery.JustaswiththeGeneExpressionOmnib
Figure. Correlation Interdependency Globes for 4 Environmental Exposures (Cotinine, Mercury, Cadmium, Trans-β-Carotene) in National Healt
Nutrition Examination Survey (NHANES) Participants, 2003-2004
A Serum cotinine B Serum total mercury C Serum cadmium D Serum trans-β-carotene
37 Total correlations 42 Total correlations 68 Total correlations 68 Total correlations
Negative correlation Positive correl
Infectious
agents
Pollutants
Nutrients
and vitamins
Demographic
attributes
Eachcorrelationinterdependencyglobeincludes317environmentalexposures
representedbythenodesaroundtheperipheryoftheglobe.Pairwisecorrelations
aredepictedbyedges(lines)betweenthenodeofinterest(arrowhead)andother
nodes.Correlationswithabsolutevaluesexceeding0.2areshown(stronge
Thesizeofeachnodeisproportionaltothenumberofedgesforanode,and
thicknessofeachedgeindicatesthemagnitudeofthecorrelation.
Opinion Viewpoint
•bioinformatics to connect exposome with phenome
•new ‘omics technologies to measure the exposome
•dense correlations
•reverse causality
•confounding
•(longitudinal) publicly available data
31. BD2K Patient-Centered Information Commons
Integrated repositories of individual-level information
PI: Isaac Kohane
http://pic-sure.org
32. with Paul Avillach, Michael McDuffie, Jeremy Easton-Marks,
Cartik Saravanamuthu and the BD2K PIC-SURE team
NHANES 1999-2006
API available now
http://bit.ly/nhanes_pici
BD2K Patient-Centered Information Commons
NHANES exposome browser
33. P
We are many phenotypes simultaneously:
Can we better categorize these P?
Body Measures
Body Mass Index
Height
Blood pressure & fitness
Systolic BP
Diastolic BP
Pulse rate
VO2 Max
Metabolic
Glucose
LDL-Cholesterol
Triglycerides
Inflammation
C-reactive protein
white blood cell count
Kidney function
Creatinine
Sodium
Uric Acid
Liver function
Aspartate aminotransferase
Gamma glutamyltransferase
Aging
Telomere length
34. Creation of a phenotype-exposure association map:
A 2-D view of 83 phenotype by 252 exposure associations
> 0
< 0
Association Size:
Clusters of exposures associated with clusters of phenotypes?
252 biomarkers of exposure × 83 clinical trait phenotypes
NHANES 1999-2000, 2001-2002, 2005-2006
~21K regressions: replicated significant (FDR < 5%) in 2003-2004
adjusted by age, age2, sex, race, income, chronic disease
Hugues Aschard, JP Ioannidis
83phenotypes
252 exposures
36. Body Mass Index
Waist circumference
Trunk fat
Total fat
Weight
Total lean fat
Thigh circumference
Calf circumference
Trunk Lean
Skinfold
CRP
Trans-b-carotene
a-carotene
cis-b-carotene
b-cryptoxanthin
lutein/xeaxanthin
VitaminD
Magnesium
Folate
Vo2Max
PCB180
Cotinine
100cigs
Ciginlast30
Cadmium
Benzene
Toluene
Smokeinhome?
Styrene
Currentsmoker
3-fluorene
2-fluorene
White blood cell count
Segmented neutrophils
Monocyte number
Lymphocyte number
Eosinophils number
Basophils number
Alkaline phosphotase
Homocysteine
Hemoglobin
Pulse rate
http://bit.ly.com/pemap
EWAS-derived phenotype-exposure association map:
Zooming in to WBC and BMI phenotype clusters
Alpha-carotene
Alcohol
VitaminEasalpha-tocopherol
Beta-carotene
Caffeine
Calcium
Carbohydrate
Cholesterol
Copper
Beta-cryptoxanthin
Folicacid
Folate,DFE
Foodfolate
Dietaryfiber
Iron
Energy
Lycopene
Lutein+zeaxanthin
MFA16:1
MFA18:1
MFA20:1
Magnesium
Totalmonounsaturatedfattyacids
Moisture
Niacin
PFA18:2
PFA18:3
PFA20:4
PFA22:5
PFA22:6
Totalpolyunsaturatedfattyacids
Phosphorus
Potassium
Protein
Retinol
SFA4:0
SFA6:0
SFA8:0
SFA10:0
SFA12:0
SFA14:0
SFA16:0
SFA18:0
Selenium
Totalsaturatedfattyacids
Totalsugars
Totalfat
Theobromine
VitaminA,RAE
Thiamin
VitaminB12
Riboflavin
VitaminB6
VitaminC
VitaminK
Zinc
NoSalt
OrdinarySalt
a-Carotene
VitaminB12,serum
trans-b-carotene
cis-b-carotene
b-cryptoxanthin
Folate,serum
g-tocopherol
Iron,FrozenSerum
CombinedLutein/zeaxanthin
trans-lycopene
Folate,RBC
Retinylpalmitate
Retinylstearate
Retinol
VitaminD
a-Tocopherol
Daidzein
o-Desmethylangolensin
Equol
Enterodiol
Enterolactone
Genistein
EstimatedVO2max
PhysicalActivity
Doesanyonesmokeinhome?
Total#ofcigarettessmokedinhome
Cotinine
CurrentCigaretteSmoker?
Agelastsmokedcigarettesregularly
#cigarettessmokedperdaywhenquit
#cigarettessmokedperdaynow
#dayssmokedcigsduringpast30days
Avg#cigarettes/dayduringpast30days
Smokedatleast100cigarettesinlife
Doyounowsmokecigarettes...
numberofdayssincequit
Usedsnuffatleast20timesinlife
drink5inaday
drinkperday
days5drinksinyear
daysdrinkinyear
3-fluorene
2-fluorene
3-phenanthrene
1-phenanthrene
2-phenanthrene
1-pyrene
3-benzo[c]phenanthrene
3-benz[a]anthracene
Mono-n-butylphthalate
Mono-phthalate
Mono-cyclohexylphthalate
Mono-ethylphthalate
Mono-phthalate
Mono--hexylphthalate
Mono-isobutylphthalate
Mono-n-methylphthalate
Mono-phthalate
Mono-benzylphthalate
Cadmium
Lead
Mercury,total
Barium,urine
Cadmium,urine
Cobalt,urine
Cesium,urine
Mercury,urine
Iodine,urine
Molybdenum,urine
Lead,urine
Platinum,urine
Antimony,urine
Thallium,urine
Tungsten,urine
Uranium,urine
BloodBenzene
BloodEthylbenzene
Bloodo-Xylene
BloodStyrene
BloodTrichloroethene
BloodToluene
Bloodm-/p-Xylene
1,2,3,7,8-pncdd
1,2,3,7,8,9-hxcdd
1,2,3,4,6,7,8-hpcdd
1,2,3,4,6,7,8,9-ocdd
2,3,7,8-tcdd
Beta-hexachlorocyclohexane
Gamma-hexachlorocyclohexane
Hexachlorobenzene
HeptachlorEpoxide
Mirex
Oxychlordane
p,p-DDE
Trans-nonachlor
2,5-dichlorophenolresult
2,4,6-trichlorophenolresult
Pentachlorophenol
Dimethylphosphate
Diethylphosphate
Dimethylthiophosphate
PCB66
PCB74
PCB99
PCB105
PCB118
PCB138&158
PCB146
PCB153
PCB156
PCB157
PCB167
PCB170
PCB172
PCB177
PCB178
PCB180
PCB183
PCB187
3,3,4,4,5,5-hxcb
3,3,4,4,5-pncb
3,4,4,5-tcb
Perfluoroheptanoicacid
Perfluorohexanesulfonicacid
Perfluorononanoicacid
Perfluorooctanoicacid
Perfluorooctanesulfonicacid
Perfluorooctanesulfonamide
2,3,7,8-tcdf
1,2,3,7,8-pncdf
2,3,4,7,8-pncdf
1,2,3,4,7,8-hxcdf
1,2,3,6,7,8-hxcdf
1,2,3,7,8,9-hxcdf
2,3,4,6,7,8-hxcdf
1,2,3,4,6,7,8-hpcdf
Measles
Toxoplasma
HepatitisAAntibody
HepatitisBcoreantibody
HepatitisBSurfaceAntibody
HerpesII
Albumin, urine
Uric acid
Phosphorus
Osmolality
Sodium
Potassium
Creatinine
Chloride
Total calcium
Bicarbonate
Blood urea nitrogen
Total protein
Total bilirubin
Lactate dehydrogenase LDH
Gamma glutamyl transferase
Globulin
Alanine aminotransferase ALT
Aspartate aminotransferase AST
Alkaline phosphotase
Albumin
Methylmalonic acid
PSA. total
Prostate specific antigen ratio
TIBC, Frozen Serum
Red cell distribution width
Red blood cell count
Platelet count SI
Segmented neutrophils percent
Mean platelet volume
Mean cell volume
Mean cell hemoglobin
MCHC
Hemoglobin
Hematocrit
Ferritin
Protoporphyrin
Transferrin saturation
White blood cell count
Monocyte percent
Lymphocyte percent
Eosinophils percent
C-reactive protein
Segmented neutrophils number
Monocyte number
Lymphocyte number
Eosinophils number
Basophils number
mean systolic
mean diastolic
60 sec. pulse:
60 sec HR
Total Cholesterol
Triglycerides
Glucose, serum
Insulin
Homocysteine
Glucose, plasma
Glycohemoglobin
C-peptide: SI
LDL-cholesterol
Direct HDL-Cholesterol
Bone alkaline phosphotase
Trunk Fat
Lumber Pelvis BMD
Lumber Spine BMD
Head BMD
Trunk Lean excl BMC
Total Lean excl BMC
Total Fat
Total BMD
Weight
Waist Circumference
Triceps Skinfold
Thigh Circumference
Subscapular Skinfold
Recumbent Length
Upper Leg Length
Standing Height
Head Circumference
Maximal Calf Circumference
Body Mass Index
-0.4 -0.2 0 0.2 0.4
Value
050100150
Color Key
and Histogram
Count
+-
37. Toward a phenotype-exposure association map:
(Re)-categorizing phenotypes with E
7 6 5 4 3 2 1 0
Distance
liver:Albumin
kidney:Bicarbonate
immunological:Basophils percent
immunological:Lymphocyte percent
immunological:Eosinophils percent
kidney:Phosphorus
liver:Total protein
liver:Aspartate aminotransferase AST
liver:Alanine aminotransferase ALT
body measures:Head Circumference
body measures:Recumbent Length
liver:Lactate dehydrogenase LDH
cancer:Prostate specific antigen ratio
cancer:PSA, free
blood:Transferrin saturation
liver:Total bilirubin
heart:Direct HDL-Cholesterol
immunological:Monocyte percent
bone:Head BMD
body measures:Standing Height
body measures:Upper Leg Length
bone:Total BMD
bone:Lumber Spine BMD
bone:Lumber Pelvis BMD
heart:Triglycerides
heart:LDL-cholesterol
heart:Total Cholesterol
blood:MCHC
blood:TIBC, Frozen Serum
blood:Hematocrit
blood:Hemoglobin
kidney:Potassium
blood:Mean cell hemoglobin
blood:Mean cell volume
kidney:Uric acid
kidney:Blood urea nitrogen
kidney:Total calcium
kidney:Creatinine
blood:Ferritin
blood:Red blood cell count
body measures:Weight
blood:Segmented neutrophils percent
body measures:Total Lean excl BMC
body measures:Trunk Lean excl BMC
body measures:Body Mass Index
body measures:Waist Circumference
body measures:Triceps Skinfold
body measures:Maximal Calf Circumference
body measures:Thigh Circumference
liver:Gamma glutamyl transferase
blood pressure:60 sec. pulse:
metabolic:Insulin
body measures:Total Fat
body measures:Trunk Fat
body measures:Subscapular Skinfold
blood pressure:mean systolic
immunological:C-reactive protein
liver:Globulin
immunological:Monocyte number
immunological:Segmented neutrophils number
immunological:Lymphocyte number
immunological:White blood cell count
immunological:Basophils number
immunological:Eosinophils number
blood:Mean platelet volume
heart:Homocysteine
nutrition:Methylmalonic acid
kidney:Osmolality
kidney:Chloride
kidney:Sodium
kidney:Albumin, urine
blood pressure:60 sec HR
cancer:PSA. total
blood:Platelet count SI
blood:Protoporphyrin
blood:Red cell distribution width
bone:Bone alkaline phosphotase
liver:Alkaline phosphotase
blood pressure:mean diastolic
metabolic:C-peptide: SI
metabolic:Glycohemoglobin
metabolic:Glucose, plasma
metabolic:Glucose, serum
inflammation
adiposity
kidney function
metabolic traits
38. 7 6 5 4 3 2 1 0
Distance
liver:Albumin
kidney:Bicarbonate
immunological:Basophils percent
immunological:Lymphocyte percent
immunological:Eosinophils percent
kidney:Phosphorus
liver:Total protein
liver:Aspartate aminotransferase AST
liver:Alanine aminotransferase ALT
body measures:Head Circumference
body measures:Recumbent Length
liver:Lactate dehydrogenase LDH
cancer:Prostate specific antigen ratio
cancer:PSA, free
blood:Transferrin saturation
liver:Total bilirubin
heart:Direct HDL-Cholesterol
immunological:Monocyte percent
bone:Head BMD
body measures:Standing Height
body measures:Upper Leg Length
bone:Total BMD
bone:Lumber Spine BMD
bone:Lumber Pelvis BMD
heart:Triglycerides
heart:LDL-cholesterol
heart:Total Cholesterol
blood:MCHC
blood:TIBC, Frozen Serum
blood:Hematocrit
blood:Hemoglobin
kidney:Potassium
blood:Mean cell hemoglobin
blood:Mean cell volume
kidney:Uric acid
kidney:Blood urea nitrogen
kidney:Total calcium
kidney:Creatinine
blood:Ferritin
blood:Red blood cell count
body measures:Weight
blood:Segmented neutrophils percent
body measures:Total Lean excl BMC
body measures:Trunk Lean excl BMC
body measures:Body Mass Index
body measures:Waist Circumference
body measures:Triceps Skinfold
body measures:Maximal Calf Circumference
body measures:Thigh Circumference
liver:Gamma glutamyl transferase
blood pressure:60 sec. pulse:
metabolic:Insulin
body measures:Total Fat
body measures:Trunk Fat
body measures:Subscapular Skinfold
blood pressure:mean systolic
immunological:C-reactive protein
liver:Globulin
immunological:Monocyte number
immunological:Segmented neutrophils number
immunological:Lymphocyte number
immunological:White blood cell count
immunological:Basophils number
immunological:Eosinophils number
blood:Mean platelet volume
heart:Homocysteine
nutrition:Methylmalonic acid
kidney:Osmolality
kidney:Chloride
kidney:Sodium
kidney:Albumin, urine
blood pressure:60 sec HR
cancer:PSA. total
blood:Platelet count SI
blood:Protoporphyrin
blood:Red cell distribution width
bone:Bone alkaline phosphotase
liver:Alkaline phosphotase
blood pressure:mean diastolic
metabolic:C-peptide: SI
metabolic:Glycohemoglobin
metabolic:Glucose, plasma
metabolic:Glucose, serum
“bad” cholesterol
“good” cholesterol
Toward a phenotype-exposure association map:
(Re)-categorizing phenotypes with E
39. 7 6 5 4 3 2 1 0
Distance
liver:Albumin
kidney:Bicarbonate
immunological:Basophils percent
immunological:Lymphocyte percent
immunological:Eosinophils percent
kidney:Phosphorus
liver:Total protein
liver:Aspartate aminotransferase AST
liver:Alanine aminotransferase ALT
body measures:Head Circumference
body measures:Recumbent Length
liver:Lactate dehydrogenase LDH
cancer:Prostate specific antigen ratio
cancer:PSA, free
blood:Transferrin saturation
liver:Total bilirubin
heart:Direct HDL-Cholesterol
immunological:Monocyte percent
bone:Head BMD
body measures:Standing Height
body measures:Upper Leg Length
bone:Total BMD
bone:Lumber Spine BMD
bone:Lumber Pelvis BMD
heart:Triglycerides
heart:LDL-cholesterol
heart:Total Cholesterol
blood:MCHC
blood:TIBC, Frozen Serum
blood:Hematocrit
blood:Hemoglobin
kidney:Potassium
blood:Mean cell hemoglobin
blood:Mean cell volume
kidney:Uric acid
kidney:Blood urea nitrogen
kidney:Total calcium
kidney:Creatinine
blood:Ferritin
blood:Red blood cell count
body measures:Weight
blood:Segmented neutrophils percent
body measures:Total Lean excl BMC
body measures:Trunk Lean excl BMC
body measures:Body Mass Index
body measures:Waist Circumference
body measures:Triceps Skinfold
body measures:Maximal Calf Circumference
body measures:Thigh Circumference
liver:Gamma glutamyl transferase
blood pressure:60 sec. pulse:
metabolic:Insulin
body measures:Total Fat
body measures:Trunk Fat
body measures:Subscapular Skinfold
blood pressure:mean systolic
immunological:C-reactive protein
liver:Globulin
immunological:Monocyte number
immunological:Segmented neutrophils number
immunological:Lymphocyte number
immunological:White blood cell count
immunological:Basophils number
immunological:Eosinophils number
blood:Mean platelet volume
heart:Homocysteine
nutrition:Methylmalonic acid
kidney:Osmolality
kidney:Chloride
kidney:Sodium
kidney:Albumin, urine
blood pressure:60 sec HR
cancer:PSA. total
blood:Platelet count SI
blood:Protoporphyrin
blood:Red cell distribution width
bone:Bone alkaline phosphotase
liver:Alkaline phosphotase
blood pressure:mean diastolic
metabolic:C-peptide: SI
metabolic:Glycohemoglobin
metabolic:Glucose, plasma
metabolic:Glucose, serum
height + BMD
Toward a phenotype-exposure association map:
(Re)-categorizing phenotypes with E
40. Triglycerides
Total Cholesterol
LDL-cholesterol
Trunk Fat
Albumin, urine
Insulin
Total Fat
Head Circumference
Blood urea nitrogen
Albumin
Homocysteine
C-peptide: SI
C-reactive protein
Body Mass Index
Ferritin
Thigh Circumference
Maximal Calf Circumference
Direct HDL-Cholesterol
Total calcium
Total bilirubin
Red cell distribution width
Gamma glutamyl transferase
Mean cell volume
Mean cell hemoglobin
White blood cell count
Uric acid
Protoporphyrin
Hemoglobin
Total protein
Alkaline phosphotase
Waist Circumference
Hematocrit
Weight
Standing Height
1/Creatinine
Creatinine
Trunk Lean excl BMC
Methylmalonic acid
Triceps Skinfold
Lymphocyte number
Subscapular Skinfold
Total Lean excl BMC
Segmented neutrophils number
Lactate dehydrogenase LDH
Bone alkaline phosphotase
TIBC, Frozen Serum
Aspartate aminotransferase AST
Phosphorus
Lumber Pelvis BMD
Glycohemoglobin
Globulin
Chloride
Bicarbonate
Alanine aminotransferase ALT
60 sec. pulse:
Upper Leg Length
Total BMD
Potassium
Glucose, serum
Glucose, plasma
Red blood cell count
Lumber Spine BMD
Platelet count SI
MCHC
Osmolality
Monocyte number
mean systolic
Lymphocyte percent
Segmented neutrophils percent
Recumbent Length
Eosinophils number
Monocyte percent
Head BMD
mean diastolic
Prostate specific antigen ratio
60 sec HR
Basophils number
Sodium
PSA, free
Mean platelet volume
Eosinophils percent
PSA. total
Basophils percent
0 10 20 30 40
R^2 * 100
1 to 66 exposures identified for 81
phenotypes
Additive effect of E factors:
Describe < 20% of variability in P
(On average: 8%)
σ2E?
Recall: Avg(h2) = 50%
Long road ahead to capture σ2
P
41. Connecting Environmental Exposure with Disease:
Missing the “System” of Exposures?
E+ E-
diseased
non-
diseased
?
Exposed to many things, but do not assess the multiplicity.
Fragmented literature of associations.
Challenge to discover E associated with disease.
42. Example of fragmentation:
Is everything we eat associated with cancer?
Schoenfeld and Ioannidis, AJCN 2012
50 random ingredients from
Boston Cooking School
Cookbook
Any associated with cancer?
FIGURE 1. Effect estimates reported in the literature by malignancy type (top) or ingredient (bottom). Only ingredients with $10 studie
outliers are not shown (effect estimates .10).
Of 50, 40 studied in cancer risk
Weak statistical evidence:
non-replicated
inconsistent effects
non-standardized
46. JCE, 2015
Janus (two-faced) risk profile
Risk and significance depends on modeling scenario!
The Vibration of Effects: beware of the Janus effect
(both risk and protection?!)
“risk”“protection”
“significant”
Brittanica.com
48. Emerging technologies to ascertain exposome will enable
biomedical discovery
High-throughput E data standards & exposome:
mitigate fragmented literature of associations
Confounding, reverse causality:
how to handle at large dimension?
e.g., EWASs in telomere length and mortality
and 81 quantitative phenotypes
Prioritize biological and epidemiological studies.
49. Can we repurpose administrative data (e.g.,
insurance, electronic medical records) to
ascertain E and σ2
E?
50. Elucidating E (and G) in larger scale without the
exposome and genome…
possible with health insurance data?
Chirag Lakhani
Jian Yang
Peter Visscher
σ2
G & σ2
E
51. Bacterial or viral triggers for T2D?
Danielle Rasooly
Isaac Kohane
Possible to study E in administrative health data
52. New ways of measuring P are here now!
Can we use them to assess E (and G)?
57. Harvard DBMI
Isaac Kohane
Susanne Churchill
Stan Shaw
Jenn Grandfield
Sunny Alvear
Michal Preminger
Harvard Chan
Hugues Aschard
Francesca Dominici
Chirag J Patel
chirag@hms.harvard.edu
@chiragjp
www.chiragjpgroup.org
NIH Common Fund
Big Data to Knowledge
Acknowledgements
CDC
Marta Gwinn
Ridgely Green
Muin Khoury
Denise Lowe
Stanford
John Ioannidis
Atul Butte (UCSF)
U Queensland
Jian Yang
Peter Visscher
Cochrane
Belinda Burford
RagGroup
Chirag Lakhani
Adam Brown
Danielle Rasooly
Arjun Manrai
Erik Corona
Nam Pho