Biomedical subjects

D M Umbach

Publications and source records attributed to D M Umbach.

30 records · Page 2Linked to original sources

PubMed1998

The role of N-acetylation polymorphisms in smoking-associated bladder cancer: evidence of a gene-gene-exposure three-way interaction.

Arylamines are known bladder carcinogens and are an important constituent of tobacco smoke. The handling of arylamines in the body is complex and includes metabolism by NAT1 and NAT2, enzymes that play a role in both activation and detoxification of arylamines and their congeners. Both NAT1 and NAT2 are polymorphic, with alleles that have been shown to correlate with higher or lower enzyme activity. To explore the combined role of these genes and exposure on bladder cancer risk, we examined the NAT1 and NAT2 genotype in a case-control study of bladder cancer in which detailed exposure histories were available on all 230 cases and 203 frequency-matched controls. Using PCR-RFLP genotyping, we determined NAT2 genotype for the five most common alleles, NAT2*4, NAT2*5, NAT2*6, NAT2*7, NAT2*14 (frequently referred to as WT, M1, M2, M3, and M4, respectively). Similarly, the NAT1 genotype was determined for the four most common alleles NAT1*3, NAT1*4, and NAT1*11, and the putative high-activity allele, NAT1*10. No association between NAT2 genotype and bladder cancer risk was found whether genotype was considered alone or in combination with smoking, in either stratified or logistic regression analysis that adjusted for age, sex, and race. Stratified and logistic regression analysis both demonstrated an increased risk for individuals carrying the NAT1*10 allele among smokers. There was evidence of a gene-dosage effect, such that those who were homozygous for the NAT1*10 allele had the highest risks. There was also evidence of a statistically significant gene-environment interaction, such that bladder cancer risk depends on both NAT1 genotype and smoking exposure. Interestingly, although NAT2 genotype did not influence risk either alone or in combination with smoking exposure, there was evidence of a statistically significant gene-gene-environment three-way interaction. Bladder cancer risk from smoking exposure is particularly high in those who inherit NAT2 slow alleles in combination with one or two copies of the NAT1*10 allele. A biological mechanism for this finding is suggested.

Acetylation↗

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↗

PubMed1997

Ontogeny of gonadotrophin and inhibin secretion in normal girls through puberty based on overnight serial sampling and a comparison with normal boys.

We measured luteinizing hormone (LH) and follicle stimulating hormone (FSH) by immunofluorometric assays and alpha-inhibin by radioimmunoassay in serum sampled every 10 min throughout the night (2100-0500 h) from 44 normal girls. Mean overnight LH values rose log-linearly from a mean of 0.2 IU/l in prepubertal girls to 3.0 IU/l in late pubertal girls. Log2 mean overnight FSH rose rapidly through early puberty and then remained constant; mean FSH rose from 1.0 IU/l in prepubertal girls to approximately 2.8 IU/l in Tanner III-V girls. Mean overnight inhibin increased through puberty, rising from 151 ng/l in prepubertal girls to 432 ng/l in fully pubescent girls. Within each of the first three Tanner stages, LH differed approximately 100-fold between the smallest and largest mean concentrations but differed <10-fold within stages IV or V. Such within-pubertal stage variability was less pronounced for FSH, which differed approximately 16-fold among Tanner I subjects and 4-10-fold at later stages, and for inhibin, which varied approximately 4-fold within each Tanner stage. The frequency of LH pulses during overnight sampling increased significantly during puberty, but the frequency of FSH and inhibin pulses remained constant. We compared the results from girls to those from 50 normal boys [Manasco et al. (1995) J. Clin. Endocrinol. Metab., 80, 20462052]. At each pubertal stage, girls had approximately the same mean overnight LH values as boys; girls had higher mean overnight FSH, particularly during Tanner stages II-IV; and boys had mean overnight alpha-inhibin immunoreactivity approximately 1.5 times that of girls at each pubertal stage. Still, hormone concentrations for individuals of both sexes intergraded at each pubertal stage.

Adolescent↗

PubMed1996

A technique for measuring epidemiologically useful features of birthweight distributions.

Birthweight distributions have been conceptualized as a predominant Gaussian distribution contaminated in the tails by an unspecified 'residual' distribution. Acknowledging this idea, we propose a technique for measuring certain features of birthweight distributions useful to epidemiologists: the mean and variance of the predominant distribution; the proportions of births in the low- and high-birthweight residual distributions, and the boundaries of support for these residual distributions. Our technique, based on an underlying multinomial sampling distribution, involves estimating parameters in a mixture model for the multinomial bin probabilities after having chosen the support of the residual distribution with a model selection criterion. A modest simulation study and experience with a few actual datasets indicate that use of a Bayesian information criterion (BIC) as model selection criterion is superior to use of Akaike's information criterion (AIC) in this application.

Analysis of Variance↗

PubMed1996

Are vitamin D receptor polymorphisms associated with bone mineral density? A meta-analysis.

Vitamin D receptor (VDR) polymorphisms have been strongly associated with bone mineral density (BMD) in some studies but not in others. We used a meta-analytic approach to assess quantitatively the association between VDR and BMD and to examine the influence of specific study characteristics (e.g., skeletal site, mean age of subjects, menopausal status) on the reported results. Sixteen papers published in peer-reviewed journals through July 1996 were included. We calculated the mean difference, percent difference, and effect size (mean difference divided by standard deviation), comparing BMD between homozygous genotypes. At the hip, BMD in the BB genotype was lower than in the bb genotype (mean difference, -0.02 g/cm2; percent difference, -2.4% and effect size -0.18; p = 0.032). At the spine, the mean difference was -0.03 g/cm2; percent difference, -2.5%; and effect size, -0.19; p = 0.062. At the distal radius, the VDR effect was estimated as the mean difference, -0.01 g/cm2; percent difference, -1.7%; and effect size, -0.16; p = 0.078. The spine measurements exhibited the greatest between- and within-study variability. The difference in hip BMD between genotypes was larger (i.e., a more negative number) among the younger women and seemed to decrease with increasing age. However, statistical evidence for this trend was weak (p = 0.06). Data from the spine and the radius showed no evidence of a comparable interaction of the VDR effect with age. When we omitted data from the first report of an association between VDR polymorphisms and BMD, our analyses gave similar results, although the overall effect estimates were smaller. In the combined data from 29 study groups, the BB genotype frequency was 17.2, 4.9, and 2.3% in studies of whites, blacks, and Asians, respectively. VDR polymorphisms represent one genetic factor affecting BMD, but further research into the mechanisms, clinical significance, and its relation between other genetic and environmental factors is needed.

Adult↗

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

Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer.

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of colorectal cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or O-acetylated by the NAT1 or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies have shown that both NAT2 and NAT1 genes exhibit variation in human populations and that rapid acetylation by the NAT2 enzyme may be a risk factor for colorectal cancer. In this study we have analyzed for genetic polymorphism in both NAT1 and NAT2 in a group of 202 colorectal cancer patients and 112 control subjects from Staffordshire, England. We find significantly increased risk (odds ratio, 1.9; 95% confidence interval, 1.2-3.2; P = 0.009) associated with the NAT1*10 allele of NAT1, an allele that contains a variant polyadenylation signal. Individuals with higher stage tumors (Duke's C) were more likely to inherit this variant allele (odds ratio, 2.5; 95% confidence interval, 1.3-4.7; P = 0.005). In contrast, rapid acetylation genotypes of NAT2 were not a significant risk factor in this English population. However, we found that the risk associated with the NAT1 variant allele (NAT1*10) was most apparent among NAT2 rapid acetylators (odds ratio, 2.8; 95% confidence interval, 1.4-5.7; P = 0.003), suggesting a possible gene-gene interaction between NAT1 and NAT2 (test for interaction; P = 0.12). This is the first study to test for cancer risk associated with the NAT1 gene, and these positive findings suggest that NAT1 alleles may be important genetic determinents of colorectal cancer risk.

Adenocarcinoma↗

PubMed1995

Age at menarche among diethylstilbestrol granddaughters.

We interviewed 542 women whose mothers were in a randomized trial of diethylstilbestrol. Effects of diethylstilbestrol on the third generation were explored by ascertaining age at menarche for the women's daughters. A total of 123 daughters were > or = 10 years old (52 exposed and 71 unexposed). Age at menarche was unaffected by mother's prenatal diethylstilbestrol exposure.

Adolescent↗

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

Ontogeny of gonadotropin, testosterone, and inhibin secretion in normal boys through puberty based on overnight serial sampling.

To investigate hormonal changes occurring in male puberty, we measured LH, FSH, testosterone, and alpha-inhibin immunoactivity in serum samples drawn every 10 min for 8 h (2100-0500 h) from each of 50 normal prepubertal and pubertal boys, aged 8.4-18.8 yr. We measured gonadotropins with ultrasensitive immunofluorometric assays, and testosterone and alpha-inhibin with RIAs. Unlike previous studies, which indexed pubertal development with Tanner stages, we used testicular volume, a more finely graduated indicator of development, to reveal patterns that were obscured when subjects were grouped by Tanner stage. The overnight mean concentration of each hormone increased with testis volume, but the rate of increase on a logarithmic scale slowed as testes grew. Log LH rose precipitously in the late prepubertal and early pubertal periods and plateaued during mid- and late puberty. Based on fitted regression curves, LH increased about 20-fold (from 0.11 IU/L) between testis volumes of 1 and 10 mL, but only an additional 1.5-fold by 30 mL. The developmental trajectory of log testosterone was like that of log LH, but rose less steeply early in puberty. From 0.14 micrograms/L at a testis volume of 1 mL, testosterone increased about 8.5-fold by 10 mL and an additional 3-fold by 30 mL. In contrast, logarithms of overnight mean FSH and alpha-inhibin concentrations rose at a more nearly constant rate throughout puberty. From 0.62 IU/L at a testis volume of 1 mL, the FSH concentration doubled by 10 mL and increased an additional 1.7-fold by 30 mL. From 270 ng/L at a testis volume of 1 mL, inhibin increased 1.5-fold by 10 mL and an additional 1.3-fold by 30 mL. Overnight pulse amplitudes exhibited developmental trajectories similar to those of the corresponding overnight mean concentrations. The number of LH and testosterone pulses during the sampling period averaged 2.2 and 2.1, respectively, at Tanner stage 1 and increased to 4.5 and 3.2, respectively, at Tanner stage 5. The number of FSH and inhibin pulses remained constant throughout puberty, averaging 3.3 and 3.5, respectively. Pairwise correlations among hormone concentrations were strong, reflecting common increasing trends through puberty; however, after accounting for developmental trends, FSH, LH, and testosterone concentrations remained correlated, whereas inhibin was uncorrelated with each of the other three hormones. Measuring gonadotropins with ultrasensitive assays and analyzing the results on a logarithmic scale as a function of testis volume made clear the dramatic hormonal changes that begin before the clinical changes of puberty.

Activity Cycles↗

PubMed1994

When will nondifferential misclassification of an exposure preserve the direction of a trend?

Dosemeci et al. (Am J Epidemiol 1990; 132:746-8) gave examples in which nondifferential misclassification of exposure reversed the direction of a trend. Gilbert (Am J Epidemiol 1991; 134:440-1) proposed that these examples occurred because the errors in exposure were systematic, and she pointed out that the relation between the measured and the true exposure was not monotonic. Assuming that the mean response either monotonically increases or decreases with the true exposure and that the exposure misclassification is nondifferential, the authors show that if the mean value of the measured exposure increases with the true exposure, then the direction of the trend cannot be reversed. Consequently, Gilbert's intimation that reversal of trend can only occur when errors are systematic is correct. However, the present authors' result is stronger in that even when errors in assessing exposure do include a systematic component, if monotonicity can be assumed, reversal of trend cannot occur. The weaker condition of positive correlation between the measured and true exposure is not sufficient to guarantee nonreversal of trend, as they show by example.

Bias↗

PubMedDate not supplied

Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis.

Dietary factors have long been suspected of being risk factors for amyotrophic lateral sclerosis (ALS), but few human studies have been reported. To address several of the dietary hypotheses, a case-control study of risk factors for ALS conducted in New England in 1993-1996 included an abbreviated food frequency questionnaire. We examined the dietary intake of calcium, magnesium and antioxidants among 107 ALS cases and 262 community controls. Overall, these dietary factors were not related to risk of ALS, though modestly protective associations were suggested for magnesium and lycopene.

Adult↗