The Complexities of Predictive Genetic Testing Peer Reviewed
BMJ. 2001 Apr 28; 322(7293): 1052–1056.
The complexities of predictive genetic testing
James P Evans
a Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA, b Department of Medical History and Ideals, University of Washington, Seattle, WA 98195, Us
Cécile Skrzynia
a Section of Medicine, Lineberger Comprehensive Cancer Centre, University of North Carolina, Chapel Loma, NC 27599, USA, b Department of Medical History and Ethics, University of Washington, Seattle, WA 98195, USA
Wylie Shush
a Department of Medicine, Lineberger Comprehensive Cancer Heart, University of North Carolina, Chapel Loma, NC 27599, USA, b Department of Medical History and Ethics, University of Washington, Seattle, WA 98195, USA
Predictive genetic testing is the use of a genetic test in an asymptomatic person to predict future hazard of disease. These tests represent a new and growing form of medical tests, differing in fundamental ways from conventional medical diagnostic tests. The hope underlying such testing is that early on identification of individuals at risk of a specific condition will pb to reduced morbidity and mortality through targeted screening, surveillance, and prevention. Still the clinical utility of predictive genetic testing for different diseases varies considerably. We explore here the factors that contribute to this variation and which volition dictate the utility of any of these new tests now or in the future.
Methods and definition of terms
The observations in this newspaper derive from our experience in clinical medicine, medical genetics, genetic counselling, and molecular biological science and from participation in educational programmes for generalists on medical genetics. The definition of utility used hither encompasses all aspects of a examination (individual and societal) that return it more or less useful in the clinical arena.
Departure from conventional medical testing
Current and future use
A conventional medical diagnostic examination, such as a blood count or an imaging written report, defines something near the patient's current condition. Although such data may have implications for the future, its overwhelming utility lies in the information it provides about the patient'due south current state.
A predictive genetic test, in dissimilarity, informs us only about a future condition that may (or may non) develop. The identified hazard is sometimes high—for case, in a positive exam for Huntington's illness)—only always contains a substantial component of uncertainty, non only about whether a specific condition will develop, but also nearly when it may appear and how astringent information technology will be. Predictive genetic tests often conduct a further element of incertitude: the interventions available for individuals at adventure are often untested, and recommendations may be based on presumed benefit rather than observations of outcomes.1 ,ii
These uncertainties contrast with the presentation of predictive genetic testing in the pop media, which often fosters an illusion that genetic run a risk is highly anticipated and determinative.3 A New York Times commodity, for example, recently described a "genetic report card" that would predict a baby's health history at birth.4 In fact, uncertainties inherent in most genetic tests represent a major limitation to their clinical utility.
Individual versus family unit
Whereas conventional diagnostic testing rarely has medical importance for anyone other than the person tested (except in the case of catching diseases) predictive genetic testing typically has direct implications for family members. Business organisation for relatives may be an important motivating factor for a patient wanting to undergo such testing; some family members, however, may resist participating in the testing because they adopt not to have information about their genetic run a risk. The utility of a predictive genetic examination will therefore depend on whose point of view is considered.
Utility of predictive genetic testing for unlike diseases
An examination of predictive genetic testing in diverse diseases helps to identify factors that decide utility. Figure one shows the degree of utility for diverse diseases (ranked according to how clinically useful testing currently is). These diseases are discussed beneath, from those for which testing is most useful through to those for which testing is least useful or even harmful.
Utility in predictive genetic testing
Multiple endocrine neoplasia type 2
The rare disorder multiple endocrine neoplasia type 2 results from mutations in the RET proto-oncogene. People with the disorder are almost certain to develop medullary thyroid carcinoma unless they undergo condom thyroidectomy.5 Studies comparison children with multiple endocrine neoplasia blazon 2 who underwent thyroidectomy with those who did not, offer compelling evidence that such surgery reduces the likelihood of dying from cancer.6 Predictive genetic testing makes it possible to identify those who will benefit from surgery.
This example illustrates that when predictive genetic testing strongly predicts a deleterious clinical consequence and an efficacious early intervention exists, it is of high utility. Indeed, such testing for multiple endocrine neoplasia type 2 is the accepted standard of intendance for individuals at risk.7
Haemochromatosis
Haemochromatosis is an uncommon (merely not rare) status of tissue iron degradation, leading to diabetes, cirrhosis, eye disease, arthritis, and gonadal dysfunction.8 Phlebotomy is a uncomplicated and effective preventive treatment, and predictive genetic testing is therefore useful to raise suspicion of this often elusive diagnosis. Testing is less useful for haemochromatosis than for multiple endocrine neoplasia type ii, still, because of low predictive value.nine ,10
Although excess iron accumulation results from a genetic predisposition, other factors contribute to the development of clinically important fe overload, including sex, diet, and exposure to liver toxins such equally alcohol. Thus the penetrance of the haemochromatosis genotype (the proportion of individuals with genetic susceptibility who volition develop the associated clinical condition) is low. The resultant uncertainty limits the utility of predictive genetic testing because preventive action based simply on the results of such testing would subject many individuals who would never develop clinical sequelae to unnecessary phlebotomy.
Colorectal cancer
About 5-10% of colorectal cancer results from inheritance of a few highly penetrant gene mutations that confer a high lifetime risk of the disease.11 Predictive genetic testing can be useful when family history suggests increased adventure—for example, iii or more affected relatives, with ane in whom the disease was diagnosed earlier age 5012—and is compatible with a diagnosis of hereditary not-polyposis colon cancer. Affected individuals have nigh a 70% lifetime take chances of colorectal cancer.12 Periodic colonoscopic surveillance of these individuals reduces the development of colorectal cancer by 62% when compared with unscreened controls,xiii showing the utility of predictive genetic testing in this circumstance.
However, hereditary not-polyposis colon cancer involves other cancer risks as well. Afflicted women have a loftier hazard of endometrial cancer, equally well as increased risks of ovarian cancer, other gastrointestinal cancers, and cancers of the ureteral tract.12 No established surveillance strategies are available for these other cancers.two Thus predictive genetic testing provides an established effect benefit for only 1 of the risks identified, and therefore although useful, it provides less clear cut do good than in a condition such as multiple endocrine neoplasia type 2.
Chest and ovarian cancer
About five-10% of breast and ovarian cancers outcome from the inheritance of mutations in the BRCA1 or BRCA2 gene.fourteen Predictive genetic testing for breast and ovarian cancer, as for hereditary non-polyposis colon cancer, can be useful to identify those at increased risk. In both chest and ovarian cancer, even so, utility is limited considering of considerable doubtfulness most the predictive value of the test.
A woman carrying a mutation in the BRCA1 or BRCA2 cistron may develop chest cancer, ovarian cancer, both cancers, or neither. Penetrance estimates range from 36-85% for breast cancer and 10-44% for ovarian cancer.15 – 17 Moreover, the historic period at which cancer occurs is widely variable. These uncertainties probably reflect a combination of factors, including the environment, modifying genes, the nature of a adult female's specific mutation, and purely stochastic processes.
The utility of predictive genetic testing for breast and ovarian cancer is further limited by the nature of available surveillance and prevention strategies. Starting mammography at age 25 to 35 is recommended for carriers of the BRCA1 or BRCA2 gene, but the efficacy of this early surveillance is unknown.1 Because mammography is already widely encouraged for women aged over 40 (in the United States) or 50 (in the Britain), information on genetic susceptibility is less relevant at later ages. Finally, adequate surveillance for ovarian cancer is not available.1
Chemoprevention with tamoxifen shows promise for reducing risk of breast cancer,18 but conflicting data exist.19 ,20 Moreover, chemoprevention increases risk of endometrial cancer and venous thromboembolic disease. Oral contraceptives may reduce risk of ovarian cancer simply may also increment risk of chest cancer.21 Prophylactic oophorectomy and mastectomy are reasonable options for some women and seem to be effective in reducing cancer take a chance.22 ,23 Such measures carry substantial burdens, however, and mastectomy in detail is not widely accepted past women at risk.24
In short, knowledge of an inherited predisposition to breast or ovarian cancer does not lead to unproblematic, straightforward measures to reduce risk, thus limiting the utility of predictive genetic testing.
Alzheimer's illness
Alzheimer'south disease illustrates the potential for predictive genetic testing to cause harm. Measurement of the apolipoprotein E genotype can predict risk of developing Alzheimer's disease in people of European descent.25 ,26 2 copies of the apolipoprotein E4 gene (present in ii% of the general population25 ,26) are associated with a ten-fold increased risk of Alzheimer'southward disease25; ane copy is associated with a twofold increased risk, and the inheritance of an apolipoprotein e2 allele is protective.26 Thus a positive exam is an imprecise measure out of risk and could result in feet, stigmatisation, or discrimination. The principle of avoiding damage suggests that currently such testing would generally exist unethical because no effective prevention is available.27 ,28
Factors affecting utility
The ideal context, therefore, is a highly predictive test for a disease that is serious and incurable but preventable by ways that are imperfect or expensive. The table shows factors affecting utility of predictive genetic testing.
Severity of disease and availability of effective treatment
The utility of predictive genetic testing declines when a affliction is curable. Testing for tuberculosis, for example, makes little sense, fifty-fifty though genetics contributes to susceptibility to the illness.29 Similarly, every bit scientific advances make chest or colon cancer curable by increasingly innocuous ways, the utility of predictive genetic testing will decline.
Screening and prevention
Constructive and inexpensive screening methods also make predictive genetic testing less useful considering these measures can be readily practical to the entire population. Testing for hypertension makes footling sense—despite evidence of strong genetic contributors to this condition30—because universal screening and treatment are the dominion. As the expense of screening rises, predictive genetic testing becomes more appealing. Thus, if magnetic resonance imaging (which is expensive) were shown to be superior to mammography (less expensive) in screening for breast cancer, testing could target those who would benefit most.
Available preventive measures must be either imperfect or expensive for predictive genetic testing to be of high utility. Testing makes sense in women at high risk of breast or ovarian cancer if they are considering oophorectomy or mastectomy: a positive exam would ostend take chances and support the use of invasive, imperfect interventions. When prevention is elementary, however, the value of testing decreases. Vaccination is so cheap, prophylactic, and effective that universal administration is rational. Thus testing has no utility in measles, mumps, or rubella despite evidence of genetic differences in susceptibility to infectious disease.29 The same would be true if an constructive, safe, and inexpensive vaccination existed for breast cancer.
Perceptions of utility
Family history and feel are important factors in determining how an individual perceives the utility of predictive genetic testing. Figures ii and 3 prove how a woman'due south perception of the utility of testing for hazard of breast cancer, for example, tin vary depending on whether other close relatives take died of the illness or on her own family construction.
Families' experiences affect their perceptions of utility of predictive genetic testing. The affected woman in family A, whose sisters and mother died of breast cancer, may perceive chemoprevention or condom surgery favourably, and welcome the guidance that predictive genetic testing can provide in making such decisions. Her analogue (arrowed) in family unit B may perceive chest cancer to exist a less traumatic illness and experience comfortable with routine surveillance, thus lessening the utility of testing for her
Conclusion
Predictive genetic testing has nifty potential for accurate risk cess and for guiding the employ of an expanding armamentarium of screening and prevention methods. The utility of testing varies widely, however, depending on the magnitude of take a chance, the accuracy of risk prediction, options available to reduce run a risk, an individual's previous experience, and the needs and feel of family unit members. In improver, the utility of a given predictive genetic test is probable to change over time as knowledge grows, new strategies for prevention are developed, and costs change. The complexity of these factors calls for discussions about testing that are highly tailored to the testing context and the individual's needs and preferences.
Family unit structure affects perceptions of utility of predictive genetic testing. The woman with four daughters unaffected by breast cancer (family A) may feel that information on chance may exist of do good for their sake, whereas for the woman with no progeny (family unit B) the utility of such testing declines
Table
Factors affecting utility of predictive genetic testing
| Increased utility | Decreased utility |
|---|---|
| High morbidity and mortality of affliction | Low morbidity and mortality of affliction |
| Effective but imperfect treatment | Highly effective and adequate treatment |
| High predictive power of the genetic test (high penetrance) | Poor predictive ability of the genetic test (depression penetrance) |
| High cost or onerous nature of screening and surveillance methods | Availability of inexpensive, adequate, and effective screening and surveillance methods |
| Preventive measures that are expensive or associated with adverse effects | Preventive measures that are inexpensive, efficacious, and highly acceptable—for example, vaccination |
Acknowledgments
We thank Drs Tim Carey and David Ransohoff for critical review of the manuscript. Portions of this work were presented at a coming together of Genetics in Chief Care, a kinesthesia development project funded by the Health Resource and Services Administration (contract No 240-98-0020).
Footnotes
Competing interests: None declared.
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