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R Prentice

Publications and source records attributed to R Prentice.

At least 19 recordsLinked to original sources
PubMed2001

Statistical modeling of large microarray data sets to identify stimulus-response profiles.

A statistical modeling approach is proposed for use in searching large microarray data sets for genes that have a transcriptional response to a stimulus. The approach is unrestricted with respect to the timing, magnitude or duration of the response, or the overall abundance of the transcript. The statistical model makes an accommodation for systematic heterogeneity in expression levels. Corresponding data analyses provide gene-specific information, and the approach provides a means for evaluating the statistical significance of such information. To illustrate this strategy we have derived a model to depict the profile expected for a periodically transcribed gene and used it to look for budding yeast transcripts that adhere to this profile. Using objective criteria, this method identifies 81% of the known periodic transcripts and 1,088 genes, which show significant periodicity in at least one of the three data sets analyzed. However, only one-quarter of these genes show significant oscillations in at least two data sets and can be classified as periodic with high confidence. The method provides estimates of the mean activation and deactivation times, induced and basal expression levels, and statistical measures of the precision of these estimates for each periodic transcript.

CDC28 Protein Kinase, S cerevisiae↗
PubMed2001

Considerations in the evaluation of surrogate endpoints in clinical trials. summary of a National Institutes of Health workshop.

We report on recommendations from a National Institutes of Health Workshop on methods for evaluating the use of surrogate endpoints in clinical trials, which was attended by experts in biostatistics and clinical trials from a broad array of disease areas. Recent advances in biosciences and technology have increased the ability to understand, measure, and model biological mechanisms; appropriate application of these advances in clinical research settings requires collaboration of quantitative and laboratory scientists. Biomarkers, new examples of which arise rapidly from new technologies, are used frequently in such areas as early detection of disease and identification of patients most likely to benefit from new therapies. There is also scientific interest in exploring whether, and under what conditions, biomarkers may substitute for clinical endpoints of phase III trials, although workshop participants agreed that these considerations apply primarily to situations where trials using clinical endpoints are not feasible. Evaluating candidate biomarkers in the exploratory phases of drug development and investigating surrogate endpoints in confirmatory trials require the establishment of a statistical and inferential framework. As a first step, participants reviewed methods for investigating the degree to which biomarkers can explain or predict the effect of treatments on clinical endpoints measured in clinical trials. They also suggested new approaches appropriate in settings where biomarkers reflect only indirectly the important processes on the causal path to clinical disease and where biomarker measurement errors are of concern. Participants emphasized the need for further research on development of such models, whether they are empirical in nature or attempt to describe mechanisms in mathematical terms. Of special interest were meta-analytic models for combining information from multiple studies involving interventions for the same condition. Recommendations also included considerations for design and conduct of trials and for assemblage of databases needed for such research. Finally, there was a strong recommendation for increased training of quantitative scientists in biologic research as well as in statistical methods and modeling to ensure that there will be an adequate workforce to meet future research needs.

Antiviral Agents↗
PubMed1999

Pyoderma gangrenosum with secondary pyarthrosis following propylthiouracil.

The association of pyoderma gangrenosum and arthritic symptoms is well documented. We present a rarely reported variant of this in a 44-year-old woman with pyoderma gangrenosum and bilateral large purulent effusions of her knees. She had no evidence of underlying rheumatoid arthritis or a specific seronegative spondyloarthropathy. Of note she had a history of Graves' disease for which she had been treated with propylthiouracil for 3 years and on investigation at this presentation had a markedly elevated perinuclear antineutrophil cytoplasm antibody (P-ANCA) level with specificities for IgM myeloperoxidase, IgG elastase and IgG lactoferrin. We believe this patient had pyoderma gangrenosum with secondary sterile pyarthrosis and a P-ANCA precipitated by propylthiouracil.

Adult↗
PubMed1999

On the assessment of statistical significance in disease-gene discovery.

One of the major challenges facing genome-scan studies to discover disease genes is the assessment of the genomewide significance. The assessment becomes particularly challenging if the scan involves a large number of markers collected from a relatively small number of meioses. Typically, this assessment has two objectives: to assess genomewide significance under the null hypothesis of no linkage and to evaluate true-positive and false-positive prediction error rates under alternative hypotheses. The distinction between these goals allows one to formulate the problem in the well-established paradigm of statistical hypothesis testing. Within this paradigm, we evaluate the traditional criterion of LOD score 3.0 and a recent suggestion of LOD score 3.6, using the Monte Carlo simulation method. The Monte Carlo experiments show that the type I error varies with the chromosome length, with the number of markers, and also with sample sizes. For a typical setup with 50 informative meioses on 50 markers uniformly distributed on a chromosome of average length (i.e., 150 cM), the use of LOD score 3.0 entails an estimated chromosomewide type I error rate of.00574, leading to a genomewide significance level >.05. In contrast, the corresponding type I error for LOD score 3.6 is.00191, giving a genomewide significance level of slightly <.05. However, with a larger sample size and a shorter chromosome, a LOD score between 3.0 and 3.6 may be preferred, on the basis of proximity to the targeted type I error. In terms of reliability, these two LOD-score criteria appear not to have appreciable differences. These simulation experiments also identified factors that influence power and reliability, shedding light on the design of genome-scan studies.

Chromosome Mapping↗
PubMed1999

Integrated designs for gene discovery and characterization.

Recent advances, including near completion of the human genome map, ever improving high-throughput technologies, and successes in discovering chronic disease-related genes, have stimulated the further development of genetic epidemiology. The primary mission of genetic epidemiology is to discover and characterize genes, whether independent of or interactive with environmental factors, that cause human diseases. To accomplish such a mission, genetic epidemiology needs to integrate both genetic and epidemiologic approaches. One of the challenges facing such an integrated approach is the identification of study designs that are efficient for both gene discovery and characterization. Because designs for gene discovery alone and designs for gene characterization alone have been elaborated in the other two panels, the focus of this paper is to describe those designs that may be useful for discovery and characterization jointly, including case-family and case-control-family designs. Examples of integrated designs are described, and studies of breast cancer conducted at the Fred Hutchinson Cancer Research Center are used for illustration. Finally, related analytic issues are also discussed.

Breast Neoplasms↗
PubMed1996

Approached to monitoring the results of long-term disease prevention trials: examples from the Women's Health Initiative.

We contrast monitoring therapeutic trials with monitoring prevention trails. We argue that in monitoring prevention trials one should place more emphasis on formally defined global measures of health, not simply on a single targeted disease, particularly when an intervention may reduce the incidence of some diseases but increase the incidence of others. We describe one approach, illustrated by the Women's Health Initiative. For each of several sets of hypothetical interim results ("scenarios"), members of the Data and Safety Monitoring Committee (DSMC) were asked whether they would continue or stop the trial. In parallel with this exercise, various statistical methods of monitoring that are based on (1) the primary targeted disease, (2) a combination of various disease outcomes, or (3) a mixture of both were applied to these scenarios. One objective was to find a statistical approach that mirrors the majority view of the DSMC. A second objective was to stimulate discussion among DSMC members in preparation for their task of monitoring the trial as the real data become available. We found that no single method fully matched the majority vote of the DSMC. However, a mixed approach requiring the primary outcome to be significant and the global index to be "supportive," with separate monitoring of adverse effects, corresponded with the majority vote quite well. This approach maintains the emphasis on the primary hypothesis while assuring that broader safety and ethical issues of multiple diseases are incorporated.

Bayes Theorem↗
PubMed1996

The Women's Health Trial Feasibility Study in Minority Populations: design and baseline descriptions.

The Women's Health Trial: Feasibility Study in Minority Populations (WHT:FSMP), a randomized trial of 2208 women, was conducted to investigate three questions. First, can women from minority and low-socioeconomic-status populations be recruited in numbers sufficient to evaluate a dietary intervention designed to lower fat intake. Second, the efficacy of a low fat, increased fruit/vegetable/ grain product intervention for reducing fat consumption. Third, will participation in the intervention lower plasma cholesterol and estradiol levels relative to the controls. The baseline results showed that an adequate number of minority and low SES women could be recruited to test the study hypotheses. A diverse study population of postmenopausal women consuming a high fat diet was recruited: 28% of participants were Black, 16% were Hispanic, 11% had less than a high school level of education, and 15.5% had household incomes of < $15,000.

Aged↗
PubMed1993

A review of the association of estrogens and progestins with cardiovascular disease in postmenopausal women.

The purpose of this article was to review, with special attention to the hypothesized mechanisms of atherosclerosis and thrombosis, the literature on the association of estrogens and progestins with cardiovascular disease. The data sources included recent reviews and their citations as well as literature searches of Medline. For coronary heart disease, we relied on a recent meta-analysis; for the lipid effects of estrogens and progestins, we refer to recent reviews and studies; for stroke, we identified all cohort and case-control studies; and for the effects of hormones on coagulation factors, we identified all relevant studies. The lipid effects of estrogens in postmenopausal women probably prevent atherosclerosis, and we would expect long duration of use rather than current use to provide the greatest benefit. Few epidemiologic studies have, however, assessed duration of estrogen use. High doses of estrogens are likely to be thrombogenic during current use, and it is possible that even moderate doses may increase the risk of clotting among women who smoke or who have existing coronary atherosclerosis. Compared with the lipid effects of estrogens alone, the lipid effects of combined therapy with progestins may increase atherosclerosis. The effect of progestins on coagulation factors is largely unknown, and no epidemiologic study has assessed the risk of cardiovascular disease associated with the use of combined hormone therapy in postmenopausal women. Cardiovascular risk or benefit associated with the use of postmenopausal hormones may involve several competing mechanisms, including effects on prostaglandins and vascular tone as well as atherosclerosis and thrombosis.

Aged↗
PubMed1991

Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group.

Five hundred forty-three patients with completely resected malignant melanoma who were considered to have a significant risk of developing recurrent disease were randomized to one of four study groups. One group received levamisole 2.5 mg/kg on 2 consecutive days weekly for 3 years, a second group received bacillus Calmette-Guérin (BCG) for 3 years. A third group alternated 8-week courses of BCG and levamisole for 3 years and a fourth group underwent clinical assessment at the same frequency as the three treatment groups. The median duration of follow-up is 8.5 years. The percentage of reduction in the death rate and the recurrence rate in the treatment groups compared with the control group was calculated using the Cox proportional hazards model and adjusted for age, sex, and stage as covariants. The patients treated with levamisole were estimated to have a 29% reduction in both the death rate (P = .08) and the recurrence rate (P = .09) compared with patients receiving no further treatment. Fifty-five patients discontinued levamisole early because of gastrointestinal intolerance or arthralgia, myalgia, fever, and immune leukopenia. The patients treated with BCG alternating with levamisole experienced a 10% reduction in the death rate and a 6% reduction in the recurrence rate, and the patients treated with BCG alone experienced a 4% reduction in the death rate and a 3% increase in the recurrence rate compared with the control group. The degree of improvement experienced by the patients that were treated by levamisole is of sufficient magnitude to warrant further investigation of this dose of levamisole as adjuvant treatment in patients with melanoma.

Adolescent↗
PubMed1990

Dietary fat reduction and plasma estradiol concentration in healthy postmenopausal women. The Women's Health Trial Study Group.

Concentrations of total and weakly bound plasma estradiol were significantly (P less than .01) reduced in 73 healthy post-menopausal women after 10-22 weeks of participation in a low-fat diet intervention program. Nonsignificant reductions in estrone sulfate and sex hormone-binding protein were also observed. The 17% reduction in average estradiol concentration was accompanied by an average reduction of 12 mg/dL in total plasma cholesterol (P less than .001), an average weight loss of 3.4 kg (P less than .001), and an average reduction in daily dietary fat from 68.5 to 29.5 g. Our review of case-control studies indicates that a 17% reduction in plasma estradiol may explain a noteworthy component of the international variation in breast cancer incidence. We find a need for further studies of (a) disease risk in relation to hormone concentrations and (b) changes in hormone concentrations as a function of the duration of low-fat diet intervention.

Aged↗
PubMed1990

Analysis of the costs of a large prevention trial.

Total direct costs of the Women's Health Trial (WHT), a large multicenter prevention trial, were reduced by more than 50% by means of research cost analysis conducted during the trial design phase. The unit costs of specific trial activities were estimated so that total direct costs of the trial could be predicted from design parameters. The relative costs of screening, treatment, and follow-up, and the fixed costs associated with each clinical center in a multicenter prevention trial were taken into account. Direct costs of the WHT were reduced from +195 million to +95 million by refinement of the trial protocol, selection of an efficient design, and consideration of trial logistics. The analyses suggest several ways to reduce costs in a prevention trial. Use of the case-cohort approach can reduce costs substantially when the protocol includes collection of specimens or data that are costly to process. When establishing and maintaining a clinical center represents a significant proportion of a clinical center's costs, use of a smaller number of larger clinical centers offers important cost savings. Because restrictive eligibility requirements reduce the recruitment potential of each clinical center, use of high-risk participants may not improve the efficiency of a prevention trial; its favorable impact on sample size may fail to compensate for its cost in terms of additional clinical centers and higher recruitment costs.

Aged↗
PubMed1990

Joint estimation of recombination fractions and interference coefficients in multilocus linkage analysis.

Estimation of recombination fractions and interference coefficients is of importance in multilocus linkage analysis. With the development of molecular genetic technologies such as RFLP, multilocus data are readily available to researchers. Several methods have been developed to analyze such data, and each performs well under restrictive conditions. The present paper proposes a method based on a multiplicative model and maximum-likelihood estimation of recombination fractions and interference coefficients. The estimators are consistent regardless of the model assumptions and are efficient if the model is a good approximation. The estimators are tractable even when there are incomplete observations. Furthermore, the interference between nonadjacent chromosomal regions or those among three chromosomal regions can be modeled and tested by a simple Z-test. The proposed method was applied to linkage analysis of four-locus data obtained from Drosophila and that of seven-locus data obtained again from Drosophila. Reanalysis of the first example revealed that there is interference between chromosomal regions 2 and 3. Analysis of the second example suggested that there is triple interference as well as pairwise interference between nonadjacent chromosomal regions; the genetic interpretation of these findings remains to be developed.

Genetic Linkage↗
PubMed1988

Statistical design of the Women's Health Trial.

The National Cancer Institute has initiated a randomized trial to determine whether a low fat diet can reduce the incidence of breast cancer among women at increased risk for this disease. A feasibility trial involving 303 women has been conducted to examine recruitment strategies, study short-term compliance and, more generally, develop and refine trial procedures. The feasibility trial group also developed a detailed full-scale trial design plan, and randomization of participants to such a trial is currently underway. The purpose of this report is to describe the major design features of this Women's Health Trial, with particular emphasis on the statistical aspects of the design. The trial is planned to last 10 years and to include 32,000 participants. Of these 32,000 women, 12,800 will be assigned to a low fat diet intervention, and the other 19,200 will constitute a control group. The sample size of 32,000 arises from a range of estimates and assumptions pertaining to (a) the incidence of breast cancer at enrollment corresponding to selected eligibility criteria, (b) the relative risk of breast cancer as a function of a woman's history of dietary fat intake, (c) compliance assumptions in terms of average percent fat in the intervention and control groups as a function of time from randomization, and (d) rates of competing causes of death. These estimates and assumptions will be discussed, as will the robustness of the intended sample sizes to departures from such design assumptions.

Aged↗
PubMed1984

Recovery of in vivo cellular immunity after human marrow grafting. Influence of time postgrafting and acute graft-versus-host disease.

Three hundred thirty-two marrow graft recipients and 241 healthy marrow donors were studied by skin testing with recall and neoantigens. Two hundred thirty patients with leukemia and seventy-eight patients with aplastic anemia received allogeneic HLA-identical sibling marrow. Twenty-four patients with leukemia received syngeneic marrow. The conditioning regimen prior to marrow infusion consisted of 120 mg/kg cyclophosphamide and 9.2-15.75 Gy total-body irradiation (leukemia) or 200 mg/kg cyclophosphamide (aplastic anemia). The patients were skin-tested with the neoantigens dinitrochlorobenzene (DNCB), keyhole limpet hemocyanin, and a battery of five recall antigens around 100, 150, 365, 730, 1095, 1460, and 1825 days after grafting. A binary logistic regression analysis was used to investigate the factors thought to influence immunocompetence. At 3 months postgrafting, the proportion of patients positive to DNCB was equal to that of normal marrow donors, but thereafter it was lower until 2 years. The proportion of patients positive to keyhole limpet hemocyanin was lower than normal regardless of the time after grafting. The proportion of patients positive to recall antigens was lower than that of normal marrow donors until 4 years after grafting. Patients with a history of acute graft-versus-host disease had the lowest probability of a positive reaction to recall antigens. None of the other factors was significantly associated with an increased or reduced level of response.

Acute Disease↗