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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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Improved health is a major goal of genomic research. The path from gene discovery to clinical application, however, is long and challenging. Development of clinically validated genetic tests requires translation from basic science discoveries, assessment of possible benefits as compared to currently available clinical resources and determination if incorporation of any new test is justified by comparison of its benefits to its risks. Additionally, test availability, potential for reimbursement, and cost-effectiveness must be considered. Also, for presymptomatic tests, benefits of enhanced prediction including the availability of effective interventions must be weighed against the potential burdens of this knowledge. Finally, clinicians and patients must educated in the use and meaning of any new genetic tests.

We are confident that new, clinically validated genetic information will enable better targeting (that is, in whom to intervene) and tailoring (how best to intervene) of preventive efforts. The potential advantages of population-wide vs. individual, high-risk preventive strategies depends on disease prevalence and the role of other major risk factors. Despite claims of efficacy from direct-to-consumer testing services and others, valid comparisons of these strategies will require rigorous clinical investigation that may take years to complete especially in the case of diseases of late onset or long duration.. Similarly, a role for pharmacogenetics in informing drug selection will require clinical studies to provide evidence for its benefits before wide acceptance can be expected. Strategies for addressing these and other challenges, including approaches for speeding the development and validation of this information and ensuring that its benefits are available to all members of our society are essential to optimize the potential benefits of genomic research for human health.

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?

Medical decision-making and patient acceptance of genetic information is strongly influenced by perception of risk. Common genetic variants affecting fitness often confer only low or modest risk. How do we evaluate these risks and when do we decide the risk is too low to be clinically efficacious? What variables should be considered in making these decisions? How can we improve our understanding of how the perception of risk influences the way clinicians and patients think and act and how can we make sure that these perceptions are based on sound epidemiological, genetic and biological principles? Under what circumstances might less common variants be more valuable for identifying high-risk persons? How might other characteristics aside from frequency of the associated variant, such as magnitude of the odds ratio, penetrance, or genetic model, influence the importance of a variant for identifying persons at risk? What biological mechanisms influence the sensitivity, specificity, and predictive value of genetic test results?

Must effective interventions to modify risk be available in order for a variant to be of medical value? How, if at all, might knowledge of immutable disease risk be useful to patients or clinicians? When is it necessary to perform randomized trials to determine whether genetically-based strategies improve patient outcomes or public health?

Current thinking tends to focus on a single risk variant when in reality each individual has a constellation of many variants, some that increase disease risk and some that reduce it. How do we integrate the sum of these variants so that we can use them to think about environmental variables, communicate them clearly and usefully, and advise patients accordingly?

How should approaches to testing for single-gene Mendelian disorders differ from those for complex disorders? What aspects are similar between the two, and which differ?

How should the value of new genetic information be assessed in the context of standard clinical information 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 can 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? How can we define the contexts in which genetic testing is most important, useful, and cost-effective? What is most likely to be useful in the next few years vs a much longer time horizon?

Should the bar for judging the value of additional information 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?

What additional quality assurance standards may be needed for clinical genetic testing and how can they best be implemented and monitored?

What special considerations might be needed for genomic-related information aside from germline DNA sequence variation, such as tissue-specific genotyping or sequencing, gene expression, epigenetics, or microbiomic data, especially those that might be affected by pharmaceutical or other treatment? Given that such information is often more dynamic than the static DNA sequence, how can decisions best be made as to how often to obtain this information and use it to understand disease course in a given patient? What additional considerations might be needed for variants whose effects are modified by environmental factors or are different at different stages of development?

2. What information will influence payers in decisions to reimburse genetic testing strategies, so that financial barriers to their application can when appropriate be minimized?

What types of evidence are most likely to influence payers? How different might these decisions be for genetic vs other clinical testing and for preventive vs diagnostic testing and therapeutic interventions?

How useful might evidence be that genetic testing leads to reduced healthcare costs? How influential might information on the potential cost of an unrecognized, untreated condition, including malpractice claims, be in motivating support for genetic testing and documentation of genetic counseling? 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 made 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, including associated costs of interpretation and education, be kept low? How can cost-effective arrangements be made for obtaining proprietary tests that are currently too expensive for most consumers and payers?

How might access to testing and reimbursement differ between federally- funded health pans (Medicare, Veterans Administration, etc) and private payers? How can appropriate access to new genetically-based tests be ensured for all patients regardless of type of health care coverage?

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? What central laboratory resources and strategies are needed for research to identify the functional biological mechanisms conferring susceptibility to disease and the clinical applications of this research?

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 make rational choices when faced with claims of benefit of individualized testing? What impact do factors like a strong family history of disease, perceived ability to modify risk, or type and severity of the condition have on patients' desire to identify and reduce their risk? Do these factors and their impact differ according to patient characteristics such as age, sex, race/ethnicity, socioeconomic status, or physical or social environment? What is the influence of genetic test results in effecting patient behavior change compared to information from family history, other laboratory measures, epidemiologic data and other current medical tools? How can the potential for stigmatization and anxiety among patients and/or family members be reduced?

What types of evidence are most likely to be meaningful to clinicians? How will they consider costs of testing or recommendations from colleagues in their decision-making? Given that clinicians and patients may insist on tests that are available, affordable, and interpretable, what characteristics of clinicians or the patient populations 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? What types of educational models will work for school children and young adults to enable them to make reasonably informed decisions for their own health? How can educational tools be tailored so they are culturally appropriate for ethnically-diverse patient populations, including non-English speaking patients? What educational tools have already been developed that could serve as models? 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 genotype results obtained independently by their patients to evaluate and incorporate this information in the delivery of 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 influences clinicians in utilizing genetically-based test information for their patients, and what tools for decision support or patient management will facilitate those choices?

How can information on genetic-testing strategies be made most useful to clinicians facing nearly overwhelming patient-care responsibilities and information overload? What will be the impact of ordering and interpreting genetic tests and discussing results with patients on clinicians' workflow? What information might be needed for implementing "pay for performance" strategies for genetic testing and what would be the advantages and disadvantages of doing so?

What are the best strategies for providing genetic testing information to clinicians with little formal training in genetics? Can the model of "GeneTests"-like 90-second summaries of benefits and risks be extended from Mendelian disorders to common, complex diseases? How useful is the GeneTests model in Mendelian disorders and how might it be improved? 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? How will clinicians know when to refer patients to a genetic specialist?

What are the best approaches for developing guidelines for clinical use of genetic testing and what is the appropriate role of the major stakeholders (patients, clinicians, payers, etc) in developing guidelines? How should models of evaluative, evidence-based medicine such as ACCE and EGAPP be incorporated in guideline development and clinician decision-making?

What are the best strategies for providing genetic testing information to patients? What methods of information delivery are likely to be most useful or effective? How might these differ by age or other demographics? How can clinicians best explain probability or statistical data to patients, and how can such explanations be improved and/or tailored to patient characteristics such as socioeconomic or educational status?

What are the best strategies for providing genetic testing information to family members and facilitating their getting tested if they choose to do so? What information can or should be given to a family member who does not have the familial genotype that has been associated with the familial disease?

How might databases of mutations causing single gene disorders aid clinicians in applying genetically-based testing strategies and aiding patients in interpreting the results?

What are the benefits and risks of linking genetic testing 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? What are the implications for clinical informatics needs (storage, presentation, linking, prompting) for these massive amounts of data and how can these be met most efficiently? In addition to the patient and their physician, who should have access to this information and what are the implications of that access?

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?

How do different ancestral backgrounds or environmental exposures affect the impact of disease-associated variants, and how should these differences be taken into account in clinical genetic testing?

What role should or will patient race/ethnicity play in clinicians' decisions to conduct genetic tests? Will specific genetic tests be targeted at patients of particular ethnicities, and if so, how will clinicians determine patient ethnicity? Is there a risk of inappropriate racial/ethnic profiling in the application of new genetic tests in clinical settings? If so, how can this risk be mitigated?

What impact might potential use of genetic information by law enforcement and similar agencies to target minorities have on patient acceptance of 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 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?

What special considerations might be needed for genetic testing of children, pregnant women, or persons of reproductive age and for implementation of interventions in these groups? How can valid research in genomics, epigenomics, and pharmacogenomics among these groups be appropriately promoted?

6. What information on prevalence, risk, modifiability, etc will be needed for clinicians and patients to understand and utilize genome sequence information 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 will patient "populations" be defined for determination of prevalence, risk, etc.? What are the potential benefits and risks of using race/ethnicity to define patient "populations," and how might these differ for highly-penetrant diseases with Mendelian inheritance versus chronic diseases with multifactorial causes?

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? Given that many variants of unknown significance will be identified, how can that information be most usefully presented to patients and clinicians?

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 and "resilient genomes" (persons identified as genetically susceptible who do not develop disease) be captured for research purposes and optimally used for developing additional genetic testing strategies?

How can the non-directive ideal of genetic counseling be integrated with the more directive world of clinical medicine? How do patients and clinicians view the non-directive approach and are there special situations in which it is or is not appropriate?

Should future genetic testing strategies be entirely clinician-dependent or is there a role for direct access by patients and the public? 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 doctors with concerns about the health impact of newly-identified 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?

To what degree should funding agencies and/or those holding patents on genetic tests support reduced costs or cost-free testing for "rare" diseases, coordination of guidelines on genetic testing, and educational programs for patients and clinicians? How can costs of testing and appropriate interventions be supported for all those likely to be in need?

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? Do changing views on privacy influence the acquisition and utilization of such information?

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?

How should the public be informed of the available evidence (or lack thereof) to support the validity of direct to consumer DNA testing?

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Last Reviewed: March 19, 2012