for Genetic Susceptibility to Disease

*The values of a, b, c, and d are derived from a random sample of the population, divided into those with and without the susceptibility genotype, and then examined for the disease (with or without longitudinal follow-up, depending on whether it is a cross-sectional or cohort study) (see later).

Frequency of the susceptibility genotype = (a + b)/N

Disease prevalence = (a + c)/N (with random sampling or a complete population survey)

Relative Risk Ratio:

=a / (a+b)c / (c+d)


RRR=Disease prevalence in carriers of susceptibility genotypeDisease prevalence in noncarriers of susceptibility genotype


Sensitivity: Fraction of individuals with disease who have the susceptibility genotype = a/(a + c)

Specificity: Fraction without disease who do not have the susceptibility genotype = d/(b + d)

Positive predictive value: Proportion of individuals with the susceptibility genotype who have or will develop a particular disease = a/(a + b)

Negative predictive value: Proportion of individuals without the susceptibility genotype who do not have or will not develop a particular disease = d/(c + d)

Clinical Validity and Utility

Clinical Validity

Susceptibility Testing Based on Genotype


Figure 18-4 Theoretical positive predictive value calculations for a susceptibility genotype for a disease, over a range of genotype frequencies, disease prevalences, and relative risks for disease conferred by the genotype.

We will illustrate the use of the 2 × 2 table in assessing the role of susceptibility alleles in a common disorder, colorectal cancer. Shown in the following Box are data from a population-based study of colorectal cancer risk conferred by a polymorphic variant in the APC gene (see Chapter 15(Case 15) that changes isoleucine to lysine at position 1307 of the protein (Ile1307Lys). This variant has an allele frequency of approximately 3.1% among Ashkenazi Jews, which means that approximately 1 in 17 individuals is a heterozygote (and 1 in 1000 are homozygous) for the allele. The prevalence of colon cancer among Ashkenazi Jews is 1%. The Ile1307Lys variant, common enough to be heterozygous in approximately 1 in 17 Ashkenazi Jews, confers a 2.4-fold increased risk for colon cancer relative to individuals without the allele. However, the small positive predictive value (≈2%) means that an individual who tests positive for this allele has only a 2% chance of developing colorectal cancer. If this had been a cohort study that allowed complete ascertainment of everyone in whom colorectal cancer was going to develop, the penetrance would, in effect, be only 2%.


The Ile1307Lys Allele of the APC Gene and Colon Cancer



Sensitivity: Fraction of individuals with colon cancer who have the Lys1307 allele = 7/45 = 16%

Specificity: Fraction without colon cancer who do not have the Lys1307 allele = 4142/4452 = 93%

Positive predictive value: Fraction of individuals with the Lys1307 allele who develop colon cancer = 7/317 = 2%

Negative predictive value: Fraction of individuals without the Lys1307 allele who do not develop colon cancer = 99%

Data from Woodage T, King SM, Wacholder S, et al: The APCl1307K allele and cancer risk in a community-based study of Ashkenazi Jews. Nat Genet 20:62-65, 1998.

Clinical Utility

In a patient who tests positive for the APC Ile1307Lys allele, how does a positive predictive value of 2% translate into clinical utility for medical practice? One critical factor is a public health economic one: can the screening be shown to be cost-effective? Is the expense of the testing outweighed by improving health outcomes while reducing health care costs, disability, and loss of earning power? In the example of screening for the APC Ile1307Lys allele in Ashkenazi Jews, more frequent screening or the use of different approaches to screening for colon cancer may be effective. Screening methods (occult stool blood testing versus fecal DNA testing, or sigmoidoscopy versus full colonoscopy) differ in expense, sensitivity, specificity, and potential for hazard, and so deciding which regimen to follow has important implications for the patient’s health and health care costs.

Even with demonstrable clinical validity and actionable clinical utility, demonstrating that testing improves health care is not always straightforward. For example, 1 in 200 to 1 in 250 white individuals are homozygous for a Cys282Tyr mutation in the HFE gene associated with hereditary hemochromatosis, a disorder characterized by iron overload that can silently lead to extensive liver damage and cirrhosis (Case 20). A simple intervention—regular phlebotomy to reduce total body iron stores—can prevent hepatic cirrhosis. The susceptibility genotype is common, and 60% to 80% of Cys282Tyr homozygotes show biochemical evidence of increased body iron stores, which suggests that screening would be a reasonable and cost-effective measure to identify asymptomatic individuals who should undergo further testing and, if indicated, the institution of regular phlebotomy. However, most Cys282Tyr homozygotes (>90% to 95%) remain clinically asymptomatic, leading to the argument that the positive predictive value of HFE gene testing for liver disease in hereditary hemochromatosis is too low to justify population screening. Nonetheless, some of these largely asymptomatic patients do have signs of clinically occult fibrosis and cirrhosis on liver biopsy, indicating that the Cys282Tyr homozygote may actually be at a higher risk for liver disease than previously thought. Thus some would argue for population screening to identify individuals in whom regular prophylactic phlebotomy should be instituted. The clinical utility of such population screening remains controversial and will require additional research to determine the natural history of the disease and whether the silent fibrosis and cirrhosis seen on liver biopsy represent the early stages of what will be a progressive illness.

APOE testing in Alzheimer disease (AD) (see Chapter 12(Case 4) is another example of the role of a careful assessment of clinical validity and clinical utility in applying genetic testing to personalized medicine. As discussed in Chapter 8, heterozygotes for the ε4 allele of the APOE gene are at a two- to threefold increased risk for development of AD compared with individuals without an APOE ε4 allele. APOE ε4/ε4 homozygotes are at a eightfold increased risk. An analysis of both the clinical validity and clinical utility of APOE testing, including calculation of the positive predictive value for asymptomatic and symptomatic individuals, is shown later (Table 18-5).

TABLE 18-5

Clinical Validity and Utility of APOE Population Screening and Diagnostic Testing for Alzheimer Disease


Positive predictive value (PPV) calculations are based on a population prevalence of Alzheimer disease (AD) of approximately 3% in individuals aged 65 to 74 years, an allele frequency for the ε4 allele in whites of 10% to 15%, a relative risk of approximately 3 for one ε4 allele, and a relative risk of approximately 20 for two ε4 alleles.

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Nov 27, 2016 | Posted by in GENERAL & FAMILY MEDICINE | Comments Off on for Genetic Susceptibility to Disease

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