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Applying Genomics to Clinical Problems-Diagnostics, Preventive Medicine, Pharmacogenomics

A white paper for the National Human Genome Research Institute

Submitted by: David Valle, M.D., and Teri Manolio, M.D., Ph.D.
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Although the path from gene discovery to effective clinical applications is long and challenging, improved health is a major goal of genomic research. Development and clinical validation of genetic tests requires translation from basic science discoveries, assessment of what these advances add to currently available clinical resources and whether incorporation of any new test is justified by the strength of its benefits as compared to potential risks. In addition, test availability, potential for reimbursement, and cost-effectiveness must be considered. Benefits of enhanced prediction must also be weighed against the potential burdens of this knowledge, and the availability of effective interventions. Clinicians and patients must be educated in how best to apply genetic knowledge.

We anticipate that genetic information will allow better targeting (that is, in whom to intervene) and tailoring (how best to intervene) of preventive efforts, but the advantages of population-wide vs. high-risk preventive strategies also depend on disease prevalence and the role of other major risk factors. Valid comparisons of these strategies will require rigorous clinical investigation that may take years to complete for chronic diseases of late onset or long duration. Drug selection informed by pharmacogenetics will similarly require clinical studies to provide evidence for its benefits before wide acceptance can be expected. Strategies are needed for addressing these and other potential challenges, as are approaches for speeding the delivery of this information and ensuring that its benefits are available to all members of our society.

Applying genomic discoveries to clinical problems thus raises several key questions:

1. What do new genetically-based diagnostic or risk assessment strategies add to the existing medical armamentarium?

Genetic variants that are common often confer only low or modest risk. Where will we set the boundary for risk too low to be clinically efficacious? What can we do to understand how risk influences how physicians and patients think and act? Under what circumstances might less common variants be more valuable for identifying high-risk persons? How might other characteristics of the associated variant aside from frequency, such as magnitude of the odds ratio, penetrance, or genetic model, influence the importance of a variant for identifying persons at risk?

Must effective interventions be available to modify risk in order for a variant to be of value? How, if at all, might knowledge of immutable disease risk be useful to patients or clinicians?

Current thinking tends to focus on a single risk variant when in reality each individual has a constellation of many variants, some risky and some protective. How do we integrate the sum of these variants and use them to think about environmental variables and advise patients accordingly?

How should the value of new genetic information be assessed in the context of standard clinical information (some of which is genetic) such as age, sex, and family history? Should the availability or ease of obtaining standard clinical vs genetic information be a factor in deciding when to use genetic information? How we make genetic information more available and in a timely fashion? Might genetic risk information be more valuable in conditions where few other risk factors have been identified? If so, should such conditions be targeted for identification of genetic risk factors?

Should the bar for judging incremental additional information to be worthwhile be higher for genetic variants than for non-genetic tests? Do patients and clinicians (rightly or wrongly) perceive genetic information to be more determinative and potentially stigmatizing, and if so, should that affect where this bar might be placed? Should current limitations on access to such testing affect this judgment?

2. What information will be needed or required by payers to convince them to reimburse genetically-based testing strategies, so that financial barriers to their application can be minimized?

What types of evidence are likely to be most persuasive to payers? How useful might evidence be that genetic testing leads to reduced healthcare costs? Is it realistic to argue that an increasingly preventative form of medicine based on up front genetic testing and risk assessment will actually reduce health care costs. How can such an evaluation be obtained in a reliable and timely way? Must proven interventions be available to justify testing? How useful might other types of data be, such as demonstrating reduced morbidity and mortality following use of genetic testing?

How can costs of testing be kept low? How can cost-effective arrangements be made for obtaining proprietary tests that are currently out of reach of most consumers and payers?

What strategies are needed to ensure that future genetic discoveries lead to affordable tests? How can the intellectual contributions to their discovery be appropriately recognized and developmental costs reimbursed while keeping costs within reach?

3. How will patients and clinicians respond to information regarding individualized genetic risk and what strategies and resources will be most effective in educating them to maximize health benefits and minimize potentially negative aspects such as stigmatization and anxiety?

What factors might make patients more likely to be swayed by claims of benefit of individualized testing? What impact do factors like a strong family history of disease have on patients' desire to identify and reduce their risk? Do these factors and their impact differ by patient characteristics such as age, sex, race/ethnicity, or socioeconomic status?

What types of evidence are most likely to influence clinicians? Given that both groups may insist on tests that are available, affordable, and interpretable, what characteristics of physicians or the patient population they care for might influence the extent to which they adopt genetic testing?

What types of educational models will work for the very different audiences of patients and clinicians? How can materials be prepared that are straightforward and time-efficient to use? To what extent should web-based resources be developed? Who should take responsibility for their accuracy and objectivity, ensuring that they neither over-represent the benefits nor minimize (nor exaggerate) potential risks?

What approaches can be developed to help clinicians presented with genome-wide genotyping obtained independently by their patients to use this information to deliver clear and effective health advice? How can clinicians capitalize on the "teachable moment" such patient-acquired testing may provide for emphasizing proven but underutilized preventive strategies?

4. What information will convince clinicians to apply genetically-based testing strategies to their patients, and what tools for decision support or patient management will encourage that choice?

How can information on genetic-testing strategies be made most useful to clinicians facing nearly overwhelming patient-care responsibilities and information overload?

What are the best strategies for providing this information to clinicians? Can the model of "GeneTests"-like 90-second summaries of benefits and risks be extended from Mendelian disorders to common, complex diseases? Would an approach that depends on existing resources such "UpToDate" be utilized? How can specific information on obtaining testing in a given clinical location or system be provided to clinicians?

What are the best strategies for providing this information to patients? What types of information delivery are likely to be most useful or effective? How might these differ by age or other demographics?

What are the benefits and risks of linking this information to electronic medical records, such as targeted prompting to identify appropriate patients to test? What on-line information and tools for might enhance their use?

5. What special approaches to genetically-based diagnostic and prevention strategies may be needed in special populations (such as prostate cancer in African-Americans) or high-risk groups (such as workers with benzene exposure)?

What impact might past misuses of genetic information and frank misinformation to stigmatize minority groups have on adoption of testing? How can potential skepticism among minority patients and clinicians about conclusions drawn from such data be addressed?

What impact might potential use of genetic information by law enforcement and similar agencies to target minorities have on testing, and how can this best be addressed in future clinical testing?

Could the possibility that "genetic explanations" for individual variation in sensitivity to toxin-mediated diseases may minimize or eliminate potential benefits to persons with high-risk occupational or residential exposures present an obstacle to testing? How might compensation and other damage-related claims be effectively separated from efforts to screen and treat exposed individuals with genetic predispositions to harmful exposures?

What is the risk that genetic strategies might be perceived as being applied to special populations in preference to more effective testing and preventive strategies to which they have had limited or no access in the past? How can improved access to genetic strategies and interventions required in follow-up be assured for population subgroups with limited past access?

What special considerations might be needed in special populations, such as tailoring interventions to be culturally appropriate or adding protections for confidentiality?

6. What information on prevalence, risk, modifiability, etc will be needed for clinicians and patients to understand and utilize genome sequence information, once it becomes widely available in diagnosis, prevention, and treatment?

What special challenges might be presented by sequence information? How can patients and clinicians best be counseled on the implications of newly-discovered variants?

How can the potential effects of very rare variants on health and well-being be assessed given that large numbers of persons with the variant will not be available for study? What priorities should be placed on the search for such phenotypic effects in an individual patient, and how can such priorities take into account conditions that are important to that patient or his/her family?

How should factors such as modifiability of any adverse effects or abnormalities found or cost and potential stigma involved in identifying them affect these priorities? How can information on patient preferences be captured for research purposes and optimally used for developing additional genetic testing strategies?

How can clinicians be better prepared to respond to individual patients who obtain sequence information (or extensive genotyping information) independently and present it to their clinicians with concerns about the health impact of newly-found variants? How can resources for addressing such concerns be best developed? What role, if any, should facilities providing the sequencing (or genotyping) services play in developing this information? What mechanisms or oversight might be needed to ensure that information provided is valid and consistent across multiple facilities?

7. What is the impact of receiving results of direct-to-consumer (DTC) genome-wide screening on patients' health behaviors, reproductive choices, quality of life, and long-term planning?

Why do "early adopters" of DTC genomic testing seek such testing? What is the decision-making process for them and their families? What sources of information do they use for selecting and interpreting the tests? How, if at all, do their health and well-being change after the testing? What actions do they take in response to their genetic information and what is the outcome of these actions?

What opportunities for research might be presented by the actions of these early adopters? How can they become engaged in research? What biases might be involved in such a group and how can they be addressed?

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Last Reviewed: March 15, 2012