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Biomedical subjects

C R Weinberg

Publications and source records attributed to C R Weinberg.

At least 19 recordsLinked to original sources
PubMed1997

Designing and analysing case-control studies to exploit independence of genotype and exposure.

Genetic susceptibility and environmental exposures play a synergistic role in the aetiology of many diseases. We consider a case-control study of a rare disease in relation to a categorical exposure and a genetic factor under the assumption that the genotype and the exposure occur independently in the population under study. Using a logistic model for risk, we describe maximum likelihood methods based on log-linear models that explicitly impose the independence assumption, something the usual logistic regression analyses cannot do. The estimator of the genotype-exposure interaction effect depends only on data from cases. Estimators for genotype and for exposure effects depend also no data from controls, but only through their respective marginal totals. All three estimators have smaller variance than they would were independence not enforced. These results have important implications for design: (i) Case-only studies can efficiently estimate gene-by-environment interactions. (ii) Studies where controls are genotyped anonymously can estimate genotype, exposure, and interaction effects as efficiently as designs where genotype and exposure data are linked. This feature addresses a growing concern of human subjects review boards. (iii) Exposure and interaction effects, but not genotype effects, can be estimated from studies where genetic information is only collected from cases (although one can recover the genotype effect if external gene prevalence data exist). Such designs have the compensatory benefit that the response rate (hence, validity) is higher when controls are not subjected to intrusive tissue sampling. However, the independence assumption can be checked only with linked genotype and exposure data for some controls. We illustrate the methods by applying them to recent study of cleft palate in relation to maternal cigarette smoking and to a variant of the transforming growth factor alpha gene in the child.

Case-Control Studies↗
PubMed1996

Statistical evidence for shared transient causes of anatomically distinct birth defects.

Certain pairs of anatomically distinct birth defects co-occur in the same baby more often than predicted under independence. Such an excess might reflects either the fact that some subpopulations of parents have inherently increased risk for both, or that certain pregnancies are at increased risk for both, even within the same couple, perhaps, due to transient exposures specific to the pregnancy. We focus on the latter possibility in the context of a large birth registry and two relatively common types of defects, by testing the null hypothesis that within sibships the two defects occur independently. Focusing on sibships where both defects occurred, we propose a test based on the total number of 'co-incidences', sibships where both occurred in the same baby. Such a test can be carried out either with or without allowance for possible dependence of risk on birth order. Applying this to club foot and sex organ defects among sibships from the Medical Birth Registry of Norway, we find strong evidence for excess within-family co-incidence, suggesting that there are shared, time-varying (hence perhaps modifiable) causal components in their aetiology.

Abnormalities, Multiple↗
PubMed1996

Vaginal douching and reduced fertility.

OBJECTIVES: This study investigated douching and reduced fertility. METHODS: The monthly probability of conception for douchers and nondouchers was compared in a sample of 840 married, parous women in King County, Washington. Data on the number of months required to conceive were analyzed. RESULTS: In comparison with nondouchers, women who douched were 30% less likely to become pregnant each month they attempted pregnancy. This relationship remained after adjustment for covariates, and it could not be explained by women douching for medical reasons. The reduction was not related to the type of douching preparation used. Young women who douched had significantly greater reductions in monthly fertility than older women (50% reduction for women 18 to 24 years old, 29% reduction for women 25 to 29 years old, and 6% reduction for women 30 to 39 years old). CONCLUSIONS: Douching was associated with reduced fertility. Further research is needed to determine whether the relationship is casual and, if so, to what extent it is mediated by pelvic infection. In the meantime, women should be informed that douching may have adverse effects.

Adolescent↗
PubMed1996

Modeling conception as an aggregated Bernoulli outcome with latent variables via the EM algorithm.

We describe a general method for analyzing aggregated Bernoulli outcomes. The research is motivated by an epidemiological reproductive study where the outcome was whether pregnancy was detected in a woman's particular menstrual cycle and the Bernoulli "trials" corresponded to days with intercourse during the cycle. Each cycle is either "viable" or not, i.e., is or is not susceptible to conception. We develop an EM algorithm approach to maximizing the observed-data pseudo-likelihood, based on a set of unobservable latent outcomes linked to the specific days with intercourse. This method is flexible in that it allows one to model effect of covariates on the susceptibility factor and on the latent outcomes. Application of the method to fertility studies enables one to investigate covariates with a long-term or transient effect on the daily conception probability. A complication is that most couples contribute more than one cycle in a prospective study. A generalized estimating equation approach adjusts for the dependency among outcomes within individual couples. The method can be applied in any setting where dependency among Bernoulli trials is induced by a susceptibility factor and the trial outcomes are only observable in the aggregate.

Algorithms↗
PubMed1996

Imputation for exposure histories with gaps, under an excess relative risk model.

In reconstructing exposure histories needed to calculate cumulative exposures, gaps often occur. Our investigation was motivated by case-control studies of residential radon exposure and lung cancer, where half or more of the targeted homes may not be measurable. Investigators have adopted various schemes for imputing exposures for such gaps. We first undertook simulations to assess the performance of five such methods under an excess relative risk model, in the presence of random missingness and under assumed independence among the true exposure levels for different epochs of exposure (houses). Assuming no other source of measurement error, one of the methods performed without bias and with coverage of nominally 95% confidence intervals that was close to 95%. This method assigns to the missing residences the arithmetic mean across all measured control residences. We show that its good properties can be explained by the fact that this approach produces approximate "Berkson errors." To take advantage of predictive information that might exist about the missing epochs of exposure, one might prefer to carry out the imputations within strata. In further simulations, we asked whether the method would still perform well if imputations were carried out within many strata. It does, and much of the lost statistical power/precision can be recovered if the stratification system is moderately predictive of the missing exposures. Thus, observed control mean imputation provides a way to impute missing exposures without corrupting the study's validity; and stratifying the imputations can enhance precision. The technique is applicable in other settings where exposure histories contain gaps.

Environmental Exposure↗
PubMed1995

Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby.

BACKGROUND: The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception, although the actual number of fertile days in a woman's menstrual cycle is uncertain. The timing of intercourse may also be associated with the sex of the baby. METHODS: We recruited 221 healthy women who were planning to become pregnant. At the same time the women stopped using birth-control methods, they began collecting daily urine specimens and keeping daily records of whether they had sexual intercourse. We measured estrogen and progesterone metabolites in urine to estimate the day of ovulation. RESULTS: In a total of 625 menstrual cycles for which the dates of ovulation could be estimated, 192 pregnancies were initiated, as indicated by increases in the urinary concentration of human chorionic gonadotropin around the expected time of implantation. Two thirds (n = 129) ended in live births. Conception occurred only when intercourse took place during a six-day period that ended on the estimated day of ovulation. The probability of conception ranged from 0.10 when intercourse occurred five days before ovulation to 0.33 when it occurred on the day of ovulation itself. There was no evident relation between the age of sperm and the viability of the conceptus, although only 6 percent of the pregnancies could be firmly attributed to sperm that were three or more days old. Cycles producing male and female babies had similar patterns of intercourse in relation to ovulation. CONCLUSIONS: Among healthy women trying to conceive, nearly all pregnancies can be attributed to intercourse during a six-day period ending on the day of ovulation. For practical purposes, the timing of sexual intercourse in relation to ovulation has no influence on the sex of the baby.

Adult↗
PubMed1995

Fertility in men exposed prenatally to diethylstilbestrol.

BACKGROUND: Prenatal exposure to diethylstilbestrol causes infertility in male mice and has been associated with malformations of the genital tract in men. However, little is known about the fertility of men who have been exposed prenatally to diethylstilbestrol. METHODS: In 1950 through 1952, 1646 pregnant women were enrolled in a randomized, placebo-controlled clinical trial of diethylstilbestrol at Chicago Lying-in Hospital. We interviewed men who were born to the women during that study about their fertility. RESULTS: Four decades after their birth, we were able to trace 548 of the surviving sons (68 percent). Ninety percent consented to be interviewed (253 who had been exposed to diethylstilbestrol in utero and 241 who had not been exposed). Congenital malformations of the genitalia were reported three times as often by the diethylstilbestrol-exposed men as by the sons of the women in the placebo group. Within the exposed group, malformations were reported twice as often among those exposed to diethylstilbestrol before the 11th week of gestation as among those exposed later (P = 0.05). Men with genital malformations were nonetheless as fertile as other men. The diethylstilbestrol-exposed men (with or without genital malformations) had no impairment of fertility by any measure, including whether they had ever impregnated a women, age at the birth of their first child, average number of children, medical diagnosis of a fertility problem, or length of time to conception in the most recent pregnancy of the female partner. Finally, diethylstilbestrol-exposed men had no impairment of sexual function, as indicated, for example, by the frequency of intercourse or reported episodes of decreased libido. CONCLUSIONS: High doses of diethylstilbestrol did not lead to impairment of fertility or sexual function in adult men who had been exposed to the drug in utero.

Abnormalities, Drug-Induced↗
PubMed1995

Nitrous oxide and spontaneous abortion in female dental assistants.

The relation between anesthetic gas exposure and spontaneous abortion remains unresolved. We examined the effect of nitrous oxide on spontaneous abortion among female dental assistants. Questionnaires were sent to 7,000 dental assistants aged 18-39 years who were registered in California in 1987; 4,856 (69%) responded. Analysis was based on 1,465 respondents whose most recent pregnancy was conceived while working full time. Women were asked how many hours a week they worked with nitrous oxide during this pregnancy and whether the excess gas was scavenged (vented). Relative risk of spontaneous abortion (through week 20) was calculated using a person-week model. This allowed women with current pregnancies (13%) or induced abortions (10%) to be included for appropriate time periods of risk. A total of 101 pregnancies (7%) ended as spontaneous abortions. An elevation in risk of spontaneous abortion was seen among women who worked with nitrous oxide for 3 or more hours per week in offices not using scavenging equipment (relative risk = 2.6, 95% confidence interval 1.3-5.0, adjusted for age, smoking, and number of amalgams prepared per week), but not among those using nitrous oxide in offices with scavenging equipment. This relation changed little when analyses were restricted to confirmed pregnancies or examined for several types of potential bias. Scavenging equipment appears to be important in protecting the reproductive health of women working with nitrous oxide.

Abortion, Spontaneous↗
PubMed1995

Follicle-stimulating hormone concentrations in relation to active and passive smoking.

OBJECTIVE: To determine the association between various forms of tobacco exposure and ovarian status, as measured by FSH concentrations, in women 38-49 years old. METHODS: Two hundred ninety women between 38-49 years old, who had not had hysterectomy or oophorectomy, completed a self-administered questionnaire that included information on tobacco exposure and had serum FSH levels measured on days 2-4 of the menstrual cycle. Linear regression was used to assess the relation between FSH and tobacco exposure. RESULTS: Controlling for age and other factors, FSH concentrations were 66% higher among current smokers (geometric mean FSH 14.0 mIU/mL) and 39% higher among nonsmokers with passive smoke exposure (11.7 mIU/mL), compared to nonsmoking women without passive smoke exposure (8.4 mIU/mL). The estimated increase in FSH for each year of age was greater for current smokers than for nonsmokers (16 versus 6%, respectively). Ex-smokers did not have higher FSH concentrations, and there was no association between prenatal exposure to tobacco smoke and FSH. CONCLUSION: Both active and passive smoking are associated with elevated FSH concentrations in women 38-49 years old. The effect, limited to women with current exposure, is consistent with a shorter duration of the menopausal transition period.

Adult↗
PubMed1995

The sex of the baby may be related to the length of the follicular phase in the conception cycle.

In a prospective study of normal couples discontinuing contraception to begin a pregnancy, the days of ovulation were estimated by hormonal assay of daily urine specimens. No hormonal interventions were used. Length of the follicular phase (from onset of menses to ovulation) was found to be related to the sex of the baby among 133 pregnancies that survived to delivery. Conception cycles with short follicular phases (early ovulation) tended to produce boys, while those with long follicular phases tended to produce girls. This relationship is consistent with other data and could explain sex-related differences in the length of gestation and the observed excess of same-sex pairs among dizygotic twins.

Adult↗
PubMed1995

Application of a method for estimating day of ovulation using urinary estrogen and progesterone metabolites.

Longitudinal epidemiologic studies of menstrual and reproductive function are more informative if one can identify day of ovulation. We previously developed a method for estimating day of ovulation that is feasible for epidemiologic studies. The method relies on the relative concentrations of estrogen and progesterone metabolites in daily first-morning urine specimens and does not require creatinine adjustment. This paper describes results of applying this method to a large study with 724 menstrual cycles from 217 women. The method estimated a credible day of ovulation in 88% of cycles. Missing data accounted for most of the failures. When we excluded anovulatory cycles (1%) and cycles with missing data, the method estimated a day of ovulation in 97% of cycles. Variance in luteal phase length was small for our sample, suggesting that this method of identifying a day of ovulation introduces no more measurement error than when day of ovulation is determined by plasma luteinizing hormone (LH), the standard clinical method.

Adult↗
PubMed1995

Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women.

We tested the hypothesis that postmenopausal women on a soy-supplemented diet show estrogenic responses. Ninety-seven postmenopausal women were randomized to either a group that was provided with soy foods for 4 weeks or a control group that was instructed to eat as usual. Changes in urinary isoflavone concentrations served as a measure of compliance and phytoestrogen dose. Changes in serum FSH, LH, sex hormone binding globulin, and vaginal cytology were measured to assess estrogenic response. The percentage of vaginal superficial cells (indicative of estrogenicity) increased for 19% of those eating the diet compared with 8% of controls (P = 0.06 when tested by ordinal logistic regression). FSH and LH did not decrease significantly with dietary supplementation as hypothesized, nor did sex hormone binding globulin increase. Little change occurred in endogenous estradiol concentration or body weight during the diet. Women with large increases in urinary isoflavone concentrations were not more likely to show estrogenic responses than were women with more modest increases. On the basis of published estimates of phytoestrogen potency, a 4-week, soy-supplemented diet was expected to have estrogenic effects on the liver and pituitary in postmenopausal women, but estrogenic effects were not seen. At most, there was a small estrogenic effect on vaginal cytology.

Aged↗
PubMed1995

Potential for bias in epidemiologic studies that rely on glass-based retrospective assessment of radon.

Retrospective assessment of exposure to radon remains the greatest challenge in epidemiologic efforts to assess lung cancer risk associated with residential exposure. An innovative technique based on measurement of alpha-emitting, long-lived daughters embedded by recoil into household glass may one day provide improved radon dosimetry. Particulate air pollution is known, however, to retard the plate-out of radon daughters. This would be expected to result in a differential effect on dosimetry, where the calibration curve relating the actual historical radon exposure to the remaining alpha-activity in the glass would be different in historically smoky and nonsmoky environments. The resulting "measurement confounding" can distort inferences about the effect of radon and can also produce spurious evidence for synergism between radon exposure and cigarette smoking.

Air Pollution, Radioactive↗
PubMed1995

A model for estimating the potency and survival of human gametes in vivo.

Sperm and ova are sensitive to numerous toxicants in animal studies; however, human vulnerability has been far more difficult to assess, due in part to a lack of methods for measuring the viable survival of human gametes in vivo. We present a parametric model for fertility, which assumes that the viable lifetime of the ovum is fixed while that of sperm is exponentially distributed. By reducing the number of parameters that must be estimated, compared to a previous approach, the model leads to improved tests for differences in sperm and egg survival between exposed and unexposed couples. Since it assumes that batches of sperm introduced on different days present independent competing "risks" (of fertilization) to the ovum, the model also provides for estimation of the age distribution, in days, of the sperm which actually fertilized the ova. This allows us to consider whether older sperm are more likely to produce defective embryos. We apply this model to data from a group of women who were intensively studied, beginning when they discontinued contraception in order to start a pregnancy. Participants kept daily records of intercourse. Daily urine specimens allowed the day of ovulation to be estimated and conceptions to be identified, based on assays of excreted hormones. Applying the parametric model to these data, the estimated mean viable lifetime for sperm is 1.4 days, while the lifetime of the ovum appears to be less than a day.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Survival↗