1. Health Disparities in the Era of Precision Medicine
Latrice Landry, MS, PhD, MMSc
Partners Personalized Medicine
Center for Advanced Molecular Diagnostics, BWH
Harvard Medical School

2. Precision Medicine
Genomic Medicine
FOUNDATION

3. Biomarkers, including Genomic Variants,
are a Key Component to Precision Medicine
Sample
DNA
Genetic Test Results
Risk
Diagnosis
Prognosis
Predict Treatment
Monitor Disease

4. Biomarkers Predictive Diagnostics Risk Prognostics
Start: A central theme of the Precision Medicine Initiative is the translation of biomarkers for clinical use.
Predictive ie predictive of drug therapy as defined by the NIH-FDA Leadership Council’s Biomarker Program
Diagnostics
Prognostics
Risk
Prognostics
Risk

5. Precision Healthcare Patient Report Molecular Findings
Stochastic Modeling
Causative Agent
Therapeutic Prospects
Disease Treatment/ Management

6. Tempered Excitement for Precision Medicine
So you might be surprised that within this precision medicine movement, there are critics. Insider Critics, who believe in the promise, but also believe there are huge oversights that will ultimately lead to the demise. Charles Rotimi is one such Critic, Senior Scienitist at NHGRI and considered one of the worlds experts in genomics. His specific expertise is in population genetics and health disparities.

8. 2017 2017 65% European ancestry ~15% European ancestry
Genomic Research
U.S. Population
World
2017
2017
65% European ancestry
~15% European ancestry
Persistent Bias
Discordance of 15%
Discordance of 65%
Whites Represent 81% of the genetic Research but only 13% of the world’s population.

9. Genetics and Genomics Research:
A View from Databases
*Databases included are the database of genotypes and phenotypes (dbGaP) and the Genome Wide Association Study Catalogue (GWAS catalogue).

13. Exhibit 3. Number of Studies in GWAS and dbGaP Databases by Disease Area and Population Group
dbGaP- Database of Genotypes and Phenotypes; GWAS- Genome-wide Asscociation Study; URM- Under represented Minority

14. Health Disparities in Two Key Biomarker Areas
Colorectal Cancer
Breast Cancer
In the breast cancer category, fewer than 5% of cohorts focused on non-European sample populations.
In the GI cancer category, there were zero cohorts focused on non-European sample populations.

15. Genetic Research Translates into Clinical Biomarkers
Lack of Genetic Research in Minorities
POSSIBLE IMPACT ON BIOMARKERS
FDA/NIH Leadership Council Biomarker Program
Missed Biomarkers
Predictive error for PGx
? Safety/ efficacy of Therapies
Conflicting Evidence of Risk
Missed/Inconclusive Diagnosis/Prognosis
Confounding, effect modification, spurious associations

16. What if? Your Genetic Test is Inconclusive Sample
The marker detected has not been seen before
It is not well characterized and the association is unclear
No treatments exist
% Inconclusive
Diverse Genetic Research
% Conclusive
Slide 5
Genetic Research Currently

17. Thought for Strategic Plan
Patients/Providers

18. Journal of Community Genetics

19. Interest in Health and PGx related biomarkers

20. Traits and Ancestry related biomarkers

21. The Provider

24. Map of ClinVar Submitters by Country

25. Thought for Strategic Plan
Clinical

28. Underrepresented Minorities have a Lower Detection Rate for both Cardiomyopathy and Hearing Loss compared to their White Counterparts.

29. The Medseq Case-Study

30. Our Existing Report
This report will stay the same for a participant who carries the CYP2C9*1,*2 or *3 genotypes with one exception: the list of rsIDs evaluated will include the additional * alleles.

31. Three Proposed changes for a participant with. 5,. 6,. 8, or
Three Proposed changes for a participant with *5,*6,*8, or *11 variants
CYP2C9 rs rs rs rs rs rs
Genotype: *5/*5
VKORC1 rs
Genotype: AA
Patients with the CYP2C9 *5/*5 genotype may require a lower dose of warfarin as compared to patients with other CYP2C9 genotypes. Patients with the VKORC1 AA may require a lower dose of warfarin as compared to patients with the VKORC1 GG genotype. Patients with the combination of CYP2C9 *5/*5 genotype with the VKORC1 A/A genotype are expected to require a lower dose of Warfarin. Refer to warfarindosing.org for dosing based on genotype and other factorsa.
Johnson,2011
Perera, 2013
Niinuma,201 Johnson, 2015
Decreased dose
requirement
You will note the combined genotype table is removed as the additional star alleles are not yet included in this algorithm. Additionally, the combined genotype frequencies are not available. Also, in this example we have a *5/*5 genotype for CYP2C9. Both *5 and *6 are in the warfarindosing.com algorithms. However *8 and *11 are not. Therefore this statement would not be included for those variants.
Note: Warfarindosing.org does not provide predictions for *8 and *11 1 2 3
Johnson, J.A., Cavallari, H.H.(2015). “Warfarin Pharmacogenomics”. Trends in Cardiovascular Medicine

32. Our Existing Report

33. Two Proposed Changes for Non-White Participants1 2

34. Building Solutions Understanding the Gaps
START
Understanding the Gaps
Building Solutions
Translational Toolbox
Clinical
Computational
Policy
Foundation for Precision Medicine

35. The Toolbox for Targeting Disparities in Genomic Medicine
Collaboration
The Toolbox for Targeting Disparities in Genomic Medicine
Academia
Government
Industry

36. Increasing Diversity in Research
Collaboration
Increasing Diversity in Research
Policies around Inclusion
Increasing Education
Building Infrastructure
Academia
Enhance Funding for Technology Development and Data Science
Government
Increasing Access to Precision Services
Analyze Disparities in Genomic Medicine
Industry

37. To Prevent the Exacerbation of Existing Disparities in Era of Precision Medicine We Must Act NOW.

38. Using Databases To Track our Progress and Prioritize Goals
Policy Recommendations
1. Submissions to databases should include ancestral information in the submission so that differences and progress across populations can be tracked.
2. Databases include information on disease prevalence, disparities in disease morbidity and death and pertinent genetic factors.
3. Scientific journals’ editorial boards specify inclusion standards, or justification for lack of diversity as a requirement for publication.
4. Implementation of innovative and culturally respectful strategies for recruiting underrepresented groups in research.
5. Patients, providers and researchers should be educated about the value of participating in research, including contributing biological samples to biobanks.
6. Genomic information be shared with patients in an accessible way.
Using Databases To Track our Progress and Prioritize Goals
Industry
Government
Academia
Community

39. Acknowledgements FDA NHGRI Partner’s Personalized Medicine CAMD at BWH Harvard Medical School Nadya Ali Heidi Rehm Vence Bonham David Williams Robert Green