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B Langholz

Publications and source records attributed to B Langholz.

At least 19 recordsLinked to original sources
PubMed2001

Counter-matching in studies of gene-environment interaction: efficiency and feasibility.

The interest in studying gene-environment interaction is increasing for complex diseases. However, most methods of detecting gene-environment interactions may not be appropriate for the study of interactions involving rare genes (G:) or uncommon environmental exposures (E:), because of poor statistical power. To increase this power, the authors propose the counter-matching design. This design increases the number of subjects with the rare factor without increasing the number of measurements that must be performed. In this paper, the efficiency and feasibility (required sample sizes) of counter-matching designs are evaluated and discussed. Counter-matching on both G: and E: appears to be the most efficient design for detecting gene-environment interaction. The sensitivity and specificity of the surrogate measures, the frequencies of G: and E:, and, to a lesser extent, the value of the interaction effect are the most important parameters for determining efficiency. Feasibility is also more dependent on the exposure frequencies and the interaction effect than on the main effects of G: and E: Although the efficiency of counter-matching is greatest when the risk factors are very rare, the study of such rare factors is not realistic unless one is interested in very strong interaction effects. Nevertheless, counter-matching appears to be more appropriate than most traditional epidemiologic methods for the study of interactions involving rare factors.

Case-Control Studies↗
PubMed2001

Factors that explain the power line configuration wiring code-childhood leukemia association: what would they look like?

We explore the question of how to characterize a factor that would explain the patterns of wire code-childhood leukemia association observed in three major United States case-control studies. In positive studies, such a factor needs to be more prevalent in "high" wire codes than "low" whereas in negative studies, the factor should not be correlated to wire code. These concepts are quantified and we use these results to characterize potential factors that might explain the wire code-childhood leukemia association. We then re-evaluate findings from a survey of correlates of wire code in Connecticut with respect to potential for explaining the wire code-leukemia association. Under the presumption that the Connecticut correlations apply to the populations in which a wire code-leukemia association has been observed, only age and type of home are correlated enough to be potential explanatory factors. In particular, it appears very unlikely that traffic density can explain a significant portion of the wire code association. We suggest that correlation studies can be useful for identifying potential explanatory factors, but they must be done in regions where a wire code-childhood leukemia association has been observed.

Biometry↗
PubMed2001

Stratified case sampling and the use of family controls.

We compare the asymptotic relative efficiency (ARE) of different study designs for estimating gene and gene-environment interaction effects using matched case-control data. In the sampling schemes considered, cases are selected differentially based on their family history of disease. Controls are selected either from unrelated subjects or from among the case's unaffected siblings and cousins. Parameters are estimated using weighted conditional logistic regression, where the likelihood contributions for each subject are weighted by the fraction of cases sampled sharing the same family history. Results showed that compared to random sampling, over-sampling cases with a positive family history increased the efficiency for estimating the main effect of a gene for sib-control designs (103-254% ARE) and decreased efficiency for cousin-control and population-control designs (68-94% ARE and 67-84% ARE, respectively). Population controls and random sampling of cases were most efficient for a recessive gene or a dominant gene with an relative risk less than 9. For estimating gene-environment interactions, over-sampling positive-family-history cases again led to increased efficiency using sib controls (111-180% ARE) and decreased efficiency using population controls (68-87% ARE). Using case-cousin pairs, the results differed based on the genetic model and the size of the interaction effect; biased sampling was only slightly more efficient than random sampling for large interaction effects under a dominant gene model (relative risk ratio = 8, 106% ARE). Overall, the most efficient study design for studying gene-environment interaction was the case-sib-control design with over-sampling of positive-family-history-cases.

Bias↗
PubMed2001

Using splines to analyse latency in the Colorado Plateau uranium miners cohort.

BACKGROUND: Different approaches have been proposed to investigate latency in epidemiologic studies where detailed exposure histories are available. METHODS: We demonstrate the application of a flexible, yet parsimonious, spline function model to investigate latency patterns for radon progeny exposure and lung cancer in the Colorado Plateau uranium miners cohort. The model extends a previously proposed bilinear model. RESULTS: The excess relative risk (ERR) reached a maximum of 0.6 per 100 working level months, for exposures received 14 years previously. The ERR then declined, and was estimated to approach zero for exposures received 35 years and more in the past. The point-wise 95% confidence intervals supported ERRs > 0 for the period 9-32 years before the event. The estimated latency curve was homogeneous across categories of attained age, duration of exposure, rate of exposure, and smoking. CONCLUSIONS: The proposed spline model is a flexible tool for latency analyses, and extends previously used methods.

Adult↗
PubMed2001

Nonrandomized comparison of surgery with and without adjuvant pelvic irradiation for patients with pT3N0 adenocarcinoma of the prostate.

The purpose of this study was to evaluate the outcome of radical prostatectomy alone and compare it with that of surgery followed by planned adjuvant radiotherapy in patients with pT3N0 prostate cancer (CaP). A total of 402 patients with CaP were treated with prostatectomy, including 311 (77%) who received a planned course of adjuvant radiotherapy (RT) (surgery [S] + RT) to the prostatic fossa (median dose: 48 Gy) and 91 (23%) who had surgery alone. Patients in the former group had worse risk factors than those in the latter group, such as a higher clinical and pathologic stage (p = 0.001), higher Gleason score (p = 0.09), and higher preoperative prostate-specific antigen (PSA) level (p = 0.0001). PSA failure was defined as more than 0.05 ng/ml. Median follow-up was 59 months. The 5- and 10-year overall survival for the 311 S+RT patients was 91% and 81%, respectively, and it was similar for those 91 in the surgery-alone group, p = 0.59. The 5- and 10-year probability of freedom from PSA and/or clinical failure for the former group was 70% and 53%, respectively, whereas it was 66% and 46%, respectively, for the latter group, p = 0.72. Any recurrence developed in a total of 96 (31%) patients in the S+RT group as compared with 23 (25%) in the surgery-alone group. Local recurrence was noted in 10 (3.2%) S+RT and in 6 (6.6%) surgery-alone patients (N.S.). The time to clinical or chemical recurrence was also similar for both treatment groups (median time: 3.0 versus 3.8 years). Patients with pT3b tumors had relatively poor 5- and 10-year disease-free survival (53% and 32%, respectively, for S+RT and 38% and 0%, respectively, for surgery alone, p = 0.82). In multivariate analyses, pathologic stage and Gleason score were independent predictors of recurrence, each with p < 0.001 after controlling for the other. The worst prognostic category included patients with pT3bN0, Gleason score 7-10 disease who had 5.0 times the risk of recurrence as compared with pT3aN0, Gleason score 2-6 patients. No significant difference in disease-free survival by the treatment group was seen in Cox regression analysis controlling for pathologic stage (p = 0.59), Gleason score (p = 0.99), and PSA (p = 0.28). S+RT patients were predicted to have disease recurrence at 83% the rate of surgery-alone patients, p = 0.42. Preoperative PSA (>25 ng/ml) was predictive of recurrence (2.0 x risk) in univariate analysis, but it was not a significant predictor in multivariate analysis. It appears that moderate-dose, localized fields postoperative irradiation reduced the incidence of local recurrence in patients who were at a higher risk of recurrence as compared with those treated with surgery alone. New treatment strategies need to be developed to manage pT3bN0, Gleason score 7-10 patients whose 10-year disease-free survival was poor.

Adenocarcinoma↗
PubMed2000

Testing linkage disequilibrium in sibships.

We describe the use of multivariate regression for testing allelic association in the presence of linkage, using marker genotype data from sibships. The test is valid, provided that the correct mean structure is modeled but does not require the correlation structure within families to be specified. The test can be implemented using standard statistical software such as the SAS programming language. In a simulation study, we evaluated this new test in comparison with one from a standard, matched-case-control analysis. First, we noted that the genetic effect needed to be quite extreme before residual familial correlation due to linkage led to false inference using the standard, matched-pair analysis. Second, we showed that under examples of extreme residual familial correlation, the new test had the correct test size. Third, we found that the test was more powerful than the sibship disequilibrium test of Horvath and Laird. Finally, we concluded that although the standard analysis may lead to correct inference for practical purposes, the new test is valid, even under extreme residual familial correlation and with no cost in power at the causal locus.

Alleles↗
PubMed2000

Skin characteristics and risk of superficial spreading and nodular melanoma (United States).

OBJECTIVE: To assess the risk for melanoma associated with moles and pigmentary characteristics. METHODS: Representative melanoma cases (773) among non-Hispanic white residents under age 65 occurring between 1 June 1978 and I December 1983 in Los Angeles County were compared to controls (752) matched to cases by age, sex, race and neighborhood of residence. Factors considered include hair, eye, and skin color; numbers of freckles and moles; and propensity to burn and tan obtained during an in-person interview. RESULTS: Five hundred and fifty-one cases were classified as superficial spreading melanoma (SSM) and 110 as nodular melanoma (NM). For SSM, the important risk determinants were hair and skin color, freckling, and mole prevalence. Light skin and more freckles were found to be more highly associated with SSM for younger compared to older subjects, whereas the associations between SSM and both hair color and moles remained independent of age. NM showed patterns of risk similar to SSM with the exception of skin color. NM showed no evidence of increasing risk with lighter skin, as compared to the strong association seen for SSM. CONCLUSION: Hair and skin color, freckling and, especially, numbers and size of moles are important determinants of melanoma risk.

Adult↗
PubMed2000

Exposure stratified case-cohort designs.

A variant of the case-cohort design is proposed for the situation in which a correlate of the exposure (or prognostic factor) of interest is available for all cohort members, and exposure information is to be collected for a case-cohort sample. The cohort is stratified according to the correlate, and the subcohort is selected by stratified random sampling. A number of possible methods for the analysis of such exposure stratified case-cohort samples are presented, some of their statistical properties developed, and approximate relative efficiency and optimal allocation to the strata discussed. The methods are compared to each other, and to randomly sampled case-cohort studies, in a limited computer simulation study. We found that all of the proposed analysis methods performed well and were more efficient than a randomly sampled case-cohort study.

Biometry↗
PubMed1999

Application of the missing-indicator method in matched case-control studies with incomplete data.

A common practice in matched case-control studies with incomplete data is to perform two analyses in parallel: a matched analysis of the complete pairs and an unmatched analysis of all subjects carried out after breaking the matching in the complete pairs. The missing-indicator method, which has the advantage of making use of the data in the incomplete pairs while still preserving the matching in the complete pairs, is recommended as an alternative method of analysis. It is shown here that its estimate of the odds ratio is a compromise between the odds ratios estimated by a matched analysis of the complete pairs and an unmatched analysis of the incomplete pairs. The method is illustrated using data from a matched case-control study of the risk of childhood leukemia from exposure to residential electric and magnetic fields.

Biometry↗
PubMed1999

Latency analysis in epidemiologic studies of occupational exposures: application to the Colorado Plateau uranium miners cohort.

BACKGROUND: Latency effects are an important factor in assessing the public health implications of an occupational or environmental exposure. Usually, however, latency results as described in the literature are insufficient to answer public health related questions. Alternative approaches to the analysis of latency effects are warranted. METHODS: A general statistical framework for modeling latency effects is described. We then propose bilinear and exponential decay latency models for analyzing latency effects as they have parameters that address questions of public health interest. Methods are described for fitting these models to cohort or case-control data; statistical inference is based on standard likelihood methods. APPLICATION: A latency analysis of radon exposure and lung cancer in the Colorado Plateau uranium miners cohort was performed. We first analyzed the entire cohort and found that the relative risk associated with exposure increases for about 8.5 years and thereafter decreases until it reaches background levels after about 34 years. The hypothesis that the relative risk remains at its peak level is strongly rejected (P < 0.001). Next, we investigated the variation in the latency effects over subsets of the cohort based on attained age, level and rate of exposure, and smoking. Age was the only factor for which effect modification was demonstrated (P = 0.014). We found that the decline in effect is much steeper at older ages (60+ years) than younger. CONCLUSION: The proposed methods can provide much more information about the exposure-disease latency effects than those generally used.

Air Pollutants, Radioactive↗
PubMed1999

Adjuvant radiotherapy in patients with pathologic Stage C (pT3N0) adenocarcinoma of the prostate.

OBJECTIVES: This report is an update on the outcomes in the management of pathologic Stage C (T3N0) prostate cancer (CaP) with postoperative irradiation. METHODS: Between 1976 and 1994, 311 patients with pathologic Stage C CaP were treated with radical prostatectomy. Pathologic stage was as follows: C1, 60 patients (19%), C2, 146 patients (47%), and C3, 105 patients (34%). Gleason score was 2 to 4 in 10 patients (3.2%), 5 to 6 in 121 (39%), 7 in 101 (32%), and 8 to 10 in 76 (24%); median prostate-specific antigen (PSA) level was 11.9 ng/mL. Postoperative irradiation consisted of a median dose of 48 Gy. Follow-up was up to 18 years (median 5). RESULTS: The 10-year actuarial survival was 81% and 10-year disease-free survival was 51%. Pathologic stage and Gleason score were independently predictive of recurrence, each with P >0.001 after controlling for the other. Patients with pathologic Stage C3 and Gleason score 7 to 10 were in the worst prognostic category and had 5.4 times the risk of recurrence compared with patients with pathologic Stage C1-C2, Gleason score 2 to 6. Preoperative PSA was a good (P = 0.02) predictor of disease-free survival. Clinical recurrence was seen in 28 patients (9%), including 10 (3.2%) with local recurrence. PSA recurrence (PSA greater than 0.05 ng/mL) developed in 68 patients (22%). CONCLUSIONS: With the known limitations of a nonrandomized clinical trial, on the basis of the experience of this study we recommend the use of moderate dose, limited-field postoperative radiotherapy in patients with pathologic Stage C disease with Gleason score greater than 4.

Actuarial Analysis↗
PubMed1999

Cohort studies for characterizing measured genes.

We describe the advantages of using established cohort studies that have collected blood samples to investigate the role of genes in the etiology of cancer. These studies include the cost-efficiency and reliability of nested case-control substudies from the cohort for exploration of gene-disease associations and gene-environment interactions as well as gene penetrance. Also, the cohort may serve as a well-defined "mini-population" from which to study population stratification and molecular markers of ethnicity. We conclude that cohort studies can play a significant role in assessing the role of genetic markers for common tumors or multiple cancer sites.

Case-Control Studies↗
PubMed1999

Comparison of outcomes of radical prostatectomy with and without adjuvant pelvic irradiation in patients with pathologic stage C (T3N0) adenocarcinoma of the prostate.

Patients with localized adenocarcinoma of the prostate gland (CaP) are frequently (approximately 50%) found at radical prostatectomy to have extracapsular disease or positive surgical margins. The management of these patients is a subject of controversy because some question the impact of this manifestation of CaP on patient survival or disease-free survival. Between 1976 and 1991, 241 patients with pathologic stage C (T3N0) were treated in this medical center. Of these 241 patients, 201 (83%) received a planned postoperative pelvic irradiation consisting of 48 Gy given to the prostatic fossa, whereas 40 (17%) patients were treated with radical prostatectomy alone. The two study urologists selected these patients not to receive postoperative irradiation based on intraoperative findings and important prognostic factors. Comparison of treatment outcomes in these two treatment groups is a subject of this report. The 201 patients treated with surgery-radiotherapy (S+RT) combination had a higher pathologic stage, greater incidence of seminal vesicle involvement, p = 0.002, and higher mean and median preoperative prostate-specific antigen level, p < 0.0001, than the 40 surgery (S) alone patients. There was no significant difference in the incidence of higher Gleason's score by the treatment group, p = 0.14. In univariate analysis, there was no significant difference in survival, disease-free survival, and time to failure between the two treatment groups. In multivariate analysis after controlling for pathologic stage and Gleason's score, the 201 adjuvant radiotherapy patients were predicted to have recurrence at 68% (95% confidence interval 39%-118%) the rate of the 40 surgery-alone patients. Local recurrence with or without metastatic disease was found in 10% of surgery-alone patients as compared to 5% in those also receiving postoperative irradiation. Treatment tolerance was very good with minor radiotherapy complications only. There was no significant difference in the incidence of incontinence between the two treatment arms. In summary: (a) The use of moderate-dose postoperative radiotherapy was of low toxicity and it did not increase the incidence of incontinence. (b) Local recurrence was 5% in S+RT and 10% in S-alone patients. (c) In multivariate analysis, S+RT patients had 68% rate of recurrence of S-alone patients. (d) Adjuvant RT probably reduces the risk of recurrence in patients with poor prognostic factors. (e) These data need to be interpreted with caution because of the nonrandomized nature of the study.

Adenocarcinoma↗
PubMed1999

Correcting for exposure measurement error in a reanalysis of lung cancer mortality for the Colorado Plateau Uranium Miners cohort.

The exposure estimates used to date for the analysis of lung cancer mortality in the Colorado Plateau Uranium Miners cohort were developed from radon progeny measurements taken in mines beginning in 1951. Since uranium miners were often exposed over long periods of time and since mines were not continuously monitored, much extrapolation and/or interpolation of measured dose-rates was needed in order to develop estimates of exposure for each of the miners in the cohort. We have recently re-examined the interpolation scheme used to create the histories in the light of the fit of a statistical model for the radon progeny measurements taken in mines within the Plateau, and we have computed revised exposure estimates for the large majority of miners in the cohort. This report describes the use of these new model-based revised exposure estimates in the analysis of lung cancer mortality, using follow-up data current through 1990. Specific issues addressed here are (1) the strength of the association between exposure and risk of lung cancer mortality; (2) effects of attained age and time since exposure upon risk of lung cancer mortality; and (3) exposure-rate effects upon risk. Results using the revised exposure estimates are compared to those obtained fitting the same models using the original Public Health Service (PHS) exposure estimates. We found evidence that the new exposure histories provide a better fit to the lung cancer mortality data than do the histories based upon the original PHS dose-rate estimates. In general, the new results show a stronger overall relationship (larger slope estimate) between lung cancer mortality and exposure per unit exposure compared to those obtained with the original estimates, while displaying similar age at exposure and time since exposure effects. In the reanalysis the impact of low dose-rate exposure is found to be relatively unchanged before and after exposure error correction, while the estimate of the effect of high dose-rate exposure is considerably increased. Even after applying our measurement error corrections, evidence of inverse dose-rate effects is found, since the estimate of the impact of high dose-rate exposure is still below that of the low dose-rates. The magnitude and statistical significance, however, of the dose-rate effect estimates are diminished when fit using the revised exposure estimates.

Adult↗
PubMed1999

Ascertainment bias in rate ratio estimation from case-sibling control studies of variable age-at-onset diseases.

Motivated by a Finnish case-control study of early onset diabetes in which diabetic children are matched to sibling controls, we investigate ascertainment bias of the usual rate ratio estimator from case-control data under simplex complete ascertainment of families during a fixed interval of time. Analytic results indicate that the assumptions necessary for valid estimation are that the disease is rare and the factors under study are exchangeable--essentially that the covariate distribution does not depend on calendar time or birth order. Further, we found that the rare disease assumption could be dropped by restricting to cases that were diagnosed during the enrollment period of the study or including all cases but eliminating the proband as a control for non-enrollment-period cases. An important consequence of this work is that standard family-based case-control studies are subject to ascertainment bias if exchangeability of the covariates under investigation does not hold.

Age of Onset↗
PubMed1999

Statistical methods for epidemiologic studies of the health effects of air pollution.

We describe two statistical designs that can provide efficient estimates of the health effects of exposure to air pollutants in epidemiologic studies. We also evaluate the effects of measurement error in exposure assessment on the accuracy of estimated health effects. The bidirectional case-crossover design is a variant of a method proposed by Maclure (1991). Our version of the method takes advantage of the fact that in epidemiologic studies involving environmental exposure, accurate information about past exposure is more readily available, and that levels of exposure are generally unaffected by the response of the subject. It differs from other case-crossover methods in that control information is assessed both before and after failure, thus avoiding confounding due to time trends in exposure. The multilevel analytic design provides a method of combining estimates of health effects made on the individual level with those made at the group level. It has great potential value in situations where variations in exposure within groups may not be great enough to provide adequate power to detect health effects, as is often the case in air pollution studies where exposure levels are similar within a geographic community. Measurement errors in exposure assessment can have substantial impact on the accuracy of estimated health effects. When the microenvironmental approach is used to estimate exposure, a standard error of 30% in estimating indoor/outdoor ratios can increase the standard error of a relative risk estimate by 50%, and introduce bias as well. Similar results hold when exposure is estimated with personal samplers. When the microenvironmental approach is used, errors in estimating indoor/outdoor ratios have more influence on the accuracy of risk estimation than do errors in estimating the time spent in microenvironments.

Absenteeism↗