Showing papers by "Muin J. Khoury published in 1996"

Nontraditional Epidemiologic Approaches in the Analysis of Gene Environment Interaction: Case-Control Studies with No Controls!

Abstract: Although case-control studies are suitable for assessing gene-environment interactions, choosing appropriate control subjects is a valid concern in these studies. The authors review three nontraditional study designs that do not include a control group : 1) the case-only study, 2) the case-parental control study, and 3) the affected relative-pair method. In case-only studies, one can examine the association between an exposure and a genotype among case subjects only. Odds ratios are interpreted as a synergy index on a multiplicative scale, with independence assumed between the exposure and the genotype. In case-parental control studies, one can compare the genotypic distribution of case subjects with the expected distribution based on parental genotypes when there is no association between genotype and disease ; the effect of a genotype can be stratified according to case subjects' exposure status. In affected relative-pair studies, the distribution of alleles identical by descent between pairs of affected relatives is compared with the expected distribution based on the absence of genetic linkage between the locus and the disease ; the analysis can be stratified according to exposure status. Some or all of these methods have certain limitations, including linkage disequilibrium, confounding, assumptions of Mendelian transmission, an inability to measure exposure effects directly, and the use of a multiplicative scale to test for interaction. Nevertheless, they provide important tools to assess gene-environment interaction in disease etiology.

Periconceptional Multivitamin Use and the Occurrence of Conotruncal Heart Defects: Results From a Population-based, Case-Control Study

Abstract: Objective. The preventive efficacy of the periconceptional use of multivitamins is well established for neural tube defects, much less so for other birth defects. We conducted a population-based, case-control study to assess the effects of multivitamin use on the risk for conotruncal defects, a group of severe heart defects that includes transposition of the great arteries, tetralogy of Fallot, and truncus arteriosus. Methods. From the population-based Atlanta Birth Defects Case-Control Study, we identified 158 case infants with conotruncal defects and 3026 unaffected, randomly chosen control infants, born from 1968 through 1980 to mothers residing in metropolitan Atlanta. Periconceptional multivitamin use was defined as reported regular use from 3 months before conception through the third month of pregnancy. We present the results of the crude analysis, because the multivariate model yielded essentially identical results. Results. Mothers who reported periconceptional multivitamin use had a 43% lower risk of having infants with conotruncal defects (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.33 to 1.00) than did mothers who reported no use. The estimated relative risk was lowest for isolated conotruncal defects (OR, 0.41; 95% CI, 0.20 to 0.84) compared with those associated with noncardiac defects (OR, 0.91; 95% CI, 0.33 to 2.52) or a recognized syndrome (OR, 1.82; 95% CI, 0.31 to 10.67). Among anatomic subgroups of defects, transposition of the great arteries showed the greatest reduction in risk (OR, 0.36; 95% CI, 0.15 to 089). Conclusions. Periconceptional multivitamin use is associated with a reduced risk for conotruncal defects. These findings could have major implications for the prevention of these birth defects.

5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects

Abstract: Persons with a thermolabile form of the enzyme 5,10 methylenetetrahydrofolate reductase (MTHFR) have reduced enzyme activity and increased plasma homocysteine which can be lowered by supplemental folic acid. Thermolability of the enzyme has recently been shown to be caused by a common mutation (677C-->T) in the MTHFR gene. We studied 41 fibroblast cultures from NTD-affected fetuses and compared their genotypes with those of 109 blood specimens from individuals in the general population. 677C-->T homozygosity was associated with a 7.2 fold increased risk for NTDs (95% confidence interval: 1.8-30.3; p value: 0.001). These preliminary data suggest that the 677C-->T polymorphism of the MTHFR gene is a risk factor for spina bifida and anencephaly that may provide a partial biologic explanation for why folic acid prevents these types of NTD.

Advanced maternal age and the risk of Down syndrome characterized by the meiotic stage of chromosomal error: a population-based study.

Abstract: The identification of DNA polymorphisms makes it possible to classify trisomy 21 according to the parental origin and stage (meiosis I [MI], meiosis II [MII], or postzygotic mitotic) of the chromosomal error. Studying the effect of parental age on these subgroups could shed light on parental exposures and their timing. From 1989 through 1993, 170 infants with trisomy 21 and 267 randomly selected control infants were ascertained in a population-based, case-control study in metropolitan Atlanta. Blood samples for genetic studies were obtained from case infants and their parents. Using logistic regression, we independently examined the association between maternal and paternal age and subgroups of trisomy 21 defined by parental origin and meiotic stage. The distribution of trisomy 21 by origin was 86% maternal (75% MI and 25% MII), 9% paternal (50% MI and 50% MII), and 5% mitotic. Compared with women or = 40 years old had an odds ratio of 5.2 (95% confidence interval, 1.0-27.4) for maternal MI (MMI) errors and 51.4 (95% confidence interval, 2.3-999.0) for maternal MII (MMII) errors. Birth-prevalence rates for women > or = 40 years old were 4.2/1000 births for MMI errors and 1.9/1000 for MMII errors. These results support an association between advanced maternal age and both MMI and MMII errors. The association with MI does not pinpoint the timing of the error; however, the association with MII implies that there is at least one maternal-age related mechanism acting around the time of conception.

The surveillance of birth defects: the usefulness of the revised US standard birth certificate.

Abstract: To assess the sensitivity and positive predictive value of birth defects reported on the 1989 revision of the US Standard Birth Certificate, a population of 76,862 Atlanta-area births during 1989 and 1990 was used as the basis for comparing 771 birth certificates that reported birth defects with 2428 live-born infant records in a birth defects registry that uses multiple sources of case ascertainment. Only 14% of birth defects in the registry records were reported on birth certificates. After the analysis was restricted to defects recognizable at birth, the sensitivity and positive predictive value of the birth certificates were 28% and 77%, respectively. Birth certificates underestimate birth defect rates and should be used cautiously for birth defect surveillance and epidemiological studies.

Is maternal obesity a risk factor for anencephaly and spina bifida

Abstract: To determine whether the risk of having an infant with anencephaly or spina bifida is greater among obese women than among average-weight women, we compared 307 Atlanta-area women who gave birth to a liveborn or stillborn infant with anencephaly or spina bifida (case group) with 2,755 Atlanta-area women who gave birth to an infant without birth defects (control group). The infants of control women were randomly selected from birth certificates and frequency-matched to the case group by race, birth hospital, and birth period from 1968 through 1980. After adjusting for maternal age, education, smoking status, alcohol use, chronic illness, and vitamin use, we found that, compared with average-weight women, obese women (pregravid body mass index greater than 29) had almost twice the risk of having an infant with spina bifida or anencephaly (odds ratio = 1.9; 95% confidence limits = 1.1, 3.4). A woman's risk increased with her body mass index: adjusted odds ratios ranged from 0.6 (95% confidence limits = 0.3, 2.1) for very underweight women to 1.9 for obese women.

From genes to public health: the applications of genetic technology in disease prevention. Genetics Working Group.

Abstract: OBJECTIVES: With advances in the Human Genome Project, the implications of genetic technology in disease prevention should be assessed. METHODS: The paradigm suggested in The Future of Public Health--assessment, policy development, and assurance--was used to examine the continuum from genetic technology to public health practice. RESULTS: First, important public health functions are to (1) assess the impact of genes and their interactions with modifiable disease risk factors on the health status of the population and (2) assess the impact and safety of genetic testing on the population. Second, given the many implications of genetic testing, the public health community should participate in policy development related to the timing and use of genetic testing in disease prevention. Third, whenever appropriate, the public health community needs to ensure the development of public health genetics programs (e.g. newborn screening) and evaluate the quality and effectiveness of the use of genetic testing in dise...

Descriptive epidemiology of holoprosencephaly and arhinencephaly in metropolitan Atlanta, 1968-1992.

Abstract: We report the descriptive epidemiology of holoprosencephaly and arhinencephaly using data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth defects surveillance system with multiple sources of ascertainment. From 1968-1992, we ascertained 63 cases of holoprosencephaly and arhinencephaly from approximately 734,000 births, for a birth prevalence of 0.86 per 10,000. Thirteen case infants with holoprosencephaly and four case infants with arhinencephaly were categorized as having syndromes. Of the case infants with non-syndromic holoprosencephaly, 55% had malformations not attributable to the underlying brain defect. The rate of holoprosencephaly and arhinencephaly increased from 0.58 per 10,000 during 1968-1972 to 1.2 per 10,000 during 1988-1992 (P for trend = 0.016). Rates were higher for females than for males (risk ratio = 1.45, 95% C.I. 0.88-2.41) and higher for nonwhites than for whites (risk ratio = 1.74, 95% C.I. 1.06-2.86). There was a U-shaped distribution of risk associated with maternal age with a slightly increased risk for younger women (risk ratio for maternal age 34 years, compared with age 25-29 years = 2.30, 95% C.I. 0.93-5.7), but this was not statistically significant. The increased risk in the older age group could be largely explained by the presence of cases with autosomal trisomies. Neonatal mortality was higher for infants with malformations that were not attributable to the underlying brain defect and for infants with syndromes than for infants with isolated holoprosencephaly. This analysis is the first population-based study with long-term data on this rare defect. Further epidemiologic studies will be necessary to assess the risk factors for holo-prosencephaly and arhinencephaly.

Does periconceptional multivitamin use reduce the risk of neural tube defects associated with other birth defects? data from two population-based case-control studies.

Abstract: The role of periconceptional folic acid in the prevention of neural tube defects (NTDs) is well established. However, it is not clear whether a protective effect exists for the subset of nonsyndromic NTD with other “unrelated” major structural birth defects (NTD-multiples). This question is important to investigate because of shared pathogenetic mechanisms between NTD and other types of birth defects, and because of the epidemiologic differences that have been shown between NTD-multiples and NTD-singles. We analyzed data from two population-based case-control studies of NTDs, Atlanta 1968–1980, and California 1989–1991, to assess whether periconceptional multivitamin use reduces the risk of NTD-multiples. Maternal vitamin histories were assessed for 47 and 65 NTD-multiples cases and 3,029 and 539 control babies in Atlanta, and California, respectively. There was a substantial risk reduction associated with periconceptional multivitamin use (−3 to +3 months) for NTD-multiples (pooled odds ratio = 0.36, 95% C.I. 0.18–0.72) that persisted after adjustment for maternal race/ethnicity and education. Also, no specific types of NTDs or NTDs with specific defects explained the risk reduction with vitamin use. These data suggest that multivitamins reduce the risk of nonsyndromic NTD cases associated with other major birth defects. The implication of this finding for the role of vitamins in the prevention of non-NTD birth defects should be further explored. © 1996 Wiley-Liss, Inc.

Analysis of Case-Parental Control Studies: Method for the Study of Associations between Disease and Genetic Markers

Abstract: Case-control studies using parents of case subjects as the control subjects provide an innovative way to study associations of genetic markers with disease risk. This approach, sometimes called the haplotype-relative risk method, has received recent attention because the use of parents as control subjects may reduce or eliminate the confounding associated with differences in race, ethnicity, or genetic background. We provide a new method for analysis of such case-parental control studies. The method of analysis is noniterative and yields simple estimates of risk ratios associated with genetic markers. It easily accommodates the situation in which data are available from only one parent. Although we illustrate the approach for a locus with two alleles, the analyses extend immediately to loci with multiple alleles.

Chorionic villus sampling and transverse digital deficiencies: evidence for anatomic and gestational-age specificity of the digital deficiencies in two studies.

Abstract: Several but not all studies indicate that chorionic villus sampling (CVS) is associated with an increased risk for transverse limb deficiencies, including digital deficiencies. It has been suggested that variations in results regarding the transverse digital deficiencies (TDDs) may be due to the use of different classification criteria. We present the combined analysis of two case-control studies, the U.S. Multistate CVS (US) study and the Italian Multicentric Birth Defects (IP-IMC) study, using two different definitions of TDDs. We compared the frequency of CVS exposure in control infants with that among those infants with any number of affected digits (any TDD), and those with all five digits of at least one limb affected (extensive TDDs). The estimated relative risk (RR) for any TDD following CVS was 10.6 (IPIMC) and 6.6 (US). For the extensive TDDs, the RR was 30.5 (IPIMC) and 10.7 (US). In both studies, extensive TDDs were less than 25% of all TDDs. Compared to all TDDs, extensive TDDs were more likely to occur after CVS performed earlier in the first trimester (before 10–11 weeks' gestation). These findings suggest a relationship between the timing of CVS and the severity of TDDs; indicate that using a restrictive definition of TDDs (all five digits affected) may limit the ability to evaluate the association between CVS and TDDs in populations in whom CVS is usually performed at or after 10 weeks' gestation; and highlight the necessity to consider gestational age in any evaluation of the relative risk for limb deficiencies associated with CVS. © 1996 Wiley-Liss, Inc.

Population-based birth-defect and risk-factor surveillance: data from the Northern Netherlands.

Abstract: In many countries, birth defect monitoring systems have been set up in order to identify new teratogens as soon as possible. The usual approach to monitoring involves analysis of the frequency of specific birth defects over time. This approach has been criticized as having poor statistical power to detect epidemics due to new rare teratogenic exposures. A proposed alternative approach is the on-going analysis of risk-factor data with a case-control approach. In this paper, we present birth-defects and risk-factor surveillance data from the Northern Netherlands (NNL). Forty years of birth 1881- 1994, 4014 cases had been registered. We investigated combinations of 32 diagnostic categories and 77 risk factors. For 10 combinations a P value < 0.01 was found; for another 25, the P value was between 0.01 and 0.05. We then checked these positive associations against data from the Metropolitan Atlanta Congenital Defects Program (MACDP) and the Maternal DRug Exposure surveillance project (MADRE). In all three data sets, an association between maternal use of psychotropic drugs (psycholeptics) and deft lip with or without cleft palate (CLP) was present. The highest odds ratio was found for CLP and maternal use of oxazepam in the NNL data (OR = 8.17, 95% CI 1.26-42.2). Both in the MACDP data and in the NNL data, an association between maternal smoking and clubfoot was found. Although the odds ratios were law, the attributable fraction derived from the NNL data was 11%. Methodologic issues that should be considered in this approach include exposure ascertainment and classification, outcome specificity, and type I errors. The strengths of this approach include its population-based nature and the ability of users to check results against results from other similar systems.

The interface between dysmorphology and epidemiology in the "diagnosis" and surveillance for fetal alcohol effects.

Abstract: We read with great interest the commentary of Aase et al entitled "Do we need the term fetal alcohol effects (FAE)?"1 As a public health agency, the Centers for Disease Control and Prevention (CDC) has been working with states and academic organizations to develop and evaluate prevention programs for fetal alcohol syndrome (FAS) A fundamental component of such programs is the design and implementation of population-based surveillance systems for FAS to track the magnitude of the problem to assess temporal trends related to intervention programs2,3

Population-based birth-defect and risk-factor surveillance: data from the Northern

Abstract: In many countries, birth defect monitoring systems have been set up in order to identify new teratogens as soon as possible. The usual approach to monitoring involves analysis of the frequency of specific birth defects over time. This approach has been criticized as having poor statistical power to detect epidemics due to new rare teratogenic exposures. A proposed alternative approach is the on-going analysis of risk-factor data with a case-control approach. In this paper, we present birth-defects and risk-factor surveillance data from the Northern Netherlands (NNL). For years of birth 1981- 1994, 4014 cases had been registered. We investigated combinations of 32 diagnostic categories and 77 risk factors. For 10 combinations a P value < 0.01 was found; for another 25, the P value was between 0.01 and 0.05. We then checked these positive associations against data from the Metropolitan Atlanta Congenital Defects Program (MACDP) and the MAternal DRug Exposure surveillance project (MADRE). In all three data sets, an association between maternal use of psychotropic drugs (psycholeptics) and cleft lip with or without cleft palate (CLP) was present. The highest odds ratio was found for CLP and maternal use of oxazepam in the NNL data (OR = 8.17, 95% CI 1.26-42.2). Both in the MACDP data and in the NNL data, an association between maternal smoking and clubfoot was found. Although the odds ratios were low, the attributable fraction derived from the NNL data was 11 %. Methodologic issues that should be considered in this approach include exposure ascertainment and classification, outcome specificity, and type I errors. The strengths of this approach include its population-based nature and the ability of users to check results against results from other similar systems.