Search PubMed⌕ Search

Biomedical subjects

D C Thomas

Publications and source records attributed to D C Thomas.

At least 145 records · Page 8Linked to original sources
PubMed1985

Effect of DNA polymerase I and DNA helicase II on the turnover rate of UvrABC excision nuclease.

UvrABC excision nuclease (UvrA, UvrB, and UvrC proteins) of Escherichia coli removes nucleotide mono- and diadducts from DNA in the form of oligonucleotides 12 or 13 bases long. We find that the purified enzyme dissociates from DNA very slowly, if at all, in the absence of other proteins implicated in excision repair. Addition of DNA polymerase I and helicase II (UvrD protein) to the reaction mixture stimulates the turnover rate of the excision nuclease to a level comparable to that observed in vivo.

Adenosine Triphosphatases↗
PubMed1985

The problem of multiple inference in studies designed to generate hypotheses.

Epidemiologic research often involves the simultaneous assessment of associations between many risk factors and several disease outcomes. In such situations, often designed to generate hypotheses, multiple univariate hypothesis-testing is not an appropriate basis for inference. The number of true positive associations in a collection of many associations can be estimated by comparing the observed distribution of p values for the positive associations to a theoretical uniform distribution, or to the observed distribution of negative associations, or to an empiric randomization distribution. None of these approaches, however, will distinguish the true from the false positive associations. Various criteria for selecting a subset of associations to report are considered by the authors, including Bonferoni adjustment of p values, splitting the sample for searching and testing, Bayesian inference, and decision theory. The authors prefer an approach in which all associations in the data are reported, whether significant or not, followed by a ranking in order of priority for investigation using empirical Bayes techniques. Methods are illustrated by application to preliminary data from a study aimed at identifying hitherto unsuspected occupational carcinogens.

Bayes Theorem↗
PubMed1985

Estimates of lifetime lung cancer risks resulting from Rn progeny exposure.

Data on five mining populations exposed to Rn progeny have been used to estimate the lifetime risk of lung cancer resulting from occupational and environmental exposure under current standards. Slopes of dose-response relations for lung cancer show a tendency to decrease with increasing dose. Our best estimate of curvilinearity is given by raising dose to the power 0.92 +/- 0.07, but the improvement in fit beyond simple linearity is not significant. On the other hand, the addition of a cell-killing term significantly improves the fit of the linear model. In any event, linear extrapolation is unlikely to underestimate the excess risk at low doses by more than a factor of 1.5. However, these inferences about curvilinearity are highly subject to error from the choice of reference populations, dosimetry, and latency. Under the linear-cell-killing model, our best estimate of excess relative risk is 2.28 +/- 0.35 per 100 working level month (WLM) (a doubling dose of 44 WLM). Attributable risks in these five studies range from 3.4-17.8 per 10(6) person-yr WLM-1. Risks from Rn progeny appear to interact with age and smoking in a form intermediate between additive and multiplicative. The "relative risk" model is therefore preferable for projecting lifetime risks, but life-table projections are described for a wide variety of assumptions. Our best estimate of the effect of a 50-yr occupational exposure to 4 WLM yr-1 is 130 excess lung cancer deaths per 1000 persons (0.65 per 1000 person-WLM), with a range from 60-250 per 1000. Similar calculations for lifetime exposure to an additional 0.02 working level (WL) beyond normal background produces an estimate of 20 excess lung cancers per 1000 persons.

Adolescent↗
PubMed1985

The problem of multiple inference in identifying point-source environmental hazards.

Point-source environmental hazards are often identified by examination of unusual clusters of disease cases. The very large number of potential clusters give rise to the statistical problem of "multiple inference," i.e., the more clusters examined, the greater the risk of "false-positive" associations emerging by chance alone. This paper first distinguishes the situation of clusters identified by anecdotal observation from those that emerge from systematic searches. The latter may or may not include a systematic enumeration of potential causal factors associated with each potential disease cluster. If exposure information is not systematically available, empirical Bayes procedures are suggested as a basis for ranking the observed clusters in order of priority for further investigation. If exposure information is systematically available, empirical Bayes procedures can be used to select associations to report or to rank them in order of priority for confirmation. In addition, procedures are described for testing the global null hypothesis of no exposure-disease associations and for estimating the number of true-positive associations. These approaches are advocated in preference to classical frequentist approaches of multiplying p values by the number of tests performed.

Environmental Pollution↗
PubMed1984

Interpersonal linkage among Hodgkin's disease patients and controls in Western Australia.

Interpersonal linkages were studied in 178 Hodgkin's disease patients, aged 60 years or younger, who lived in Western Australia between 1964 and 1975, and in their matched controls. Eighty-nine living subjects were interviewed about places and periods of residence, school attendance and employment, and possible linkages were computed based on concurrence of these events. Subjects were also shown the names of all patients and controls and asked to mark the names they recognized, giving details of acquaintanceships. The acquaintanceship method yielded more and the concurrence method fewer case-case links than expected. Little overlap occurred in linkages identified by the two methods. The acquaintanceship method is thought to be the more reliable. Risk factors suggested in the literature were also investigated. Increased risk of Hodgkin's disease in living patients was associated with being unmarried, being born outside Western Australia, smoking cigarettes, and having lived and worked on a farm and worked with animals. These effects did not explain the excess of case-case linkages found by the acquaintanceship method.

Adolescent↗
PubMed1984

Prognostically controlled comparison of dialysis and renal transplantation.

Because the comparison of survival in patients with renal failure treated by dialysis and transplantation may be biased by pretreatment prognostic differences in the patients who receive these two therapies, we quantified the pretreatment prognosis of all 430 dialysis and transplant patients who began therapy for end-stage renal disease at two hospitals from 1970 to 1980. Five pretreatment factors had a statistically significant adverse effect on survival: age, duration of diabetes, left ventricular failure, myocardial infarction, and other serious comorbid illness. Dialysis patients had a worse pretreatment prognosis than transplant patients did. When we controlled for these pretreatment differences, the actuarial 5-year patient survivals were 80% for dialysis (D), 79% for cadaver transplantation (CT), and 91% for living donor transplantation (LDT), (P = 0.9 for CT vs. D, and P = 0.05 for LDT vs. D). This similarity in survival with dialysis and cadaver transplantation was quite different from the results obtained when pretreatment prognosis was not controlled; the uncontrolled 5-year patient survivals were 43% for D, 77% for CT, and 89% for LDT (P less than 0.001 for CT vs. D, and P less than 0.001 for LDT vs. D). Our data suggest that the major factor determining differences in survival with dialysis and renal transplantation is not the relative efficacy of the two treatments but the pretreatment prognostic status of the patients chosen to receive them.

Adult↗
PubMed1984

Fibre exposure and mortality from pneumoconiosis, respiratory and abdominal malignancies in chrysotile production in Quebec, 1926-75.

To define the relationships between chrysotile exposure in fibre terms and death from specific cancers, and pneumoconiosis, all 11,379 persons born 1891-1920 who had worked in the asbestos mines and mills of Quebec for a month or more before 1967 were followed to the end of 1975. Among the 10,939 men, there had been 4,463 deaths, 634 from these causes. For each death, referents were randomly selected from among men in the cohort born in the same year as the case and known to have survived to a greater age. For each case and his referents, exposures accumulated up to nine years before the death of the case had been obtained as (million particles per cubic foot) x years. Fibre counts were estimated for each work-place so that all exposures could be expressed in (fibres/ml) x years. The ratio of the means for all 2,586 accumulated exposures was 3.46 (f/ml)/mpcf. Relative Risks (RR) were related to exposure by matched analysis. For pneumoconiosis and lung cancer, RR = 1 + b.(f/ml).y fitted well, with b estimated as 0.00647 and 0.00038, respectively. For cancers of upper and of lower G.I. tract, severe exposure was associated with elevated RRs, but rather unclearly. For other abdominal cancers, and laryngeal cancer, risks and exposure were not positively associated. The asbestos-smoking interaction in lung cancer was closer to multiplicative than to additive.

Abdominal Neoplasms↗
PubMed1983

The relative efficiencies of matched and independent sample designs for case-control studies.

We have studied the asymptotic and small sample efficiencies of dependent (pair-matched or stratified) and independent samples as design techniques for case-control studies, and of matched, stratified, covariance-adjusted, and crude comparisons as methods of analysis. The asymptotic efficiencies of dependent sample designs relative to independent sample designs with adjustment were found to vary with the strengths of the relationships of disease with exposure and potential confounder: as the relationship with exposure increases, dependent samples lose efficiency; as the relationship with confounder increases, dependent samples gain efficiency. The relative efficiency also depends in a complicated manner on such other factors as the distribution of exposure and the strength of the exposure-confounder relationship. In the majority of situations examined, however, dependent samples were found to be somewhat more efficient than independent samples when confounding was present, while the reverse was true when confounding was absent. Results of small sample simulations do not differ importantly from the asymptotic results, except for pair-matching on a non-confounder, where the inefficiency of matching is greater in small samples.

Monte Carlo Method↗
PubMed1983

Statistical methods for analyzing effects of temporal patterns of exposure on cancer risks.

Two approaches to the inclusion of temporal factors in the analysis of exposure-response relations are compared: (i) multivariate logistic analysis incorporating simple exposure indices, together with additional temporal variables and their interactions, and (ii) direct fitting to models of the disease process. These approaches are illustrated on case-referent data relating lung cancer to asbestos and smoking. From approach i average age at exposure, age at risk, and duration of exposure were found to contribute direct or interaction effects. Two models of carcinogenesis were fit. In a two-stage initiation-latency model the median latency period was estimated at 11.0 years overall, but was somewhat longer for asbestos-induced and shorter for smoking-induced tumors. When this difference was allowed for, latency periods seemed to be inversely related to the average intensities of both asbestos and smoking. In the multistage model, the best fit was obtained with asbestos acting at the fourth and smoking at the fifth of six stages. Lifetime risks of lung cancer are projected under the different models.

Asbestosis↗
PubMed1983

Nonparametric estimation and tests of fit for dose-response relations.

Various parametric models have been used to describe the dependence of disease risks on continuous explanatory variables. The fit of such models is generally tested either against some larger but still parametric class of alternatives, or by making the covariates discrete in some arbitrary fashion. This communication introduces a more general concept of residuals which may be useful for visualizing the fit of the data. Subject only to the constraint of monotonicity, the maximum likelihood estimate (MLE) of the dose-response relation for a single covariate is shown to be a step function with discontinuities only at the covariate values of the failures. The MLE is found by a constrained Newton-Raphson search, and a procedure for reducing the dimensions of the search is suggested. Applications to the risk of lung cancer in relation to asbestos exposure are given.

Asbestos↗
PubMed1982

Deoxyribonucleic acid dependent adenosinetriphosphatases from the Novikoff hepatoma. Characterization of a homogeneous adenosinetriphosphatase that stimulates DNA polymerase beta.

Five chromatographically distinct DNA-dependent ATPase activities have been identified in high salt-detergent extracts of the Novikoff hepatoma. One of these, ATPase III, has been purified to apparent homogeneity as judged by polyacrylamide gel electrophoresis and has a specific activity of 12 mumol of ATP hydrolyzed min-1 (mg of protein)-1. The enzyme, a dimer of Mr 65000 subunits, has a sedimentation coefficient of 7.0 S in both high salt and low salt, a Stokes radius of 43 A, and a frictional coefficient of 1.31. In the presence of Mg2+ ion and a polynucleotide effector, the enzyme catalyzes hydrolysis of ATP or dATP to a diphosphate with a Km of 206 microM and 110 microM, respectively, for the two substrates. Although single-stranded effectors are preferred, the enzyme has significant activity with double-stranded effectors. The Km for effector is 0.4 microM (nucleotide). The analogues adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S), dideoxyadenosine triphosphate (ddATP), and adenosine 5'-(alpha, beta-methylenetriphosphate) (alpha, beta-Me-ATP) are competitive inhibitors of the enzyme while adenosine tetraphosphate (ATP-P), 8-bromoadenosine 5'-triphosphate (8-Br-ATP), 5'-adenylyl imidodiphosphate (AMP-PNP), and adenosine 5'-(beta, gamma-methylenetriphosphate) (beta, gamma-Me-ATP) do not inhibit. The enzyme is insensitive to nalidixic acid, novobiocin, and berenil but is sensitive to N-ethylmaleimide. ATPase III is capable of stimulating DNA polymerase beta on duplex DNA, but this effect is abolished in the presence of ATP gamma S. Polymerase stimulation is further enhanced in the presence of a single-stranded DNA-binding protein. These data suggest that ATPase III may play a role in DNA repair.

Adenosine Triphosphatases↗
PubMed1982

On the need for the rare disease assumption in case-control studies.

The conditions under which matched and unmatched odds ratios are consistent estimators of the incidence-density ratio in case-control studies are examined. Under "incidence-density" sampling, in which controls are selected from those at risk at the time of onset of each case, the matched estimator is shown to be consistent. In contrast, the unmatched estimator is biased unless the proportion exposed in the population at risk is constant over the study period; the bias is, however, negligible unless there is very large variation in the proportion exposed. No assumption of rarity of the disease is needed for these results. On the other hand, when the risk ratio is the parameter of interest, the assumption of rarity is needed for the odds ratio to be a consistent estimator. In such situations, the odds ratio obtained under "incidence-density" sampling will in general provide a better approximation to the risk ratio than will the odds ratio obtained under "cumulative-incidence" sampling, in which controls are selected from those still unaffected at the end of the study period. Even if the disease is rare, however, the odds ratio obtained under cumulative sampling need not consistently estimate any parameter of interest unless the proportion exposed is approximately constant.

Epidemiology↗
PubMed1982

Predicting survival in adults with end-stage renal disease: an age equivalence index.

To quantify prognosis in patients with end-stage renal disease, we evaluated pretreatment clinical state and ascertained the outcome of all 220 patients who began therapy at two hospitals from 1970 to 1975. Each of three pretreatment characteristics made a statistically significant independent contribution to the relative risk of death: age (relative risk for 10-year increments = 2.2, p less than 0.001); duration of diabetes (relative risk for 10-year increments = 2.2, p less than 0.001); and left-sided heart failure (relative risk = 2.0, p less than 0.001). We combined the effects of these factors in an age-equivalence index that showed a strong gradient in survival rates from lower to higher values; the 5-year survival rate differed between 92% in patients with a score of 30 or less and 6% in patients with a score over 70. This index, which is simple to use, should prove helpful in patient care and can improve the scientific validity of therapeutic comparisons in patients with end-stage renal disease by identifying and adjusting for the selection biases that occur in the allocation of different treatments.

Adolescent↗
PubMed1981

Biological models and statistical interactions: an example from multistage carcinogenesis.

From the assessment of statistical interaction between risk factors it is tempting to infer the nature of the biologic interaction between the factors. However, the use of statistical analyses of epidemiologic data to infer biologic processes can be misleading. as an example, we consider the multistage model of carcinogenesis. Under this biologic model, it is shown, by means of simple hypothetical examples, that even if carcinogenic factors act independently, some pairs may fit an additive statistical model, some a multiplicative statistical model, and some neither. The elucidation of biological interactions by means of statistical models requires the imaginative and prudent use of inductive and deductive reasoning; it cannot be done mechanically.

Cell Transformation, Neoplastic↗