Associate Professor - Med Center Line, Medicine - Primary Care and Population Health
Boards, Advisory Committees, Professional Organizations
Member, Stanford Hospital and Clinics Ethics Committee (2016 - Present)
Member, Lucile Packard Children's Hospital Ethics Committee (2016 - Present)
Postdoc, Stanford University School of Medicine, Bioethics (2008)
PhD, Stanford University School of Medicine, Epidemiology (Minor Genetics) (2002)
AB, Harvard University, History and Science (1994)
Current Research and Scholarly Interests
My research focuses on ethical issues in genetics and genomics, specifically return of results and translation for exome and whole genome sequencing and translation of genomic sequencing into the clinical setting. I also conduct research on ethical issues in clinical care and research for patients and families with autism and other developmental and cognitive disabilities.
My46: a Web-based tool for self-guided management of genomic test results in research and clinical settings.
Genetics in medicine
A major challenge to implementing precision medicine is the need for an efficient and cost-effective strategy for returning individual genomic test results that is easily scalable and can be incorporated into multiple models of clinical practice. My46 is a Web-based tool for managing the return of genetic results that was designed and developed to support a wide range of approaches to disclosing results, ranging from traditional face-to-face disclosure to self-guided models. My46 has five key functions: set and modify results-return preferences, return results, educate, manage the return of results, and assess the return of results. These key functions are supported by six distinct modules and a suite of features that enhance the user experience, ease site navigation, facilitate knowledge sharing, and enable results-return tracking. My46 is a potentially effective solution for returning results and supports current trends toward shared decision making between patients and providers and patient-driven health management.Genet Med advance online publication 15 September 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.133.
View details for DOI 10.1038/gim.2016.133
View details for PubMedID 27632689
Use of metaphors about exome and whole genome sequencing.
American journal of medical genetics. Part A
2016; 170A (5): 1127-1133
Clinical and research uses of exome and whole genome sequencing (ES/WGS) are growing rapidly. An enhanced understanding of how individuals conceptualize and communicate about sequencing results is needed to ensure effective, mutual exchange of information between care providers and patients and between researchers and participants. Focus groups and interviews participants were recruited to discuss their attitudes and preferences for receiving hypothetical results from ES/WGS. African Americans were intentionally oversampled. We qualitatively analyzed participants' speech to identify unsolicited metaphorical language pertaining to genes and health, and grouped these occurrences into metaphorical concepts. Participants compared genetic information to physical objects including tools, weapons, contents of boxes, and formal documents or reports. These metaphorical concepts centered on several key themes, including locus of control; containment versus release of information; and desirability, usability, interpretability, and ownership of genetic results. Metaphorical language is often used intentionally or unintentionally in discussions about receiving results from ES/WGS in both clinical and research settings. Awareness of the use of metaphorical language and attention to its varied meanings facilitates effective communication about return of ES/WGS results. In turn, both should foster shared and informed decision-making and improve the translation of genetic information by clinicians and researchers.
View details for DOI 10.1002/ajmg.a.37571
View details for PubMedID 26822973
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.
American journal of human genetics
2015; 97 (2): 199-215
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.
View details for DOI 10.1016/j.ajhg.2015.06.009
View details for PubMedID 26166479
"We Don't Know Her History, Her Background": Adoptive Parents' Perspectives on Whole Genome Sequencing Results
JOURNAL OF GENETIC COUNSELING
2015; 24 (1): 67-77
Exome sequencing and whole genome sequencing (ES/WGS) can provide parents with a wide range of genetic information about their children, and adoptive parents may have unique issues to consider regarding possible access to this information. The few papers published on adoption and genetics have focused on targeted genetic testing of children in the pre-adoption context. There are no data on adoptive parents' perspectives about pediatric ES/WGS, including their preferences about different kinds of results, and the potential benefits and risks of receiving results. To explore these issues, we conducted four exploratory focus groups with adoptive parents (N = 26). The majority lacked information about their children's biological family health history and ancestry, and many viewed WGS results as a way to fill in these gaps in knowledge. Some expressed concerns about protecting their children's future privacy and autonomy, but at the same time stated that WGS results could possibly help them be proactive about their children's health. A few parents expressed concerns about the risks of WGS in a pre-adoption context, specifically about decreasing a child's chance of adoption. These results suggest that issues surrounding genetic information in the post-adoption and ES/WGS contexts need to be considered, as well as concerns about risks in the pre-adoption context. A critical challenge for ES/WGS in the context of adoption will be balancing the right to know different kinds of genetic information with the right not to know. Specific guidance for geneticists and genetic counselors may be needed to maximize benefits of WGS while minimizing harms and prohibiting misuse of the information in the adoption process.
View details for DOI 10.1007/s10897-014-9738-z
View details for Web of Science ID 000348131000008
View details for PubMedID 25011977
Pathogenic Variants for Mendelian and Complex Traits in Exomes of 6,517 European and African Americans: Implications for the Return of Incidental Results
AMERICAN JOURNAL OF HUMAN GENETICS
2014; 95 (2): 183-193
Exome sequencing (ES) is rapidly being deployed for use in clinical settings despite limited empirical data about the number and types of incidental results (with potential clinical utility) that could be offered for return to an individual. We analyzed deidentified ES data from 6,517 participants (2,204 African Americans and 4,313 European Americans) from the National Heart, Lung, and Blood Institute Exome Sequencing Project. We characterized the frequencies of pathogenic alleles in genes underlying Mendelian conditions commonly assessed by newborn-screening (NBS, n = 39) programs, genes associated with age-related macular degeneration (ARMD, n = 17), and genes known to influence drug response (PGx, n = 14). From these 70 genes, we identified 10,789 variants and curated them by manual review of OMIM, HGMD, locus-specific databases, or primary literature to a total of 399 validated pathogenic variants. The mean number of risk alleles per individual was 15.3. Every individual had at least five known PGx alleles, 99% of individuals had at least one ARMD risk allele, and 45% of individuals were carriers for at least one pathogenic NBS allele. The carrier burden for severe recessive childhood disorders was 0.57. Our results demonstrate that risk alleles of potential clinical utility for both Mendelian and complex traits are detectable in every individual. These findings highlight the necessity of developing guidelines and policies that consider the return of results to all individuals and underscore the need to develop innovative approaches and tools that enable individuals to exercise their choice about the return of incidental results.
View details for DOI 10.1016/j.ajhg.2014.07.006
View details for Web of Science ID 000340076000005
View details for PubMedID 25087612
Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset
HUMAN MOLECULAR GENETICS
2014; 23 (8): 1957-1963
The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
View details for DOI 10.1093/hmg/ddt588
View details for Web of Science ID 000333269400001
Ethical implications of array comparative genomic hybridization in complex phenotypes: points to consider in research
GENETICS IN MEDICINE
2007; 9 (9): 626-631
As with many new diagnostic technologies, the recent rapid emergence of array comparative genome hybridization in clinical genetics provides the power to observe new biological phenomena before their clinical significance is well understood. This raises ethical issues for clinicians when applying the technologies. However, at this early stage of research and development on array comparative genome hybridization, the ethical implications of the conduct of research, as well as how research findings are presented and interpreted, should also be considered by the research, clinical, and ethics communities. These considerations are especially important in the use of array comparative genome hybridization to study complex and common traits. We examined recent publications on autism as an example of the application of array comparative genome hybridization to a complex phenotype. Our goal was to identify points to consider for researchers, clinicians, and patients/families to ensure responsible and ethical design, presentation, and interpretation of these kinds of studies.
View details for DOI 10.1097/GIM.0b013e3181485688
View details for Web of Science ID 000249640800010
View details for PubMedID 17873651
Candidate-gene approaches for studying complex genetic traits: practical considerations
NATURE REVIEWS GENETICS
2002; 3 (5): 391-A396
Association studies with candidate genes have been widely used for the study of complex diseases. However, this approach has been criticized because of non-replication of results and limits on its ability to include all possible causative genes and polymorphisms. These challenges have led to pessimism about the candidate-gene approach and about the genetic analysis of complex diseases in general. We believe that these criticisms can be usefully countered with an appeal to the principles of epidemiological investigation.
View details for DOI 10.1038/nrg796
View details for Web of Science ID 000175350000016
View details for PubMedID 11988764