Showing papers by "Muin J. Khoury published in 2000"

Limb defects associated with major congenital anomalies: clinical and epidemiological study from the International Clearinghouse for Birth Defects Monitoring Systems.

Abstract: Although limb defects associated with other congenital anomalies are rarely studied, they may provide insights into limb development that may be useful for etiologic studies and public health monitoring. We pooled data from 11 birth defect registries that are part of the International Clearinghouse for Birth Defects Monitoring Systems. We identified 666 infants, born from 1983 through 1993, who had a non-syndromal limb defect plus at least one other major malformation (rate 12.9/100,000 population). We used observed/expected ratios and log-linear models to detect association patterns. We found that specific limb defects occurred with relatively distinct sets of malformations. Preaxial limb defects occurred more frequently with microtia, esophageal atresia, anorectal atresia, heart defects, unilateral kidney dysgenesis, and some axial skeleton defects; postaxial defects with hypospadias; transverse defects with craniofacial defects, micrognathia, ring constrictions, and muscular defects; intercalary defects with omphalocele; split hand/foot with encephalocele; and amelia with anorectal atresia, omphalocele, severe genitalia defects, unilateral kidney dysgenesis, gastroschisis, and ring constriction. Log-linear modeling identified higher order associations among some of these same malformations.

Effect of prenatal diagnosis on epidemiologic studies of birth defects.

Abstract: Prenatal diagnostic technology makes it possible to offer women the option of electively terminating pregnancies affected by birth defects. Excluding these pregnancies from epidemiologic studies may affect study results. We explored this effect using examples from the literature. We calculated the bias in the odds ratio caused by excluding prenatally diagnosed pregnancies when the exposure of interest is not correlated with the likelihood of terminating an affected pregnancy and when it is correlated with an increase or decrease in this likelihood. We assumed that control infants did not have birth defects. When the exposure is not associated with the likelihood of a pregnancy termination, studies excluding terminations suffer a loss of precision. When the exposure is associated with an increase or decrease in this likelihood, the odds ratios are biased toward or away from the null, respectively. The magnitude of the bias will vary according to characteristics of the study population such as the prevalence of the exposure and the frequency with which prenatal diagnosis and elective termination are used. Whenever possible, pregnancies terminated after prenatal diagnosis must be included in epidemiologic studies.

Bias Associated with Study Protocols in Epidemiologic Studies of Disease Familial Aggregation

Abstract: The effect of selection bias has not been well evaluated in epidemiologic studies which focus on familial aggregation. The authors illustrate this type of bias for a reconstructed cohort study. With the reconstructed cohort design, cases and controls are first selected from the population and their relatives form the exposed and unexposed cohorts, respectively. The recurrence risk ratio (RRR) is calculated to assess and measure familial aggregation. The ways of utilizing information from relatives affects the estimate of RRR, and the authors show that a traditional method used in epidemiologic studies can yield a severely biased estimate of the RRR. However, this traditional approach can give approximately unbiased estimates under special conditions. A novel selection approach is proposed which yields an unbiased estimate of RRR. In conclusion, when relatives are identified through cases or controls, they should be included and counted in the study cohorts each time a case or control is selected, even if they or other family members have already been included.

The interface of genetics and public health: research and educational challenges.

Abstract: ▪ Abstract As the target date for the sequencing of the human genome approaches, there is growing recognition that public health practice, research, and education will be impacted by new genetic technologies and information and that a multidisciplinary approach is required. Research in the emerging field of public health genetics encompasses a broad range of disciplines and will increasingly involve the interactions among the investigators in these fields. An overview of these areas of research is provided, with illustrative examples. Education in public health genetics needs to address a variety of audiences, including public health graduate students and practitioners, students from related disciplines, and health care professionals. Two new graduate programs at the Universities of Michigan and Washington and training opportunities for public health professionals are described. These educational efforts must be ongoing so that the potential of genetic technology and information can be appropriately used ...

Genetic susceptibility to birth defects in humans: from gene discovery to public health action.

Abstract: ADVANCES IN HUMAN GENETIC RESEARCH With the relentless progress of the Human Genome Project, by the year 2001, most-if not all-of the estimated 100,000 human genes will have been found (Collins, '98). Close to 10,000 genes have already been cataloged (Online Mendelian Inheritance in Man, '98), and tests for more than 700 genes are already available in medical practice (Pagon, '98). The genes identified thus far range from those associated with rare metabolic disorders to those associated with common diseases including cancer and adult-onset conditions. Genetic variants confer increased susceptibility to a variety of environmental factors (including chemical, infectious, physical, social, psychological, be-havioral, and nutritional factors), thus increasing the risk of carriers for many diseases including birth defects. Although birth defects remain the leading cause of infant mortality in the United States (CDC, '98), the causes of most birth defects remain elusive. Nevertheless, an increasing number of clinical and epidemiologic studies are beginning to identify risk factors for birth defects (Khoury, '95). Over the last two decades , numerous investigators have identified malformations associated with rare single-gene disorders. Table 1 shows the results of a quick search of the Online Mendelian Inheritance in Man Catalog on the Internet. As can be seen, dozens of genes (mostly in a few families) have been reported to be associated with a variety birth defects leading to malformation syndromes. Increasingly, more common gene variants have been associated with the risk for common birth defects. For example, the me-thylene tetrahydrofolate reductase (MTHFR) polymorphism has been associated with the risk for neural tube defects (Posey, '96). The interaction between gene variants at multiple loci with environmental exposures is likely to explain most common defects such as neural tube defects, oral clefts, and congenital car-diovascular malformations. As a result of genetic research, information on differential genetic susceptibility to birth defects will be accumulating. Ideally, information on genetic susceptibility to birth defects will be used to target beneficial interventions that reduce the risk for birth defects (e.g., nutritional interventions such as folic acid), or to avoid certain pregnancy exposures for individuals at greatest risk (e.g., avoiding certain anti-epileptic drugs on the basis of a person's genetic metabolic profile). However, complex ethical, legal, and social issues are already being raised about the pitfalls of genetic testing in general (Lewontin, '96). The effective use of genetic knowledge and technology is becoming a crucial challenge to the public health community. The …

Is the G985A allelic variant of medium-chain acyl-CoA dehydrogenase a risk factor for sudden infant death syndrome? A pooled analysis.

Abstract: To the Editor. Studies examining the relationship between medium-chain acyl-CoA dehydrogenase deficiency (MCADD) and sudden infant death syndrome (SIDS) have shown conflicting results. With >90% of individuals diagnosed with MCADD possessing at least one copy of the G985A allelic variant, it seems likely that if an association between MCADD and SIDS existed, an association would also be seen between the G985A and SIDS. …