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

Precision Medicine Genomic Medicine FOUNDATION

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

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

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

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.

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.

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).

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

Health Disparities in Two Key Biomarker Areas Colorectal Cancer Breast Cancer https://www.cdc.gov/cancer https://www.cdc.gov/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.

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

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

Thought for Strategic Plan Patients/Providers

Journal of Community Genetics

Interest in Health and PGx related biomarkers

Traits and Ancestry related biomarkers

The Provider

Map of ClinVar Submitters by Country

Thought for Strategic Plan Clinical

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

The Medseq Case-Study

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.

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 rs1799853 rs1057910 rs28371686 rs9332131 rs7900194 rs28371685 Genotype: *5/*5 VKORC1 rs9923231 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. 25. 33-41.

Our Existing Report

Two Proposed Changes for Non-White Participants 1 2

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

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

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

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

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

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