Empowering individuals in the prevention of genetic disease.

As the International Human Genome Project nears the term of a long gestation, the ethical and social implications of complex new genetic technologies will require a new breed of clinicians for a safe delivery. Clinical genetic care has been time intensive as performed by medical specialists. Empowering individuals to take advantage of new opportunities for genetic testing to prevent disease will require clinician education and decision support in the context of individual values.

Clinical commentary: the challenges of genetic medicine to the patient-physician relationship.

Author explores the interface between the current clinical reality for patients and evolving genetic research results, noting how knowledge about various genetic disorders is posing a major challenge to the patient-physician relationship.

First trimester isolated fetal nuchal lucency: significance and outcome.

In this study, we determined the outcome in cases of isolated nuchal lucency seen sonographically in the first trimester in fetuses without karyotypic abnormalities. We reviewed all cases of isolated localized fetal nuchal lucency (3 mm or greater) in 9 to 14 week fetuses over a 4 year period. Fetuses with additional sonographic abnormalities were excluded. The width of the nuchal lucency at initial sonogram as well as findings on subsequent scans were tabulated. Karyotypic, pathologic, and clinical follow-up data were obtained. Of 44 fetuses with an isolated, localized first trimester nuchal lucency, one was lost to follow-up and two were excluded owing to pregnancy termination without karyotype or pathologic analysis, thus resulting in 41 fetuses in our study group. Five fetuses (12%) had abnormal karyotypes. Twenty-seven of the remaining 36 fetuses had normal karyotypes, eight others showed no evidence of aneuploidy at birth, and one patient underwent spontaneous abortion prior to a karyotypic analysis. Among the 36 fetuses without evidence of aneuploidy, six had a poor outcome: two were spontaneous abortions, one was a therapeutic abortion of a fetus with hydrops and a pericardial effusion seen on fetopsy; one fetus died at birth of pulmonary hypoplasia associated with autosomal recessive polycystic kidney disease, and one fetus each had Noonan syndrome, and Joubert syndrome. In addition, three patients delivered their infants prematurely. Overall, 32 of 41 fetuses survived, and two (6%) were abnormal. Excluding premature infants, 27 were normally grown, term survivors. We conclude that other than having an increased risk for aneuploidy, fetuses with isolated nuchal lucency are also at risk for spontaneous miscarriage, premature delivery, and congenital anomalies unassociated with an abnormal karyotype.

Quality assurance in the clinical genetics setting-Report of a workshop.

Participants in a panel discussion sponsored by thead hoc Quality Assurance Committee of the National Society of Genetic Counselors discuss early efforts to develop and implement quality assurance instruments at institutional, state, and regional levels. Uniform guidelines and self-assessment tools can help genetic counselors and clinical geneticists to provide the best possible care to individuals affected by genetic diseases. Further work will be needed to address aspects not covered here and to assure that guidelines allow for creative variation among professionals and centers. An interdisciplinary approach to such standard-setting is recommended.

The amniocentesis decision: ten years of decision analytic experience.

Over the past decade we have used a decision analytic model to counsel 840 patients (468 women, 381 men, 432 couples) about amniocentesis for prenatal diagnosis. The model explicitly considers the possibilities of miscarriage (both after amniocentesis and spontaneously), an affected child (as a function of maternal age), and various diagnostic errors. Prospective parents are shown the model after routine counseling is used to explain the options and potential outcomes. Using the lottery technique (in which they are asked to choose between therapeutic abortion and carrying a pregnancy to term without the benefit of amniocentesis, where the likelihood of an affected child is varied in a structured sequence), prospective parents expressed their attitudes on a utility scale, where zero corresponds to an unaffected child and where 100 corresponds to an affected child. On that scale, the mean assessed disutility of therapeutic abortion was 33.7 +/- 32.6 (35.8 +/- 32.1 among women, 30.9 +/- 32.9 among men). The decision model encourages couples to confront their attitudes toward specific reproductive outcomes, to clarify their values and to incorporate them, along with their current risks, into a logical decision about prenatal diagnosis.

Prescriptive models to support decision making in genetics.

Formal prescriptive models can help patients and clinicians better understand the risks and uncertainties they face and better formulate well-reasoned decisions. Using Bayes rule, the clinician can interpret pedigrees, historical data, physical findings and laboratory data, providing individualized probabilities of various diagnoses and outcomes of pregnancy. With the advent of screening programs for genetic disease, it becomes increasingly important to consider the prior probabilities of disease when interpreting an abnormal screening test result. Decision trees provide a convenient formalism for structuring diagnostic, therapeutic and reproductive decisions; such trees can also enhance communication between clinicians and patients. Utility theory provides a mechanism for patients to understand the choices they face and to communicate their attitudes about potential reproductive outcomes in a manner which encourages the integration of those attitudes into appropriate decisions. Using a decision tree, the relevant probabilities and the patients' utilities, physicians can estimate the relative worth of various medical and reproductive options by calculating the expected utility of each. By performing relevant sensitivity analyses, clinicians and patients can understand the impact of various soft data, including the patients' attitudes toward various health outcomes, on the decision making process. Formal clinical decision analytic models can provide deeper understanding and improved decision making in clinical genetics.

The effect of private attitudes on public policy. Prenatal screening for neural tube defects as a prototype.

The quantitative use of patients' attitudes in medicine has thus far been limited to decisions involving either treatment alternatives or the use or nonuse of a particular diagnostic test. Preference theory has not been applied either to the use of screening tests or to the development of large-scale health-related public policy decisions. In this paper we have, in a prototypical fashion, analyzed the effect patient attitudes have on a public policy decision faced by many countries today--whether or not to institute a screening program for neural tube defects. We have assessed the attitudes of 338 prospective parents toward many of the sequelae expected from the introduction, or lack thereof, of the alpha-fetoprotein screening program--induced abortion from amniocentesis, elective abortion, and the birth of a defective child. Using these data and information collected by the United Kingdom study on alpha-fetoprotein, we have estimated the proportion of patients coming to genetic counseling who would benefit from the availability of a screening program for neural tube defects.

Prenatal diagnosis: a directive approach to genetic counseling using decision analysis.

The decision which prospective parents face concerning mid-trimester amniocentesis for prenatal diagnosis was examined by decision analysis. The prospective parents' decision depends on the likelihood of the birth of a child affected by a genetic disorder, the risk of amniocentesis, and the probability that the diagnoses provided by the amniocentesis will be correct. The couple's decision must also depend on their attitudes toward each possible outcome. The likelihoods of the outcomes can be obtained from appropriate medical consultation, while the relative costs or burdens of the outcomes should be obtained from the prospective parents. A truly informed decision for this couple can then be formulated from these probabilities and values, thus allowing genetic counseling to be more directive. The technique is illustrated for the prenatal diagnosis of Down's syndrome, meningomyelocele, and Duchenne muscular dystrophy.