Invited commentary: Testing for Hardy-Weinberg disequilibrium using a genome single-nucleotide polymorphism scan based on cases only.
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Epidemiologic Methods↗
Biomedical subjects
Clarice R Weinberg
Publications and source records attributed to Clarice R Weinberg.
Gene selection and clustering for time-course and dose-response microarray experiments using order-restricted inference.
We propose an algorithm for selecting and clustering genes according to their time-course or dose-response profiles using gene expression data. The proposed algorithm is based on the order-restricted inference methodology developed in statistics. We describe the methodology for time-course experiments although it is applicable to any ordered set of treatments. Candidate temporal profiles are defined in terms of inequalities among mean expression levels at the time points. The proposed algorithm selects genes when they meet a bootstrap-based criterion for statistical significance and assigns each selected gene to the best fitting candidate profile. We illustrate the methodology using data from a cDNA microarray experiment in which a breast cancer cell line was stimulated with estrogen for different time intervals. In this example, our method was able to identify several biologically interesting genes that previous analyses failed to reveal.
Algorithms↗
Subfecundity as a correlate of preeclampsia: a study within the Danish National Birth Cohort.
A long interpregnancy interval is associated with preeclampsia. If some women experiencing a long interval between births had difficulty conceiving, subfecundity and preeclampsia may share a common etiology. Therefore, the authors examined the association between subfecundity and preeclampsia. By using interview data collected during the second trimester of pregnancy (1998-2001) from women participating in the Danish National Birth Cohort, they identified 20,034 and 24,698 singleton livebirths to primiparous and multiparous women, respectively, for whom preeclampsia information was available from hospital birth records. Among women with no known hypertension, the authors estimated a higher risk of preeclampsia in those with longer times to pregnancy (TTPs), after adjustment for maternal age, prepregnancy body mass index, and smoking. Compared with primiparas who became pregnant right away (referent category), the risk of preeclampsia increased with TTP and then stabilized for women taking 6 months or longer to conceive, whose risk of preeclampsia increased by 50%. Multiparas also had an increased risk, but only those reporting a TTP longer than 12 months (odds ratio = 2.47, 95% confidence interval: 1.30, 4.69). The authors found that a long TTP was associated with preeclampsia, supporting the hypothesis that some factors delaying clinically recognized conception may also be in a causal pathway for preeclampsia.
Adult↗
Studying parents and grandparents to assess genetic contributions to early-onset disease.
Suppose DNA is available from affected individuals, their parents, and their grandparents. Particularly for early-onset diseases, maternally mediated genetic effects can play a role, because the mother determines the prenatal environment. The proposed maximum-likelihood approach for the detection of apparent transmission distortion treats the triad consisting of the affected individual and his or her two parents as the outcome, conditioning on grandparental mating types. Under a null model in which the allele under study does not confer susceptibility, either through linkage or directly, and when there are no maternally mediated genetic effects, conditional probabilities for specific triads are easily derived. A log-linear model permits a likelihood-ratio test (LRT) and allows the estimation of relative penetrances. The proposed approach is robust against genetic population stratification. Missing-data methods permit the inclusion of incomplete families, even if the missing person is the affected grandchild, as is the case when an induced abortion has followed the detection of a malformation. When screening multiple markers, one can begin by genotyping only the grandparents and the affected grandchildren. LRTs based on conditioning on grandparental mating types (i.e., ignoring the parents) have asymptotic relative efficiencies that are typically >150% (per family), compared with tests based on parents. A test for asymmetry in the number of copies carried by maternal versus paternal grandparents yields an LRT specific to maternal effects. One can then genotype the parents for only the genes that passed the initial screen. Conditioning on both the grandparents' and the affected grandchild's genotypes, a third log-linear model captures the remaining information, in an independent LRT for maternal effects.
Age of Onset↗
Rescue of the corpus luteum in human pregnancy.
Rescue of the corpus luteum from its programmed senescence maintains progesterone production required for pregnancy. In primates, chorionic gonadotropin produced by the developing conceptus acts as the primary luteotrophic signal. The purpose of this research was to assess corpus luteum rescue by examining changes in daily urinary progesterone metabolite levels during the first week after implantation. We determined the variability in progesterone metabolite profiles and evaluated its relationship to early pregnancy loss in 120 naturally conceived human pregnancies, including 43 early pregnancy losses. In other primates, an abrupt increase in the progesterone metabolite occurs at the time of implantation. This pattern occurred in an estimated 45% of the pregnancies in the present study. In the remaining pregnancies, there was a delayed rise (18%), neither a rise or decline (22%), or a decline (15%) during the week after implantation. The estimated rate of early pregnancy loss increased across these categories (from 5% loss with an abrupt rise at implantation to 100% loss with progesterone metabolite decline). Low urinary hCG levels in early pregnancy were significant determinants of a decline in postimplantation progesterone metabolite. However, preimplantation steroid metabolite levels were not significant, suggesting no inherent problem with the corpus luteum. Examination of individual progesterone metabolite profiles in relation to hCG profiles also indicated that few losses were caused by corpus luteum failure. Delineating the functional importance of an abrupt progesterone rise at the time of implantation may provide new strategies for promoting successful implantation in assisted reproduction.
Abortion, Spontaneous↗
A prospective study of the onset of symptoms of pregnancy.
The objective of this study was to provide prospectively collected data on the onset of pregnancy symptoms. Two hundred twenty-one women attempting pregnancy kept daily records of the occurrence of symptoms of pregnancy. Among 136 women delivering live infants, half began experiencing symptoms by day 36 after their last menstrual period (LMP), and 89% by the end of the eighth week. Onset of symptoms occurred later in pregnancies that went on to miscarry. Among 48 women with biochemically detected pregnancy loss before 6 weeks LMP, symptoms were substantially reduced but not entirely absent. Women who smoked tobacco or marijuana tended to have delayed onset of symptoms. Nearly 90% of women with successful pregnancies experience symptoms within 8 weeks LMP. Even pregnancies lost very early (before 6 weeks) are sometimes symptomatic. The earliest symptoms do not begin until after key stages of embryogenesis, reinforcing the need for women to initiate sound health behaviors before pregnancy is apparent. Published by Elsevier Science Inc.
Adult↗
Regarding "parental genotypes in the risk of a complex disease".
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Cytochrome P-450 CYP2E1↗
Analysis of clustered binary outcomes using within-cluster paired resampling.
Conditional logistic regression (CLR) is useful for analyzing clustered binary outcome data when interest lies in estimating a cluster-specific exposure parameter while treating the dependency arising from random cluster effects as a nuisance. CLR aggregates unmeasured cluster-specific factors into a cluster-specific baseline risk and is invalid in the presence of unmodeled heterogeneous covariate effects or within-cluster dependency. We propose an alternative, resampling-based method for analyzing clustered binary outcome data, within-cluster paired resampling (WCPR), which allows for within-cluster dependency not solely due to baseline heterogeneity. For example, dependency may be in part caused by heterogeneity in response to an exposure across clusters due to unmeasured cofactors. When both CLR and WCPR are valid, our simulations suggest that the two methods perform comparably. When CLR is invalid, WCPR continues to have good operating characteristics. For illustration, we apply both WCPR and CLR to a periodontal data set where there is heterogeneity in response to exposure across clusters.
Adult↗