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Clarice R Weinberg

Publications and source records attributed to Clarice R Weinberg.

At least 19 recordsLinked to original sources
PubMed2006

Orofacial cleft risk is increased with maternal smoking and specific detoxification-gene variants.

Maternal smoking is a recognized risk factor for orofacial clefts. Maternal or fetal pharmacogenetic variants are plausible modulators of this risk. In this work, we studied 5,427 DNA samples, including 1,244 from subjects in Denmark and Iowa with facial clefting and 4,183 from parents, siblings, or unrelated population controls. We examined 25 single-nucleotide polymorphisms in 16 genes in pathways for detoxification of components of cigarette smoke, to look for evidence of gene-environment interactions. For genes identified as related to oral clefting, we studied gene-expression profiles in fetal development in the relevant tissues and time intervals. Maternal smoking was a significant risk factor for clefting and showed dosage effects, in both the Danish and Iowan data. Suggestive effects of variants in the fetal NAT2 and CYP1A1 genes were observed in both the Iowan and the Danish participants. In an expanded case set, NAT2 continued to show significant overtransmission of an allele to the fetus, with a final P value of .00003. There was an interaction between maternal smoking and fetal inheritance of a GSTT1-null deletion, seen in both the Danish (P=.03) and Iowan (P=.002) studies, with a Fisher's combined P value of <.001, which remained significant after correction for multiple comparisons. Gene-expression analysis demonstrated expression of GSTT1 in human embryonic craniofacial tissues during the relevant developmental interval. This study benefited from two large samples, involving independent populations, that provided substantial power and a framework for future studies that could identify a susceptible population for preventive health care.

Arylamine N-Acetyltransferase↗
PubMed2006

Trends in fetal and infant survival following preeclampsia.

CONTEXT: Management of preeclampsia often culminates in induced delivery of a very preterm infant. While early termination protects the fetus from an intrauterine death, the newborn then faces increased risks associated with preterm delivery. This practice has increased in recent decades, but its net effect on fetal and infant survival has not been assessed. OBJECTIVE: To assess the effect on fetal and infant survival of increased rates of early delivery of preeclamptic pregnancies. DESIGN, SETTING, AND PARTICIPANTS: Population-based observational longitudinal study using registry data from 804 448 singleton first-born infants with Norwegian-born mothers and registered in the Medical Birth Registry of Norway between 1967 and 2003. MAIN OUTCOME MEASURES: Odds ratio (OR) of fetal and early childhood death in relation to preeclampsia. RESULTS: Among preeclamptic pregnancies, inductions before 37 weeks increased from 8% in 1967-1978 to nearly 20% in 1991-2003. During this period, the adjusted OR for stillbirth decreased from 4.2 (95% confidence interval [CI], 3.8-4.7) to 1.3 (95% CI, 1.1-1.7) for preeclamptic compared with nonpreeclamptic pregnancies. During the same period, the OR for neonatal death after preeclamptic pregnancy remained relatively stable (1.7 in 1967-1978 vs 2.0 in 1991-2003). Later infant and childhood mortality also showed little change. CONCLUSIONS: Fetal survival in preeclamptic pregnancies has vastly improved over the past 35 years in Norway, presumably because of more aggressive clinical management. However, the relative risk of neonatal death following a preeclamptic pregnancy has not changed over time.

Cesarean Section↗
PubMed2006

Misclassification of gestational age in the study of spontaneous abortion.

Most studies of spontaneous abortion are subject to left truncation, because conception is not observed and thus pregnant women are enrolled postconception. Cox regression can account for left truncation but uses gestational age data, which may be inaccurate. Dating is affected by reporting errors and variability in the day of ovulation. These errors may be differential by outcome, because gestational ages are more likely to be clinically corrected in continuing pregnancies than in pregnancies ending in spontaneous abortion. Errors may be differential by exposure status as well, if exposures affect the time of ovulation. The authors designed a simulation to examine bias caused by errors in gestational age. Pregnancies were assigned true and alternative gestational ages using different assumptions about random reporting error and error due to variation in the time between the last menstrual period and ovulation. In separate scenarios, the errors were differential by outcome, differential by exposure, differential by both exposure and outcome, or nondifferential. Hazard ratios were compared using accurate versus erroneous gestational ages. For proportional hazards, bias was only introduced when the error in gestational age was differential by exposure status. Bias was greatest when the magnitude of error for pregnancies at higher risk was much larger than that for pregnancies at lower risk.

Abortion, Spontaneous↗
PubMed2006

Birth weight and mortality: causality or confounding?

The association between birth weight and mortality is among the strongest seen in epidemiology. While preterm delivery causes both small babies and high mortality, it does not explain this association. Fetal growth restriction has also been proposed, although its features are unclear because it lacks a definition independent of weight. If, as some postulate, birth weight is not itself on the causal path to mortality, its relation with mortality would have to be explained by confounding factors that decrease birth weight and increase mortality. In this paper, the authors explore the characteristics such confounders would require in order to achieve the observed association between birth weight and mortality. Through a simple simulation, they found that the observed steep gradient of risk for small babies at term can be produced by a rare condition or conditions (with a total prevalence of 0.5%) having profound effects on both fetal growth (-1.7 standard deviations) and mortality (relative risk = 160). Candidate conditions might include malformations, fetal or placental aneuploidy, infections, or imprinting disorders. If such rare factors underlie the association of birth weight with mortality, it would have broad implications for the study of fetal growth restriction and birth weight, and for the prevention of infant mortality.

Birth Weight↗
PubMed2006

Phase analysis of circadian-related genes in two tissues.

BACKGROUND: Recent circadian clock studies using gene expression microarray in two different tissues of mouse have revealed not all circadian-related genes are synchronized in phase or peak expression times across tissues in vivo. Instead, some circadian-related genes may be delayed by 4-8 hrs in peak expression in one tissue relative to the other. These interesting biological observations prompt a statistical question regarding how to distinguish the synchronized genes from genes that are systematically lagged in phase/peak expression time across two tissues. RESULTS: We propose a set of techniques from circular statistics to analyze phase angles of circadian-related genes in two tissues. We first estimate the phases of a cycling gene separately in each tissue, which are then used to estimate the paired angular difference of the phase angles of the gene in the two tissues. These differences are modeled as a mixture of two von Mises distributions which enables us to cluster genes into two groups; one group having synchronized transcripts with the same phase in the two tissues, the other containing transcripts with a discrepancy in phase between the two tissues. For each cluster of genes we assess the association of phases across the tissue types using circular-circular regression. We also develop a bootstrap methodology based on a circular-circular regression model to evaluate the improvement in fit provided by allowing two components versus a one-component von-Mises model. CONCLUSION: We applied our proposed methodologies to the circadian-related genes common to heart and liver tissues in Storch et al. 2, and found that an estimated 80% of circadian-related transcripts common to heart and liver tissues were synchronized in phase, and the other 20% of transcripts were lagged about 8 hours in liver relative to heart. The bootstrap p-value for being one cluster is 0.063, which suggests the possibility of two clusters. Our methodologies can be extended to analyze peak expression times of circadian-related genes across more than two tissues, for example, kidney, heart, liver, and the suprachiasmatic nuclei (SCN) of the hypothalamus.

Animals↗
PubMed2006

Indoor radon and lung cancer risk in connecticut and utah.

Radon is a well-established cause of lung cancer in miners. Residents of homes with high levels of radon are potentially also at risk. Although most individual studies of indoor radon have failed to demonstrate significant risks, results have generally been consistent with estimates from studies of miners. We studied 1474 incident lung cancer cases aged 40-79 yr in Connecticut, Utah, and southern Idaho. Population controls (n = 1811) were identified by random telephone screening and from lists of Medicare recipients, and were selected to be similar to cases on age, gender, and smoking 10 yr before diagnosis/interview using randomized recruitment. Complete residential histories and information on known lung cancer risk factors were obtained by in-person and telephone interviews. Radon was measured on multiple levels of past and current homes using 12-mo alpha-track etch detectors. Missing data were imputed using mean radon concentrations for informative subgroups of controls. Average radon exposures were lower than anticipated, with median values of 23 Bq/m3 in Connecticut and 45 Bq/m3 in Utah/southern Idaho. Overall, there was little association between time-weighted average radon exposures 5 to 25 yr prior to diagnosis/interview and lung cancer risk. The excess relative risk (ERR) associated with a 100-Bq/m3 increase in radon level was 0.002 (95% CI -0.21, 0.21) in the overall population, 0.134 (95% CI -0.23, 0.50) in Connecticut, and -0.112 (95% CI -0.34, 0.11) in Utah/Idaho. ERRs were higher for some subgroups less prone to misclassification, but there was no group with a statistically significant linear increase in risk. While results were consistent with the estimates from studies of miners, this study provides no evidence of an increased risk for lung cancer at the exposure levels observed.

Adult↗
PubMed2006

Xenobiotic-metabolizing genes and small-for-gestational-age births: interaction with maternal smoking.

BACKGROUND: Little is known about the role of xenobiotic-metabolizing gene variants as risk factors for small-for-gestational-age (SGA) births or as modifiers for the effects of exposures such as maternal smoking. METHODS: We conducted 2 joint studies: a case-control design including 493 cases (birth weight below the 10th percentile according to gestational age and sex) and 472 controls (at or above the 10th percentile) and a family-based study (mother, father, and newborn) with approximately 250 case trios and a similar number of control trios. Logistic regression and a log-linear model were used to analyze the association between genetic variants such as CYP1A1*2A, CYP1A1*2B, CYP1A1*4, GSTT1, GSTM1, and XRCC3 and SGA. The interaction between genetic variants and maternal smoking was also studied. RESULTS: The odds ratio (OR) for the association of complete maternal GSTT1 deletion with SGA was 0.63 (95% confidence interval = 0.41-0.97), and that for the complete newborn GSTM1 deletion was 0.74 (0.55-0.98). Newborns with the partial GSTT1 deletion had an OR of 1.40 (1.01-1.95), and newborns homozygous for CYP1A1*2A had an OR of 4.28 (1.02-18.0). These results were coherent with the trio-based results. Significant interactions were observed between maternal smoking in the third trimester and CYP1A1*2A (P = 0.03), XRCC3 (P = 0.03), and newborn GSTT1 (P = 0.01). CONCLUSIONS: Certain genetic variants involved in the metabolism of xenobiotics increase the risk of SGA, as well as modify the effects of maternal smoking by increasing or decreasing its risk.

Adult↗
PubMed2005

A method for using incomplete triads to test maternally mediated genetic effects and parent-of-origin effects in relation to a quantitative trait.

The authors recently developed a semiparametric family-based test for linkage and association between markers and quantitative traits. This quantitative polytomous logistic regression test allows for analysis of families with incomplete information on parental genotype. In addition, it is not necessary to assume normality of the quantitative trait. Previous simulations have shown that the new test is as powerful as the other widely used tests for linkage disequilibrium in relation to a quantitative trait. Here the authors propose an extension to quantitative polytomous logistic regression that allows testing for maternally mediated effects and parent-of-origin effects in the same framework. Missing data on parental genotype are accommodated through an expectation-maximization algorithm approach. Simulations show robustness of the new tests and good power for detecting effects in the presence or absence of offspring effects. Methods are illustrated with birth weight and gestational length, two quantitative outcomes for which data were collected in a Montreal, Canada, study of intrauterine growth restriction between May 1998 and June 2000.

Computer Simulation↗
PubMed2005

Parent-of-origin transmission of thrombophilic alleles to intrauterine growth-restricted newborns and transmission-ratio distortion in unaffected newborns.

Findings on the role of thrombophilic polymorphisms in adverse pregnancy outcomes, particularly intrauterine growth restriction, are inconsistent. Such inconsistencies may be partly due to two types of effects which have not been considered before with regard to thrombophilic genes: parent-of-origin effects (imprinting) and transmission-ratio distortion effects (allele transmission differing from that expected in unaffected subjects). In this study of infants born at a Canadian hospital (1998-2000), the authors investigated both types of effects. Cases (n = 493) were defined as newborns whose birth weight for gestational age and sex was below the 10th percentile by national standards, and controls (n = 472) as newborns at or above the 10th percentile. Log-linear models were used to analyze the transmission of variant alleles among case- and control-parent trios. A single copy of a common polymorphism, Val34Leu in factor XIII, increased the risk of intrauterine growth restriction approximately 70% when the parent of origin was the father as opposed to the mother (p < 0.05). Among unaffected newborns, transmission of A1298C in the methylenetetrahydrofolate reductase gene (p < 0.005), transmission of the G1691A variant in factor V Leiden (p < 0.002), and transmission of the G20210A variant in the prothrombin (factor II) gene (p < 0.001) occurred significantly less often than expected (transmission-ratio distortion). Affected newborns also inherited the prothrombin G20210A variant significantly less often than expected. These results suggest that these three genes exhibit segregation distortion or reduce gestational survival.

Alleles↗
PubMed2005

Evaluation of offspring and maternal genetic effects on disease risk using a family-based approach: the "pent" design.

Diseases that develop during gestation may be influenced by the genotype of the mother and the inherited genotype of the embryo/fetus. However, given the correlation between maternal and offspring genotypes, differentiating between inherited and maternal genetic effects is not straightforward. The two-step transmission disequilibrium test was the first, family-based test proposed for the purpose of differentiating between maternal and offspring genetic effects. However, this approach, which requires data from "pents" comprising an affected child, mother, father, and maternal grandparents, provides biased tests for maternal genetic effects when the offspring genotype is associated with disease. An alternative approach based on transmissions from grandparents provides unbiased tests for maternal and offspring genetic effects but requires genotype information for paternal grandparents in addition to pents. The authors have developed two additional, pent-based approaches for the evaluation of maternal and offspring genetic effects. One approach requires the assumption of genetic mating type symmetry (pent-1), whereas the other does not (pent-2). Simulation studies demonstrate that both of these approaches provide valid estimation and testing for offspring and maternal genotypic effects. In addition, the power of the pent-1 approach is comparable with that of the approach based on data using all four grandparents.

Age of Onset↗
PubMed2005

Intact HCG, free HCG beta subunit and HCG beta core fragment: longitudinal patterns in urine during early pregnancy.

BACKGROUND: Detecting and monitoring early pregnancy depend on the measurement of HCG. Little is known about how production of various forms of HCG may evolve over the earliest weeks of pregnancy, particularly in naturally conceived pregnancies. METHODS: We describe the daily excretion of three urinary HCG analytes during the first 6 weeks post-conception in 37 naturally conceived pregnancies ending in singleton birth. We assayed daily first morning urine samples for intact HCG, free beta subunit and beta?core fragment, plus the combined measurement of these HCG forms. We calculated doubling times for each analyte and the inter- and intra-subject day-to-day variation. RESULTS: Intact HCG and the free beta subunit were initially the predominant forms of HCG, with the beta core fragment emerging as the predominant form in the fifth week after conception. Intact HCG and the free beta subunit showed the most day-to-day variability, and were transiently undetectable even 10 days after detection of pregnancy. The most stable estimate of doubling time was provided by the combined measurement of all these forms. CONCLUSIONS: Although intact HCG is usually regarded as the main analyte for detection and monitoring of early pregnancy, it can fluctuate markedly during early pregnancy. This variability could affect pregnancy test results based on early pregnancy urine, and may distort estimates of doubling time. Assays that combine several forms of HCG may be more reliable.

Adult↗
PubMed2005

Seasonal influence on the onset of idiopathic inflammatory myopathies in serologically defined groups.

OBJECTIVE: To assess possible seasonal patterns in the onset of polymyositis (PM) and dermatomyositis (DM). METHODS: The study group comprised 503 patients who met the criteria for probable or definite PM or DM and for whom detailed data on the time of myositis onset were available. Statistical analyses were performed using a Poisson model that assessed associations of ethnicity, sex, autoantibody presence, and month of onset of muscle weakness. RESULTS: There were no significant seasonal patterns of disease onset in myositis patients as a whole or in the total PM or DM populations. Significant seasonal associations were present, however, in the serologically defined groups. In the 131 patients with antisynthetase autoantibodies who were categorized as non-black, myositis onset peaked in March-April (P = 0.03). Among the antisynthetase-positive patients, the association was predominantly in those with PM (n = 85; P = 0.05) and in men (n = 51; P = 0.042). Patients with anti-signal recognition particle autoantibodies, however, did not have a significant seasonal onset, which is in contrast to previous findings. Patients without myositis-specific autoantibodies showed a significant peak in summer, with myositis onset in June-July (n = 252; P = 0.03); this seasonal association was significant in women (n = 182; P = 0.005), whereas there was no seasonal pattern in men (P = 0.9). CONCLUSION: These findings, in conjunction with other data, suggest that diverse environmental agents, acting upon different immunogenetic backgrounds, result in distinct immune responses and clinical syndromes in the idiopathic inflammatory myopathies. Our results emphasize the importance of considering more homogeneous disease groups, based on clinicopathologic features, immune responses, ethnicity, and sex, when attempting to decipher the pathogeneses of autoimmune disorders.

Autoantibodies↗
PubMed2005

A method for identifying genes related to a quantitative trait, incorporating multiple siblings and missing parents.

When studying either qualitative or quantitative traits, tests of association in the presence of linkage are necessary for fine-mapping. In a previous report, we suggested a polytomous logistic approach to testing linkage and association between a di-allelic marker and a quantitative trait locus, using genotyped triads, consisting of an individual whose quantitative trait has been measured and his or her two parents. Here we extend that approach to incorporate marker information from entire nuclear families. By computing a weighted score function instead of a maximum likelihood test, we allow for both an unspecified correlation structure between siblings and "informative" family size. Both this approach and our original approach allow for population admixture by conditioning on parental genotypes. The proposed method allows for missing parental genotype data through a multiple imputation procedure. We use simulations based on a population with admixture to compare our method to a popular non-parametric family-based association test (FBAT), testing the null of no association in the presence of linkage.

Alleles↗
PubMed2005

Has human fertility declined over time?: why we may never know.

BACKGROUND: Reports of decreased semen quality over time have raised concerns about possible reductions in human fertility. Studies of couple fertility have produced conflicting results. We evaluate how changes in the availability and use of effective contraception and induced abortion might bias the direct study of time trends in couple fertility. METHODS: We assess the potential for bias in the context of 2 common study designs: (1) a study of time-to-pregnancy that estimates fecundability (excluding unintended pregnancies) and (2) a study of infertility rates that categorizes couples as fertile or infertile (including couples with unintended pregnancies as fertile). RESULTS: In time-to-pregnancy studies, bias alone could produce more than a 2-fold apparent increase in fecundability over recent decades. In studies of infertility rates, the bias works in the opposite direction: a 30% underestimation of infertility during earlier decades could produce an apparent decrease in fertility over time. CONCLUSIONS: Over the past 5 decades, changes in social factors that affect the rate and fate of unintended pregnancies could substantially bias time trends in fertility. These biases may explain the conflicting reports in the literature. Except in rare settings in which the factors affecting reproductive choices have not changed, it is probably impossible to identify biologic changes in fertility over recent decades.

Abortion, Induced↗
PubMed2004

On the frequency of intercourse around ovulation: evidence for biological influences.

BACKGROUND: Intercourse in mammals is often coordinated with ovulation, for example through fluctuations in libido or by the acceleration of ovulation with intercourse. Such coordination has not been established in humans. We explored this possibility by examining patterns of sexual intercourse in relation to ovulation. METHODS: Sixty-eight sexually active North Carolina women with either an intrauterine device or tubal ligation provided data for up to three menstrual cycles. These women collected daily urine specimens and kept daily diaries of intercourse and menstrual bleeding. Major estrogen and progesterone metabolites excreted in urine were used to identify the day of ovulation. The fertile days of the cycle were defined as the 6 consecutive days ending with ovulation. Women contributed a total of 171 ovulatory cycles. Menstrual bleeding days were excluded from analysis. RESULTS: The frequency of intercourse rose during the follicular phase, peaking at ovulation and declining abruptly thereafter. The 6 consecutive days with most frequent intercourse corresponded with the 6 fertile days of the menstrual cycle. Intercourse was 24% more frequent during the 6 fertile days than during the remaining non-bleeding days (P < 0.001). CONCLUSIONS: There apparently are biological factors that promote intercourse during a woman's 6 fertile days.

Adult↗
PubMed2004

Height and risk of severe pre-eclampsia. A study within the Danish National Birth Cohort.

BACKGROUND: Pre-eclampsia shares a number of risk factors with cardiovascular disease (CVD). Women with recurrent pre-eclampsia or pre-eclampsia early in pregnancy reportedly have an increased long-term risk of CVD. Short stature is a risk factor for CVD but has rarely been examined in relation to pre-eclampsia. METHODS: We used data from 59 968 singleton live births in the Danish National Birth Cohort born between 1998 and 2001 to assess risk of severe pre-eclampsia/eclampsia (296 cases) in relation to self-reported height. We examined the association in multiple logistic regressions stratified by parity. RESULTS: Among primiparas there was a weak association (compared with women <165 cm, women >172 cm had on OR of 0.79, 95% CI: 0.55, 1.14). Among multiparas, the tallest women had an adjusted OR of 0.42 (95% CI: 0.20, 0.87) of developing severe pre-eclampsia compared with women <165 cm. The OR per centimetre was 0.94 (95% CI: 0.91, 0.97). Self-reported pre-existing hypertension did not explain this association, which also persisted when the analysis was restricted to non-overweight women. CONCLUSIONS: Short stature was associated with a higher risk of severe pre-eclampsia in multiparas participating in the Danish National Birth Cohort.

Body Height↗
PubMed2004

A random-periods model for expression of cell-cycle genes.

We propose a nonlinear regression model for quantitatively analyzing periodic gene expression in studies of experimentally synchronized cells. Our model accounts for the observed attenuation in cycle amplitude by a simple and biologically plausible mechanism. We represent the expression level for each gene as an average across a large number of cells. For a given cell-cycle gene, we model its expression in each cell in the culture as following the same sinusoidal function except that the period, which in any individual cell must be the same for all cell-cycle genes, varies randomly across cells. We model these random periods by using a lognormal distribution. The variability in period causes the measured amplitude of the cyclic expression trajectory to attenuate over time as cells fall increasingly out of synchrony. Gene-specific parameters include initial amplitude and phase angle. Applying the model to data from Whitfield et al. [Whitfield, M. L., Sherlock, G., Saldanha, A. J., Murray, J, I., Ball, C. A., et al. (2002) Mol. Biol. Cell 13, 1977-2000], we fit the trajectories of 18 well characterized phase-marker genes and find that the fit does not suffer when a common lognormal distribution is assumed for all 18 genes compared with a separate distribution for each. We then use the model to identify 337 periodically expressed transcripts, including the 18 phase-marker genes. The model permits estimation of and hypothesis testing about biologically meaningful parameters that characterize cycling genes.

Gene Expression↗