Human Genome Epidemiology (2nd ed.): Building the evidence for using genetic information to improve health and prevent disease
necessarily represent the views of the funding agency.”
Rodolfo Valdez, Muin J. Khoury, and Paula W. Yoon
With the advent of molecular genetics, the accelerated mapping of human genes to specific chromosome locations was made possible without the use of detailed pedigrees. Moreover, following the sequencing of the human genome, new techniques now allow for the scanning of entire genomes in search of genes or gene markers associated with a given trait, regardless of the pattern of inheritance. Among these major advances, however, it is not likely that an instrument as useful as family history will be rendered obsolete as a genomic tool. In this chapter we will argue not only that the use of family history will continue to be valid in clinical settings, but also that family history is poised to become a tool of widespread use in public health settings. Since our emphasis will be on the latter argument, we will address the clinical aspects of family history briefly.
Family History in the Clinical Setting
A well-documented family history for a suspected genetic condition should include a standard pedigree with three generations of relatives, age and sex of each relative, age at onset of the condition for the affected relatives, and age at death and cause of death for the deceased relatives. Complementary information could include ethnic background, adoption, consanguinity, and reproductive history. Such information is rich in clinical applications (1). For example, it could help
- establish the genetic nature of a condition and its pattern of inheritance
- identify healthy family members at risk and to estimate their risk for a condition
- diagnose some conditions
- decide on type and frequency of screening and diagnostic tests
- anticipate the development and decide on the management of a condition
- assess the probability that future family members will inherit a condition
- educate patients and their relatives about the probabilistic nature of genetic inheritance and the influence of environmental factors on inherited conditions.
These applications of family history in the clinical setting will gain even more importance as the discovery of new genes and phenotypes accumulates at a rapid pace. For example, the pattern of inheritance of all these new genes and phenotypes will surely need clarification and family history is a great tool for this task. Genes spread through families and their expression is ultimately affected by the environment shared by family members. The timely collection, interpretation, and translation of family history information into routine health care practice will be the domain of clinical genetics for the foreseeable future.
Family History in the Public Health Setting
Family History Captures the Joint Effect of Genes and Environment on Phenotypes
Several diseases of great public health importance for their high prevalence in the general population are thought to have a genetic component; however, they do not seem to follow Mendelian patterns of inheritance. And even if they did, the number of genetic loci involved would make it extremely difficult to discern these patterns. Moreover, additional genetic and nongenetic factors (i.e., gene–gene and gene– environment interactions) may compound the difficulty of unveiling these already intricate patterns. The high level of difficulty, however, has not deterred efforts to bring to light the genetic component of major diseases such as cancer, heart disease, diabetes, and many other chronic diseases. Almost daily there are scientific reports of genes or genetic markers found associated with a major disease. Furthermore, meta-analyses and systematic reviews begin to show some consistency among a few gene–disease associations that have been replicated. But for major chronic diseases like diabetes, the effect sizes of these associations remain small, and therefore of uncertain utility in public health (2).
Family health history can be the tool of choice as a first step toward examining the role that genes and environment play in the emergence of complex conditions in populations. Complex conditions that result from the interaction of genes and environment are more likely to concur among close relatives for several reasons: first, close relatives share a substantial proportion of their genes; second, close relatives might have been exposed to the same environment for prolonged periods of their lives; third, shared family life and culture bring the opportunity to acquire and practice long-lasting habits and behaviors that ultimately may affect health.
The observation that the risk for a condition is elevated among the close relatives of a person already affected with that condition has broad practical applications in public health. For example, the collection of family history from index cases became a very important tool to track and control infectious disease outbreaks early in the past century (3). Hence, the knowledge of the familial aggregation of a condition may help to control it, even when the mechanism of transmission is unknown.
Family History as a Risk Assessment Tool
A large and growing body of evidence indicates that family history can in fact be counted as a risk factor that is significantly and independently associated with several diseases of public health importance (specific examples will be discussed later in this chapter). However, the widespread use of family history in preventive medicine has been hindered by several factors, which include difficulty in allocating time to collect the information during visits to health care providers, inadequate systems for data collection and decision support, limited knowledge and skill among health care personnel for interpreting family histories and for counseling patients according to their familial risk, and unclear reimbursement policies (4).
In our opinion, a major obstacle for the widespread use of family history in public health is the lack of a standard approach to define familial risk. A good definition should convey properly the health risks associated with having relatives affected with a condition. More often than not, family history is casually defined in epidemiologic studies as a dichotomous variable (positive/negative) depending on the presence or absence of one or more affected individuals among the close (first- or second-degree) relatives of a healthy patient or proband. To fully realize the potential of family history as a public health tool, a more systematic approach to risk assessment is necessary. At a minimum, a family history collected to assess familial risk for a condition should include the following (5)
- the type and degree of relationship among family members (pedigree)
- age and sex of each relative
- age at diagnosis for each family member affected with the condition
- age, cause, and date of death if the relative has died
- ethnicity and ancestry may be important in some cases
- chronic habits and behaviors that might influence health among relatives.
There are tools designed to assess familial risk based on this type of information. The next step, their implementation in public health settings, should be subjected to the same standards required for genetic tests and other well-established risk assessment tools. The current standards are known as the ACCE framework, first designed to assess the benefits and risks of genetic tests (6). This framework includes four elements to be evaluated: (i) analytical validity (ability to identify the true health status); (ii) clinical validity (ability to accurately predict disease status); (iii) clinical utility (capability of motivating positive changes in health care systems and personal behaviors); and (iv) ethical, legal, and social issues (see Chapter 24).
Family History as a Risk Factor
In the next section we will present ample, current evidence supporting the association between family history and the risk of several major chronic diseases. Even though this evidence is highly suggestive of a distinct genetic influence on these diseases, it is virtually impossible to distinguish the genetic from the environmental contributions to the development of these diseases. In any case, most studies were not designed to test the independence of these contributions.
In addition, family history has been used to detect preclinical signs of some diseases. Table 29.1 presents examples of studies that report physiological alterations, which may lead to chronic disease, among healthy individuals with diseased relatives. Despite differences in the definitions of family history, the implication that family history can detect early signs of disease is clear. And the public health implications of such detection are promising, as early detection is a desirable goal in disease prevention.
Recent Epidemiologic Findings Using Family History
Family history, alone or in combination with other risk factors, can identify individuals and families who are at increased risk for chronic diseases. Ultimately, we believe, family history can play a role in the prevention and management of common chronic diseases through risk assessment in populations and interventions in high-risk groups. The assessment of familial risk can be the basis for recommendations that may include lifestyle changes, screening, chemoprevention, and genetic testing (16). For example, the United States Preventive Services Task Force (USPSTF) has issued recommendations based on relevant family history. These recommendations include screening and the adoption of certain behaviors to prevent breast cancer, colorectal cancer, dyslipidemias, cardiovascular disease, and abdominal aortic aneurysm (17).
Epidemiologic evidence indicates that family history is a significant and prevalent risk factor for many common diseases such as cardiovascular disease (CVD), type 2 diabetes, and cancer. One of the first population-based studies to examine the association between family medical history and cardiovascular disease was the Health Family Tree Study in Utah (18). This study showed not only that family history of coronary heart disease (CHD) and the occurrence of the disease were strongly related but, perhaps more importantly, that the disease and associated risk factors were clustered in a small proportion of families (high risk). Data from 122,155 families showed that 72% of early onset cases of CHD (aged < 55 years) in the population was concentrated in just 14% of all families. Likewise, 86% of cases of early onset stroke was concentrated in just 11% of families. In the 20 years since findings from the Utah study were first reported, hundreds of papers have been published on the association between family history and CVD and the use of family history for predicting disease (19). Recent studies have focused on determining which characteristics of family history contribute most to the risk increase (e.g., number of affected relatives, lineage, age of onset, type of relative). Many studies have shown that the association gains strength as the number of affected first-degree relatives increases (20–22) and the age at onset of the disease decreases (22–25). Interestingly, several studies have shown that having a sibling with CVD may confer a greater risk for the disease than having an affected parent (20,26,27). For example, data from the Framingham Offspring Study, a prospective study with validated CVD events, indicate that having a sibling with CVD resulted in greater risk for the disease (OR = 2.0) than having an affected parent (OR = 1.5), even after adjusting for age and traditional risk factors (26).
Less is known about stroke and family history, although several studies have shown increased risk for stroke associated with having parents and other first-degree relatives with the disease (28–35). It has been reported that having a first-degree relative diagnosed with any vascular event before age 65 years was associated with a two-fold increased risk of ischemic stroke (35). In a case-control study of women aged 18–44 years, the risk of hemorrhagic or ischemic stroke was double for the cases with parental or sibling history of stroke (32). Another study, using a three-tiered familial risk stratification method, found that people in the high familial risk stratum were about four times more likely to report having had a stroke compared to people in the moderate and average risk strata, independently of demographic factors and other health conditions (36). Among patients who suffered a transient ischemic attack, family history of stroke and family history of myocardial infarction were associated with hypertension (37). Hypertension is one of the strongest risk factors for stroke and has been found to aggregate in families (38–40). Despite the epidemiologic evidence that family history of stroke is an independent risk factor for stroke, its use for risk assessment, alone or in combination with other risk factors such as hypertension, has been limited.
Recent research on the association of family history of CHD and the risk for the disease supports the use of family history in the detection of intermediate phenotypes or subclinical signs of disease. The Johns Hopkins Sibling study identified asymptomatic women aged 30–59 years who were the sisters of women hospitalized with premature CHD (41). Framingham global coronary risk scores were then calculated for the asymptomatic sisters. Ninety-eight percent of these women were classified as low risk, but one out of three of them had significant coronary atherosclerosis based on their coronary artery calcification (CAC) scores. Similarly, among asymptomatic individuals enrolled in the Multi-Ethnic Study of Atherosclerosis, a significant association, which varied by type of relative, was found between family history and CAC (42). The association was strongest in participants reporting a family history in both a parent and a sibling (OR = 2.7), followed by a sibling only (OR = 2.1), and a parent only (OR = 1.5). This type of evidence has led to the modification of existing risk algorithms to add family history and other novel risk factors (43,44). For example, a modified version of the Framingham Risk Score, the Reynolds Risk Score, includes the usual risk factors plus parental history of early myocardial infarction (age < 60 years) and C-reactive protein, an inflammatory marker. When applied to a cohort of healthy women aged 45 years and older who had been followed up for 10 years, the Reynolds score greatly improved the accuracy of the risk estimation compared to the current ATP-III prediction scores. Nearly 50% of the women classified at intermediate risk by the ATP-III scores were more accurately reclassified into the higher and lower risk categories by the Reynolds score. Obviously, more validation needs to be done for risk algorithms that include family history of CHD, but the evidence clearly suggests that individuals with a family history may benefit from strategies to screen and treat early several risk factors for CHD.
It has been well established that the risk of diabetes among those with a family history of the disease is greater than the risk in the general population. Most studies report a two- to six-fold increased risk independent of other risk factors (45). And there seems to be a dose response effect: the risk is higher when both parents are affected than when only one parent is affected (46–49). A few studies have also suggested that a maternal history may be associated with greater risk than paternal history (50,51). Studies employing a familial risk stratification methodology have shown that the association between familial risk and diabetes is graded and independent of other major risk factors (49,52,53). Data from the 2004 HealthStyles national survey evaluated a three-tiered familial risk stratification algorithm (52). For the stratification, the algorithm considered the number of relatives with diabetes, their degree of relationship, the lineage or side of the family with cases of diabetes, and age at diagnosis. Diabetes was assessed by self-report. Compared to respondents with a weak familial risk for diabetes, moderate and strong familial risk categories were associated respectively with 3.6-fold (95% CI: 2.8, 4.7) and 7.6-fold (95% CI: 5.9, 9.8) increase in diabetes after adjusting for common demographic factors. A more recent analysis (53), with 6-year data from the National Health and Nutrition Examination Survey (NHANES, 1999–2004, n = 16,388 adults), included three risk categories: (i) high: at least two first-degree relatives, or one first-degree and at least two second-degree relatives with diabetes from the same lineage; (ii) moderate: just one first-degree and one second-degree relative with diabetes, or only one first-degree relative with diabetes, or at least two second-degree relatives with diabetes from the same maternal or paternal line; (iii) average: no family history of diabetes or, at most, one second-degree relative with diabetes. Diabetes was assessed by self-report or a fasting plasma glucose measurement. Overall, 70% of the U.S. adults were in the average, 23% in the moderate, and 7% in the high familial risk category for diabetes. After accounting for sex, race/ethnicity, age, body mass index, hypertension, income, and education, the odds of having diabetes for people in the moderate and high familial risk categories, when compared to the average, were 2.3 and 5.5 times higher, respectively. Another study (49), using NHANES data from 1999 to 2002, showed a significant association between high familial risk and the presence of diabetes among people who did not know they had the disease. Undiagnosed cases of diabetes were detected by fasting plasma glucose. Since, nationally, nearly one-third of people with diabetes are not aware they have the disease (54), family history is a potential screening tool to not only identify people with an intermediate phenotype of the disease (prediabetes), but to find those who already have diabetes but have not been diagnosed.
Many screening tools have been developed for early detection of type 2 diabetes. These tools include noninvasive measurements like age, gender, body mass index, and family history to facilitate their use in a primary care setting and even outside of a clinical setting (55–61). These tools may be of great value as a first step in serial diagnostic strategies and for raising awareness of diabetes risk factors in community settings. However, studies have repeatedly shown that screening tools developed in one population rarely apply to others. Sensitivities, specificities, and predictive values are usually higher for the population where the tool was developed (62,63). This may be due to differences in population characteristics and in the distribution of risk factors. Risk assessment tools for diabetes may have to be adapted or recalibrated to the populations where they are being used.
Even the recommendations to screen for diabetes with glucose measurements are not uniform. The USPSTF recommends screening for type 2 diabetes in adults with hypertension or dyslipidemias (64). The USPSTF does not recommend universal diabetes screening for adults. The American Diabetes Association recommends screening every 3 years for adults beginning at age 45. But adults with a family history of diabetes, obesity, or other characteristics should be screened at younger ages and more frequently, every 1–2 years (65). Although screening criteria differ, there is evidence that family history influences screening practices in the primary care setting. It has been reported that having a family history of diabetes is strongly associated with providers ordering a plasma glucose test even after adjusting for the patient’s age, weight, and blood pressure (OR =2.9; 95% CI: 1.3, 6.7). However, having a first-degree relative with diabetes did not influence the providers recommending diet or exercise counseling (66). A few population-based studies have found that family history of diabetes was associated with greater awareness of risk and higher reporting of risk-reducing behaviors (67,68). The prevention of type 2 diabetes in high-risk individuals involves the adoption of lifestyle behaviors that have proven difficult to change and maintain. It remains to be seen whether using family history to personalize risk might empower people at above average risk to seek medical advice and practice healthy behaviors.
Based on substantial epidemiologic evidence, family history is already a key component of risk assessment for many cancers. It is estimated that 5–10% of cancers have a strong hereditary basis. Examples of these include hereditary nonpolyposis colorectal cancer (HNPCC) (69) and breast and ovarian cancers associated with the BRCA1 and BRCA2 genes (70). Approximately 10–30% of cancers are considered familial. These cancers cluster in families but the genetic mutations that may cause them are not known. Familial cancers may be due to shared susceptibility genes and common environments and behaviors. Much work has been done on developing cancer risk assessment tools based on family history. Clinicians and genetic counselors have been using self-administered questionnaires for many years to gather detailed information about cancer among first- and second-degree relatives. A more recent trend is the use of computerized assessment tools that include sophisticated algorithms that assign risk categories, and in some cases recommend strategies for disease prevention, early detection, and genetic testing (71,72). Automating the risk assessment process has highlighted the need to validate and standardize the risk assessment algorithms being used in these tools. Recently the USPSTF issued a clinical guideline defining family history criteria that could be used to identify women who should be referred for genetic risk assessment and testing for breast and ovarian cancer susceptibility (73). Much of the evidence for creating risk algorithms based on family history, including the USPSTF guidelines, comes from clinical data sets and case-control studies that have used registries of cancer patients. Population-based studies are needed to evaluate the effectiveness of these algorithms in other settings. The need for the evaluation of the clinical validity of these algorithms is exemplified by a recent study in which six different cancer family history screening protocols were applied to the same cohort of women aged 21–55 years. The proportion of women who met the criteria for genetic testing ranged from 4.4% to 7.8%, depending on the protocol used. Based on the Kappa statistic, the protocols had only low to fair agreement (74).
From a public health perspective, it is hoped that awareness of family history of cancer might motivate people to adhere to screening guidelines. In 2004, only 51.8% of U.S. adults aged 50 years or older had recently undergone a sigmoidoscopy or colonoscopy or a fecal occult blood test (FOBT). This figure varied by state: from 42.5% in Mississippi to 64.6% in Rhode Island (75). Barriers are numerous, but any strategy that could improve participation in colorectal cancer screening would likely have an impact on morbidity and mortality from this disease. As with CVD and diabetes, there are few data describing the impact of familial risk assessment for cancer on the adoption of health-related behaviors (76). As an alternative, decision analysis methods have been used to estimate the impact of family-based screening (77,78). The clinical and economic impact of using family history to identify persons for colorectal cancer screening younger than age 50 years has been estimated: for the year 2004 approximately one million people would have been eligible for early colonoscopy, resulting in 2,800 invasive cancers detected and 29,300 life years gained, at a total cost of $900 million. This works out to a discounted cost per life year gained of about $58,000. While results from these simulation studies are promising, further data are needed to determine the effectiveness of this strategy for disease prevention and the social burden of the disease.
Summary and Conclusion
The use of family history and pedigrees has a venerable history in genetics. This use long precedes the discoveries that firmly established the rules of inheritance; however, those discoveries and more recent advances in genetics and genomics have not weakened and actually may have strengthened the role that this simple but informative tool can play in medicine and public health. On the one hand, the fast pace of current gene discoveries has created new and exciting challenges for clinical geneticists who must rely on family histories for many aspects of their work. On the other hand, family history appears to act as a good proxy for the genetic component of some diseases of major public health importance. This is not to deny that family history also reflects the actions of environments that family members have shared totally or partially—genes don’t operate in a vacuum, after all. It is rather to affirm that, at least for some diseases, family history can be interpreted as a risk exposure that starts at birth. It is then expected that individuals with a family history for these diseases will show intermediate phenotypes or preclinical signs of the disease earlier in life than individuals without such family history. This interpretation has obvious implications for public health. Indeed, many guidelines consider family history of a disease as a relevant criterion for early screening and as a trigger of more aggressive approaches to prevention.
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