Maren T. Scheuner

Can family history be used as a tool for public health and preventive medicine

Most common chronic diseases are the result of complex interactions between multiple genetic variants and environmental factors. Despite significant advances in the last decade in the understanding of our genome, there are substantial limitations in epidemiological and analytic approaches to studying the effects of genetic determinants of common chronic diseases. Knowledge of genetic variation underlying disease susceptibility should improve our ability to diagnose, manage, and prevent these disorders. To date, however, DNA-based testing is limited for the most part to analysis of highly penetrant single gene disorders that account for approximately 5% of the total disease burden in the population.1, 2 It may be years before DNAbased tests are routinely applied to predict the onset of common diseases, their natural history, and response to therapy.

Family history: A comprehensive genetic risk assessment method for the chronic conditions of adulthood

Targeting individuals with increased risk for common, chronic disease can improve the efficiency and efficacy of preventive efforts by improving the predictability of screening tests and participant compliance. Individuals with the greatest risk for these disorders are those with a genetic susceptibility. The purpose of this study was to determine the feasibility of using a single, comprehensive family history as a method for stratifying risk for many preventable, common genetic disorders. Family histories obtained in a prenatal diagnostic clinic were reviewed regarding cardiovascular diseases, diabetes and several cancers; 42.5% of individuals reported a family history for at least one of the disorders under study. Familial coronary artery disease was most commonly reported (29% of participants), followed by noninsulin-dependent diabetes (14%). Qualitative characterization of disease susceptibility was also accomplished using family history data. For example, occurrence of different cancers within pedigrees was suggestive of familial cancer syndromes, and clustering of noninsulin-dependent diabetes and cardiovascular disease suggested an insulin resistance syndrome. Depending on the specific disease, 5 to 15% of at-risk individuals had a moderately increased risk (2 to 5 times the population risk), and approximately 1 to 10% had a high risk (absolute risks approaching 50%). Family history reports of common, chronic disease are prevalent among the population at large, and collection and interpretation of comprehensive family history data is a feasible, initial method for risk stratification for many preventable, chronic conditions. These findings may have important implications for disease prevention and management.

Family History of Premature Coronary Heart Disease and Coronary Artery Calcification Multi-Ethnic Study of Atherosclerosis (MESA)

Background— A family history of premature coronary heart disease (CHD) is a known risk factor for CHD events. The purpose of this study was to assess the strength of the association between a family history of premature CHD and coronary artery calcification (CAC) in a multiethnic cohort of asymptomatic individuals. We also sought to determine whether individuals with a reported family history of premature CHD have an increased atherosclerotic burden among those classified as being at low to intermediate risk on the basis of the conventional Framingham risk score. Methods and Results— The association of family history of premature CHD with CAC was assessed in 5347 asymptomatic individuals (47% men; mean age 62±10 years) in the Multi-Ethnic Study of Atherosclerosis (MESA). The demographics (age, gender, and race)–adjusted OR for CAC >0 with versus without a family history of premature CHD was 1.94 (95% CI, 1.64 to 2.29). On adjustment for CHD risk factors, the association was slightly attenuated to an OR of 1.84 (95% CI, 1.55 to 2.19). Family history of premature CHD was significantly associated with CAC in all ethnic groups. The age-, gender-, and race-adjusted prevalence of CAC >0 was significantly higher with presence of any family history of premature CHD than for those with no family history of premature CHD among individuals classified as low risk (35% versus 23%, P<0.0001) and among those at intermediate risk (70% versus 60%, P=0.01). Similarly, the prevalence of age-gender-race–based CAC ≥75th percentile in low-risk (24% versus 14%, P=0.0003) and intermediate-risk (34% versus 20%, P<0.001) individuals was also higher among those with a family history of premature CHD. Compared with those without a family history of premature CHD, the association with the presence of CAC was strongest in participants reporting such history in both a parent and a sibling (odds ratio, 2.74; 95% CI, 1.64 to 4.59), followed by those reporting a family history in a sibling only (odds ratio, 2.06; 95% CI, 1.64 to 2.58) and those reporting a family history of premature CHD only in a parent (odds ratio, 1.52; 95% CI, 1.19 to 1.93). Conclusions— An association between family history of premature CHD and the presence of any CAC, as well as advanced CAC, was observed in the present population-based multiethnic study. The relationship was independent of other risk factors and Framingham risk score, which supports the utility of including information on family history of premature CHD in current methods of global risk assessment and practice guidelines.

Family history of type 2 diabetes: A population-based screening tool for prevention?

Purpose: To evaluate the use of self-reported family medical history as a potential screening tool to identify people at-risk for diabetes.Methods: The HealthStyles 2004 mail survey comprises 4345 US adults who completed a questionnaire to ascertain personal and family history of diabetes, perceived risk of diabetes, and practice of risk-reducing behaviors. Using number and type of affected relatives, respondents were ranked into three familial risk levels. Adjusted odds ratios (AORs) were obtained to evaluate associations between familial risk and prevalent diabetes, perceived risk of disease, and risk-reducing behaviors. Validity of family history as a screening tool was examined by calculating sensitivity, specificity, and positive and negative predictive values.Results: Compared to those of average risk, people with moderate and high familial risk of diabetes were more likely to report a diagnosis of diabetes (AOR: 3.6, 95% CI: 2.8, 4.7; OR: 7.6, 95% CI: 5.9, 9.8, respectively), a higher perceived risk of diabetes (AOR: 4.6, 95% CI: 3.7, 5.7; OR: 8.5, 95% CI: 6.6, 17.7, respectively), and making lifestyle changes to prevent diabetes (AOR: 2.2, 95% CI: 1.8, 2.7; OR: 4.5, 95% CI: 3.6, 5.6, respectively). A positive familial risk of diabetes identified 73% of all respondents with diabetes and correctly predicted prevalent diabetes in 21.5% of respondents.Conclusion: Family history of diabetes is not only a risk factor for the disease but is also positively associated with risk awareness and risk-reducing behaviors. It may provide a useful screening tool for detection and prevention of diabetes.

Implementing screening for Lynch syndrome among patients with newly diagnosed colorectal cancer: summary of a public health/clinical collaborative meeting

Lynch syndrome is the most common cause of inherited colorectal cancer, accounting for approximately 3% of all colorectal cancer cases in the United States. In 2009, an evidence-based review process conducted by the independent Evaluation of Genomic Applications in Practice and Prevention Working Group resulted in a recommendation to offer genetic testing for Lynch syndrome to all individuals with newly diagnosed colorectal cancer, with the intent of reducing morbidity and mortality in family members. To explore issues surrounding implementation of this recommendation, the Centers for Disease Control and Prevention convened a multidisciplinary working group meeting in September 2010. This article reviews background information regarding screening for Lynch syndrome and summarizes existing clinical paradigms, potential implementation strategies, and conclusions which emerged from the meeting. It was recognized that widespread implementation will present substantial challenges, and additional data from pilot studies will be needed. However, evidence of feasibility and population health benefits and the advantages of considering a public health approach were acknowledged. Lynch syndrome can potentially serve as a model to facilitate the development and implementation of population-level programs for evidence-based genomic medicine applications involving follow-up testing of at-risk relatives. Such endeavors will require multilevel and multidisciplinary approaches building on collaborative public health and clinical partnerships.Genet Med 2012:14(1):152–162

Familial risk assessment for early-onset coronary heart disease

Purpose: We examined the performance of a familial risk assessment method that stratifies risk for early-onset coronary heart disease by considering the number of relatives with coronary disease, degree of relationship, lineage, and age at diagnosis.Methods: By using data from the HealthStyles 2003 survey, we assessed the associations between familial risk and early-onset coronary heart disease, diabetes, hypercholesterolemia, hypertension, and obesity. By using area under the curve statistics, we evaluated the discriminatory ability of various risk assessment models.Results: Of 4035 respondents, 60% were female and 72% were white, with a mean age of 48.8 years. After adjustment for demographics, strong and moderate risk were significantly associated with approximately a five- and twofold risk of early-onset coronary disease, respectively. After adjustment for demographics and personal history of cardiovascular disease, strong familial risk was also significantly associated with diabetes, hypercholesterolemia, hypertension, and obesity. A risk assessment model that included familial risk, demographics, and personal history of diabetes, hypercholesterolemia, hypertension, and obesity was most optimal with an area under the curve statistic of 87.2%Conclusions: Familial risk assessment can stratify risk for early-onset coronary heart disease. Several conditions associated with increased familial risk can be prevented. These results have important implications for risk assessment and risk-reducing interventions.

Are electronic health records ready for genomic medicine

Purpose: The goal of this project was to assess genetic/genomic content in electronic health records.Methods: Semistructured interviews were conducted with key informants. Questions addressed documentation, organization, display, decision support and security of family history and genetic test information, and challenges and opportunities relating to integrating genetic/genomics content in electronic health records.Results: There were 56 participants: 10 electronic health record specialists, 18 primary care clinicians, 16 medical geneticists, and 12 genetic counselors. Few clinicians felt their electronic record met their current genetic/genomic medicine needs. Barriers to integration were mostly related to problems with family history data collection, documentation, and organization. Lack of demand for genetics content and privacy concerns were also mentioned as challenges. Data elements and functionality requirements that clinicians see include: pedigree drawing; clinical decision support for familial risk assessment and genetic testing indications; a patient portal for patient-entered data; and standards for data elements, terminology, structure, interoperability, and clinical decision support rules. Although most said that there is little impact of genetics/genomics on electronic records today, many stated genetics/genomics would be a driver of content in the next 5–10 years.Conclusions: Electronic health records have the potential to enable clinical integration of genetic/genomic medicine and improve delivery of personalized health care; however, structured and standardized data elements and functionality requirements are needed.

Expanding the definition of a positive family history for early-onset coronary heart disease

Purpose: Assessing familial risk for early-onset coronary heart disease (CHD) is typically limited to first-degree relatives with early-onset CHD. To evaluate the impact of additional family history, we examined the associations between various family history definitions and early-onset CHD.Methods: By using the national HealthStyles 2003 survey data, we assessed associations between self-reported family history and personal history of early-onset CHD (diagnosed at or before age 60 years), adjusting for demographics, hypercholesterolemia, hypertension, and obesity.Results: Of 4035 respondents, 60% were female and 72% were white, with a mean age of 48.8 years; 4.4% had early-onset CHD. In addition to having at least one first-degree relative with early-onset CHD, other significant associations included having at least one first-degree relative with late-onset CHD, at least one second-degree relative with early-onset CHD, and two or more affected second-degree relatives regardless of age of onset of CHD. Early-onset stroke in at least one first-degree relative and, in women, having at least one first-degree relative with diabetes were also significantly associated with early-onset CHD.Conclusions: Family history beyond early-onset CHD in first-degree relatives is significantly associated with prevalent CHD diagnosed at or before age 60 years.

Genetic evaluation for coronary artery disease

There is substantial evidence that genetic factors contribute to coronary artery disease (CAD). Currently, family history collection and interpretation is the best method for identifying individuals with genetic susceptibility to CAD. Family history reflects not only genetic susceptibility, but also interactions between genetic, environmental, cultural, and behavioral factors. Stratification of familial risk into different risk categories (e.g., average, moderate, or high) is possible by considering the number of relatives affected with CAD and their degree of relationship, the ages of CAD onset, the occurrence of associated conditions, and the gender of affected relatives. Familial risk stratification should improve standard CAD risk assessment methods and treatment guidelines (e.g., Framingham CAD risk prediction score and Adult Treatment Panel III guidelines). Individuals with an increased familial risk for CAD should be targeted for aggressive risk factor modification. Individuals with a high familial risk might also benefit from early detection strategies and biochemical and DNA-based testing, which can further refine risk for CAD. In addition, individuals with the highest familial risk might have mendelian disorders associated with a large magnitude of risk for premature CAD. In these cases, referral for genetic evaluation should be considered, including pedigree analysis, risk assessment, genetic counseling and education, discussion of available genetic tests, and recommendations for risk-appropriate screening and preventive interventions. Research is needed to assess the feasibility, clinical validity, clinical utility, and ethical, legal, and social issues of an approach that uses familial risk stratification and genetic evaluation to enhance CAD prevention efforts.

Contribution of Mendelian disorders to common chronic disease: Opportunities for recognition, intervention, and prevention

Recognizing Mendelian disorders should improve health care for persons with strong familial risks for common chronic diseases. The Online Mendelian Inheritance in Man (OMIM) database was reviewed to identify Mendelian disorders featuring 17 common chronic diseases, including 9 cardiovascular conditions, diabetes, and 7 common cancers. Mendelian disorders were selected if any one of the 17 diseases was reported in more than two families manifesting in adulthood. Patterns of chronic diseases and modes of inheritance associated with these Mendelian disorders are described. The GeneTests/Reviews database and other websites were reviewed to determine availability of genetic testing and management and prevention recommendations for the selected disorders. Of 2,592 (OMIM) entries reviewed, 188 Mendelian disorders were selected. Most (67.7%) are autosomal dominant disorders. Almost half (45.8%) feature combinations of the chronic diseases under study. At least one gene is known for 68.8% of the selected disorders, and clinical genetic testing is available for 55% of disorders. Guidelines for management and prevention are available for 33.9% of these, ranging from recommendations for supportive care to guidelines for managing affected persons and screening relatives. Significant clinical heterogeneity exists for Mendelian disorders that might present as strong family histories of common chronic diseases. Recognition of the different combinations of diseases within a pedigree, including mode of inheritance and heritable disease risk factors, facilitates diagnosis of these Mendelian disorders. Genetic testing is available for most disorders, which can further clarify the genetic risk, and for some, recommendations for management and prevention are available. However, evidence‐based guidelines are needed.