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M J Khoury

Publications and source records attributed to M J Khoury.

At least 19 recordsLinked to original sources
PubMed2001

Informed consent for population-based research involving genetics.

Bridging the gap between gene discovery and our ability to use genetic information to benefit health requires population-based knowledge about the contribution of common gene variants and gene-environment interactions to the risk of disease. The risks and benefits associated with population-based research involving genetics, especially lower-penetrance gene variants, can differ in nature from those associated with family-based research. In response to the urgent need for appropriate guidelines, the Centers for Disease Control and Prevention formed a multidisciplinary group to develop an informed consent approach for integrating genetic variation into population-based research. The group used expert opinion and federal regulations, the National Bioethics Advisory Commission's report on research involving human biological materials, existing consent forms, and literature on informed consent to create suggested language for informed consent documents and a supplemental brochure. This language reflects the premise that the probability and magnitude of harm, as well as possible personal benefits, are directly related to the meaning of the results for the health of the participant and that appropriate disclosures and processes for obtaining consent should be based on an assessment at the outset of the likelihood that the results will generate information that could lead directly to an evidence-based intervention. This informed consent approach is proposed to promote discussion about how best to enable potential participants to make informed decisions about population-based research involving genetics and to suggest issues for consideration by research sponsors, institutional review boards, and investigators.

DNA↗
PubMed2001

Delta-aminolevulinic acid dehydratase genotype and lead toxicity: a HuGE review.

The ALAD gene (chromosome 9q34) codes for delta-aminolevulinic acid dehydratase (ALAD) (E.C. 4.2.1.24). ALAD catalyzes the second step of heme synthesis and is polymorphic. The ALAD G177C polymorphism yields two codominant alleles, ALAD-1 and ALAD-2, and it has been implicated in susceptibility to lead toxicity. Genotype frequencies vary by geography and race. The rarer ALAD-2 allele has been associated with high blood lead levels and has been thought to increase the risk of lead toxicity by generating a protein that binds lead more tightly than the ALAD-1 protein. Other evidence suggests that ALAD-2 may confer resistance to the harmful effects of lead by sequestering lead, making it unavailable for pathophysiologic participation. Recent studies have shown that individuals who are homozygous for the ALAD-1 allele have higher cortical bone lead levels; this implies that they may have a greater body lead burden and may be at higher risk of the long-term effects of lead. Individuals exposed to lead in occupational settings have been the most frequent subjects of study. Genotype selection bias may limit inferences from these studies. No firm evidence exists for an association between ALAD genotype and susceptibility to lead toxicity at background exposure levels; therefore, population testing for the ALAD polymorphism is not justified.

Gene Frequency↗
PubMed2001

Commentary: facing the challenge of gene-environment interaction: the two-by-four table and beyond.

As a result of the Human Genome Project, epidemiologists can study thousands of genes and their interaction with the environment. The challenge is how to best present and analyze such studies of multiple genetic and environmental factors. The authors suggest emphasizing the fundamental core of gene-environment interaction-the separate assessment of the effects of individual and joint risk factors. In the simple analysis of one genotype and an exposure (both dichotomous), such study can be summarized in a two-by-four table. The advantages of such a table for data presentation and analysis are many: The table displays the data efficiently and highlights sample size issues; it allows for evaluation of the independent and joint roles of genotype and exposure on disease risk; and it emphasizes effect estimation over model testing. Researchers can easily estimate relative risks and attributable fractions and test different models of interaction. The two-by-four table is a useful tool for presenting, analyzing, and synthesizing data on gene-environment interaction. To highlight the role of gene-environment interaction in disease causation, the authors propose that the two-by-four table is the fundamental unit of epidemiologic analysis.

Environment↗
PubMed2001

Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States.

CONTEXT: Population-based estimates of the prevalence of disease-associated mutations, such as hemochromatosis (HFE) gene mutations, are needed to determine the usefulness of genetic screening. OBJECTIVE: To estimate the prevalence of the HFE mutations C282Y and H63D in the US population. DESIGN: Cross-sectional population-based study of samples in the DNA bank from phase 2 of the Third National Health and Nutrition Examination Survey conducted from 1992 to 1994. SETTING AND PARTICIPANTS: Genotyped samples of cells from a total of 5171 participants, cross-classified by sex, age, and race/ethnicity in the analysis. MAIN OUTCOME MEASURES: Estimates of the prevalence of C282Y and H63D mutations. RESULTS: The prevalence of C282Y homozygosity is estimated to be 0.26% (95% confidence interval [CI], 0.12%-0.49%); 1.89% (95% CI, 1.48%-2.43%) for H63D homozygosity; and 1.97% (95% CI, 1.54%-2.49%) for compound heterozygosity. The prevalence estimates for C282Y heterozygosity (C282Y/wild type) are 9.54% among non-Hispanic whites, 2.33% among non-Hispanic blacks, and 2.75% among Mexican-Americans. The prevalence estimates of the C282Y mutation in the US population are 5.4% (95% CI, 4.7%-6.2%) and 13.5% (95% CI, 12.5%-14.8%) for the H63D mutation. CONCLUSIONS: Estimates of prevalence of HFE mutations are within the expected range for non-Hispanic whites and blacks but the estimated prevalence of the C282Y mutation among Mexican-Americans is less than expected. Mutation data now need to be linked to clinically relevant indices, such as transferrin saturation level.

Genotype↗
PubMed2001

A case-control study of maternal alcohol consumption and intrauterine growth retardation.

PURPOSE: Heavy maternal drinking during pregnancy causes fetal alcohol syndrome, but whether more moderate alcohol consumption is associated with such adverse pregnancy outcomes as intrauterine growth retardation (IUGR) remains controversial. METHODS: Using data from a case-control study, we examined the association between maternal alcohol consumption and risk for IUGR among 701 case and 336 control infants born during 1993-1995 in Monroe County, New York. RESULTS: Our results provide no evidence of an independent association between moderate maternal alcohol consumption (<14 drinks per week) and risk for IUGR. The risk for IUGR among heavy drinkers (> or =14 drinks per week) around the time of conception was OR = 1.4 (95% CI 0.7-2.6) for IUGR < or = 5th percentile and OR = 1.4 (95% CI 0.7-2.8) for IUGR 5th-10th percentile. For heavy drinkers during the first trimester, the OR was 1.3 (95% CI 0.4-4.5) for IUGR < or = 5th percentile and OR = 1.3 (95% CI 0.4-4.8) for IUGR 5th-10th percentile. CONCLUSIONS: Since IUGR is a heterogeneous outcome with a possible multifactorial origin, further studies are needed to examine the combined effects of alcohol and other environmental and genetic factors on IUGR risk for subgroups of IUGR.

Adult↗
PubMed2001

Application of population screening principles to genetic screening for adult-onset conditions.

Recent advances in molecular genetics have highlighted the potential use of genetic testing to screen for adult-onset chronic diseases. Several issues must be addressed, however, before such tests can be recommended for population-based prevention programs. These issues include the adequacy of the scientific evidence, the balance of risks and benefits, the need for counseling and informed consent, and the costs and resources required. Ongoing assessment of the screening program and quality assurance of laboratory testing are also needed. This paper considers the application of general principles for mass screening to genetic testing for susceptibility to adult-onset chronic diseases. Evaluation of proposals for genetic screening in context of these principles reveals that needed evidence is often absent, particularly with respect to the predictive value of tests, efficacy of interventions, and social consequences of testing. The principles of population screening are developed into a framework for public health policy on genetic screening that has three stages: assessment of the screening test and interventions for those who test positive, including assessment of risks and costs, policy development, and program evaluation. Essential elements are identified, including evaluation of evidence and processes for consensus development and program evaluation. The proposed framework for public health policymaking outlined in this commentary, when combined with future efforts that involve an authoritative consensus process, may be useful for the evaluation and planning of genetic screening programs aimed at reducing morbidity and mortality from adult-onset chronic diseases.

Adult↗
PubMed2001

Vitamin A and cardiac outflow tract defects.

To assess the relationship between maternal intake of vitamin A and cardiac outflow tract defects, we examined data from a population-based case-control study among liveborn infants born from 1987 through 1989 to mothers residing in the Baltimore-Washington area. Case infants (126) had a nonsyndromic cardiac outflow tract defect. Control infants (679) did not have birth defects and were a stratified random sample of liveborn infants from the same area. The main exposure was average daily maternal intake of retinol and provitamin A carotenoids from foods and supplements during the year before conception. Compared with an average intake of less than 10,000 IU, retinol intake of 10,000 IU or more from supplements was associated with a ninefold increased risk for transposition of the great arteries (odds ratio = 9.2; 95% confidence interval = 4.0-21.2), but not for outflow tract defects with normally related arteries (odds ratio = 0.8; 95% confidence interval = 0.1-6.6). Similar intakes of carotenoids and dietary retinol were not associated with an increased risk for either type of outflow tract defect.

Adult↗
PubMed2001

Public attitudes regarding the donation and storage of blood specimens for genetic research.

OBJECTIVE: As sequencing of the human genome is completed, there is a need for population-based research to assess frequencies of genetic variants and their associations with human diseases. The authors therefore assessed the current climate regarding the donation and storage of blood for genetic research. METHODS: Data from the American Healthstyles Survey fo health attitudes and behavior were examined. In the 1998 survey, four questions regarding blood donation and storage for genetic research were posed to the participants. RESULTS: Of 3,130 participants, 2,621 (84%) completed these questions. Of the respondents, 42% were in favor of both blood donation and long-term storage for genetic research, 37% were in favor of either blood donation or storage but not both and 21% were not willing to donate blood or have it stored for genetic research under any circumstances. Loglinear analysis demonstrated that the characteristics of respondents who favored blood donation and long-term storage for genetic research were attitudinal; specifically, those believing that genetic research will prevent disease [odds ratio (OR) 2.9; p<0.001]; those believing in genetic determinism (OR 1.5; p=0.004) and those agreeing they would participate in government research (OR 2.9; p<0.001). The model also demonstrated that characteristics indirectly associated with attitudes toward blood donation/storage for genetic research were demographic and included higher education, white race, living in the Mountain/Pacific or mid-Atlantic regions of the United States and positive family history of a genetic disorder (p<0.05). CONCLUSION: Understanding the various factors contributing to knowledge, attitudes and behavior regarding the donation and storage of blood specimens for genetic research will contribute to future actions in communication genetic research goals to the public and recruitment for population-based genetic studies.

Adult↗
PubMed2001

Early diagnosis of cystic fibrosis in the newborn period and risk of Pseudomonas aeruginosa acquisition in the first 10 years of life: A registry-based longitudinal study.

OBJECTIVE: Controlled clinical trial data have suggested that identifying asymptomatic cystic fibrosis (CF) patients through newborn screening improves health outcomes of affected children in the first decade of life. However, it is unclear whether these improvements also include a reduction in risk for bronchial infection, the major determinant of CF morbidity. The authors therefore investigated the association between early CF diagnosis and acquisition of Pseudomonas aeruginosa, the major bronchial pathogen, in the first decade of life. METHODOLOGY: Longitudinal data on 3625 CF patients diagnosed between 1982 and 1990 and before 36 months of age were ascertained from the National Cystic Fibrosis Patient Registry. We compared P aeruginosa acquisition in the first 10 years of life among 4 groups: EAD (early asymptomatic diagnosis)-<6 weeks, by pre/neonatal screening, genotype, family history (n = 157); ESD (early symptomatic diagnosis) (n = 227); LAD (late asymptomatic diagnosis)-6 weeks to 36 months (n = 161); and LSD (late symptomatic diagnosis) (n = 3080). P aeruginosa acquisition was determined from yearly sputum and/or bronchoscopy cultures. Children whose CF diagnoses followed meconium ileus or whose cultures were obtained only from nasal samples were excluded from the study. RESULTS: Kaplan Meier analyses for P aeruginosa acquisition were conducted for each diagnostic group. Regression models were used to generate adjusted relative hazards with EAD as the referent group. Relative hazards were 0.9 (95% confidence interval [CI]: 0.7-1.2) for ESD, 0.8 (95% CI: 0.6-1.2) for LAD, and 1.0 (95% CI: 0.7-1.2) for LSD. The risk of acquiring P aeruginosa was therefore not significantly different between children diagnosed early, late, asymptomatically, or symptomatically. CONCLUSIONS: These data suggest that, despite improvements in other health outcomes from newborn screening for CF, early asymptomatic diagnosis of CF does not affect P aeruginosa acquisition.

Analysis of Variance↗
PubMed2000

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

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.

Cleft Palate↗
PubMed2000

Bias associated with study protocols in epidemiologic studies of disease familial aggregation.

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.

Bias↗