Introduction and Background: The Web-based PhenX Toolkit (consensus measures for Phenotypes and eXposures, https://www. phenxtoolkit.org/) is a catalog of standard measures designed to facilitate collaborative biomedical research. PhenX measures help ensure that phenotypes from different studies are collected and represented in a consistent format. This consistency can enable data comparability across sites in large cohorts (e.g., Precision Medicine Initiative) and facilitates combining data to validate clinically actionable variants, increase statistical power (e.g., studies of rare genetic conditions or gene-enviroment interactions), or compare treatments and outcomes between patients.

1. RTI International is a trade name of Research Triangle Institute
The PhenX Toolkit: Standard Measures for
Collaborative Research
Human Variome Project
June 2, 2016
Wayne Huggins, PhD
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2. PhenX: consensus measures for Phenotypes and
eXposures
• PhenX is funded by the National Human Genome Research Institute (NHGRI),
Project Scientist, Dr. Erin Ramos with co-funding from the National Institute on Drug
Abuse (NIDA)
• In September 2007, RTI International was awarded a Cooperative Agreement (U01)
to select and define high priority measures for GWAS (phase 1)
• In July 2013, RTI International was awarded a Genomics Resource grant (U41) to
expand the Toolkit, review existing measure and add features (phase 2)
• PhenX uses an established consensus based process and is driven by the scientific
community
• Initially focused on measures for genome-wide association studies, the scope has
broadened to clinical, translational and epidemiological research

3. Why Use Standard Measures?
• Increased sample size provides greater statistical power
– For GWAS, to identify moderate associations and more complex
interactions
– For other types of studies, increases statistical confidence in
results
• Study findings require validation
– Initial findings need to be replicated, standard measures aid
comparisons
• Cross-study analyses increase the impact of individual studies
– Many diseases and conditions share common risk factors
– Use of standard (common) measures facilitates cross-study
analyses

4. PhenX Project Organization
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5. Criteria for Selecting PhenX Measures
• Clearly defined
• Well established
• Broadly applicable
• Validated
• Reproducible
• Specific
• Reliable
• Standard measurement protocols exist
• Criteria defined by the PhenX Steering Committee
• Working Groups select measures to be included in the Toolkit

6. • Alcohol, Tobacco, and Other
Substances
• Anthropometrics
• Cancer
• Cardiovascular
• Demographics
• Diabetes
• Environmental Exposures
• Gastrointestinal
• Geriatrics
• Infectious Diseases and Immunity
• Neurology
• Nutrition and Dietary Supplements
• Obesity
• Ocular
• Oral Health
• Physical Activity and Physical
Fitness
• Pregnancy
• Psychiatric
• Psychosocial
• Rare Genetic Conditions
• Reproductive Health
• Respiratory
• Skin, Bone, Muscle, and Joint
• Social Environments
• Speech and Hearing
PhenX - Research Domains

7. PhenX Supplements - adding depth to the Toolkit
• PhenX Measures for Sickle Cell Disease Research (funded by NHLBI)
– Ellen Werner, Project Scientist
– Sickle Cell Disease Research and Scientific Panel (SRSP)
– Collaborating with H3Africa (Human Heredity and Health in Africa) on a Sickle Cell
Disease ontology
• PhenX Measures for Mental Health Research (funded by NIMH)
– Greg Farber, Project Scientist
– Mental Health Research Scientific Panel (MHRP)
• PhenX Measures for Tobacco Regulatory Science (funded by TRSP)
– Kay Wanke, Project Scientist
– Tobacco Regulatory Research Scientific Panel (TRRP)
• PhenX Measures for Substance Abuse and Addiction (funded by NIDA)
– Kevin Conway, Project Scientist
– Substance Abuse and Addiction Scientific Panel (SSP)

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9. Toolkit Features
• Browse or Search entire Toolkit
– Browse by “Domain”, “Measure,” or “Collection”
– Search using “Smart Query Tool”
• Add measures to “My Toolkit”
– Identifies “Essential Measures”
– Recommends “Related Measures”
– Registration allows users to save and share multiple Toolkits
• Download information about selected measures
– Custom Reports
– Custom Data Collection Worksheets (DCW)
– Data Dictionaries (DD) support data submission to dbGaP
– REDCap zip instrument files to upload to studies in REDCap
• Translations – Spanish and Chinese coming soon
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10. PhenX Measures are Connected to
Standards and Resources
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11. PhenX Collaborations - dbGaP
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• Goal: Identify dbGaP studies that can be combined with PhenX
measures for potential use in cross-study analysis
• Annotate use of PhenX measures Data submission
• Mapping PhenX variables to dbGaP study variables
retrospectively (PhenX has relatively small number of variables
compared to dbGaP)
• PhenX in dbGaP advanced search
• dbGaP adding PhenX in Faceted Browsing (in design phase)

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Mapping to retrospective studies

13. PhenX Collaborations - REDCap
• Research Electronic Data Capture (REDCap) application
allows users to build and manage online surveys and
databases quickly and securely
• Web-based data collection for PhenX protocols
• All PhenX protocols have REDCap Zip Instruments, which can
be uploaded directly to REDCap
• Accessible at both REDCap (a link to PhenX) and PhenX sites
• REDCap available for use on mobile devices
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14. RTI International is a trade name of Research Triangle Institute

16. PhenX Collaborations - Translations
Translated protocols
– Sharing Spanish translations in the Toolkit
– Template for other languages e.g. Chinese
– Spanish
• Major sources include NHANES, CDC, GAIN, NHLBI, NSDUH
• To date, we retrieved 59 of 194
– Chinese
• Dr. Jim Zhang, Director, Shanghai Key Laboratory of Children’s
Environmental Health, Institute of Translational Medicine SJTU
• Chinese translation for all 21 domains, received 2 domains, expect
remaining in May
– Toolkit navigation is in English
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17. PhenX Collaborations – H3Africa
• H3Africa
– Sickle Cell Disease Ontology
– African population-specific protocols for the Toolkit?
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18. Registered Users and FOAs Recommending
PhenX Measures Over Time
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19. Summary - PhenX and HVP
• PhenX for epidemiology, clinical and translational research as well as
genomics
– PhenX Measures for Rare Genetic Conditions
– Supplements
• Most PhenX measures are agnostic, but provide information that leads to
diagnoses
– Diagnostic criteria change
– Modular approach, multiple measures may be needed to make a “diagnoses”
• Expansion of PhenX Ontology
– Compatible with HPO and Monarch
– Collaboration with H3Africa on SCD ontology
• Adoption of standard vocabulary (e.g. UMLS) and definitions (e.g. MeSH)
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20. Acknowledgements
• NHGRI
– Erin Ramos (Project Scientist)
– Brenda Iglesias (Program Analyst)
• PhenX Steering Committee
– Mary Marazita, Co-Chair
– Cathy McCarty, Co-Chair
• WG Chairs / Members
• NIH Liaisons
• Other Liaisons, HHS, DoD, CDC, FDA,
VA
• NIDA lead – Kevin Conway
• TRSP lead – Kay Wanke
• NIMH lead – Greg Farber
• NHLBI lead – Ellen Werner
• RTI Team
– Carol Hamilton (Principal
Investigator)
– Tabitha Hendershot (Co-
Investigator)
– Amanda Riley (Project Manager)
– Darigg Brown
– Wayne Huggins
– Debbie Maiese
– Destiney Nettles
– Helen Pan
– Mike Phillips
– Toolkit team
– Communications team
– Logistics team
– Collaborators

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Questions?

22. Resources
• www.phenxtoolkit.org
– Find PhenX measures for inclusion in your study
– Quick Start guide
– Tutorial
• www.phenx.org
– Provides general information about the PhenX project
– Register to receive periodic updates via e-mail of the PhenX Newsletter and notification of
new surveys

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25. PhenX Terminology
• DOMAIN: Topical area with a unifying
theme
• COLLECTION: A collection of
measures with a shared characteristic,
target population or topic. The
measures included in a Collection may
cut across research Domains
• MEASURE: A certain characteristic of,
or related to, a study subject
• PROTOCOL: Standard procedure
recommended by a Working Group to
collect and record a PhenX measure

26. RTI International is a trade name of Research Triangle Institute
Cross-reference table for PhenX measures and variables
PhenX
variable
PhenX ID dbGaP
variable
LOINC
code
Current Age PXV010101020000 phv00023938.v1
phv00024004.v1
21612-7
Ethnicity
PXV010501010000 phv00023941.v1
phv00024007.v1
56050-8
Gender
PXV010701010000 phv00023939.v1
phv00024005.v1
46607-8
P3G
variable*
Age
Ethnicity
Gender
eMERGE
variable
caDSR
CDE
Age 2423393
Ethnicity 2200284
Gender 2179640
* P3G DataShaPER doesn’t distinguish between “exact” and “similar” mappings to PhenX measures

27. New Frontiers for PMI – and PhenX
• Hand-held devices for gathering data
• PhenX in EHRs / Linking to EHRs
• Inclusion in patient portals
• 23andMe etc
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28. PhenX Measures Being Included in Current
Initiatives and NIH-Funded Studies
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NIH Research Initiative/Study Number of PhenX
Measures
Sample size
Adolescent Brain Cognitive Development (ABCD) Study 43 10,000*
Precision Medicine Initiative (PMI) 16 1 million*
Population Assessment of Tobacco and Health (PATH) 16 46,000
Tobacco Centers of Regulatory Science (TCORS) 38 unknown
Environmental influences on Child Health Outcomes: Patient
Reported Outcomes Research Resource Center Core (ECHO
PRO Core)
PhenX recommended in
RFA
50,000*
Data Coordinating Center for Sickle Cell Disease Implementation
Consortium (SCDIC):
PhenX recommended in
RFA
2,100*
* Planned

29. PhenX Measures Enable Cross-Study Analysis
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30. • Review each of 21 original domains to ensure measures still reflect
current science
– ERP 1 – Anthropometrics, Diabetes, Nutrition and Dietary
Supplements, & Physical Activity and Physical Fitness
– ERP 2 – Demographics, Environmental Exposures, Social
Environments
– ERP 3 – Alcohol, Tobacco, and Other Substances, Substance Abuse
and Addiction Collections
– ERP 4 – Psychiatric, Neurology, Psychosocial
– ERP 5 – Reproductive Health
Expert Review Panels (ERPs)
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31. 1. Ataxia Rating Scale
2. Body Proportions
3. Bone Age
4. Child Oral Health Pain
5. Complete Blood Count
(CBC)
6. Disability Index
7. Disease Progression and
Regression
8. Disorders of Respiratory
Control with Inherent
Autonomic Dysregulation
9. Echocardiography
Phenotypes
10. Family Health History
11. Growth Charts
12. Quality of Life
13. Scale of Developmental
Domains of Early Childhood
14. Scoliosis - Physical
Assessment
15. Scoliosis - Quality of Life
16. Sweat Chloride Test
Rare Genetic Conditions
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