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D Tritchler

Publications and source records attributed to D Tritchler.

At least 19 recordsLinked to original sources
PubMed2001

Modeling complex disease with demographic and environmental covariates and a candidate gene marker.

We randomly chose replicates 28 and 29 of the simulated data sets of Genetic Analysis Workshop 12 to model the dependence of affection status on covariates, quantitative traits, and genes using all living pedigree members. First we explored the relationship of affection status to demographic and environmental factors using logistic regression and the Cox proportional hazards models. In the second stage of our analyses the generalized transmission disequilibrium test (GTDT) was applied to nuclear families with at least two affected siblings to select single markers and high-risk alleles, which were tested in the population association analyses including all pedigree members. Multiple logistic regression models were fitted to investigate the joint contributions of genetic and nongenetic factors and a block-recursive modeling approach was adopted to study inherent hierarchical dependence structure in the data. We found that allele 2 on marker 35 of chromosome 6 is associated with higher risk compared with the other 3 alleles of this marker. In addition to this significant genetic effect, age at exam and four of the five quantitative traits (QT1, QT2, QT4, and QT5) had a significant association with the disease. Our results were obtained without knowledge of the true disease generating models.

Adolescent↗
PubMed1999

Reasoning about data with directed graphs.

This paper constructs graphical models for two important analysis problems to demonstrate how graphs can clearly represent complex relationships. A powerful property of graphical models called d-separation describes the statistical associations in a given graphical model. This allows the effects of unmeasured variables to be predicted, and suggests conditional analyses which can distinguish conjectured models. If an assumption called quasi-linearity is made, further conclusions can be drawn based on the structure of the graph and d-separation. Making the quasi-linearity assumption explicit also contributes to our understanding of which aspects of our causal intuition are based on linearity assumptions. The examples that we consider are the scientific interpretation of interventions and the evaluation of the validity of candidate surrogate endpoints for clinical trials. Intervention studies can be plagued by non-compliance with assigned treatment and ambiguity in interpreting results when treatment assignment manipulates multiple factors. We show graphically the conclusions that can be drawn under various assumptions. The topic of surrogate endpoints is addressed in causal terms and modelled graphically.

Bayes Theorem↗
PubMed1999

Modelling study quality in meta-analysis.

When summarizing studies in a meta-analysis, the methodological quality of the studies can vary widely. This variation is often described by assigning quality scores to studies. This paper presents a probability model for the effect of quality on a summary effect measure. The model motivates criteria used to assess quality, and can be used to incorporate quality into the calculation of a summary effect. We derive a number of summarization methods and compare them for simulated data and an actual set of studies.

Analysis of Variance↗
PubMed1999

A comparison of some allele-sharing based linkage analysis methods for detecting complex trait loci.

Using randomly selected sib pairs from a subset of the GAW11 simulated data in Problem 2, we compared the results of some linkage analysis methods based on allele sharing. One method was the Haseman-Elston test for a binary disease outcome (unaffected vs. mild or severe). The other methods, which analyzed the trinary ordered outcome unaffected/mild/severe were the Haseman-Elston test, an extended Haseman-Elston incorporating sib-pair sums, variance components analysis, and regression analysis. Our analysis was done without knowledge of the generating model.

Alleles↗
PubMed1997

Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial. Canadian Diet and Breast Cancer Prevention Study Group.

BACKGROUND: The appearance of breast tissue on mammography varies according to its composition. Fat is radiolucent and appears dark on mammography, while stromal and epithelial tissue has greater optical density and appears light. Extensive areas of radiologically dense breast tissue seen on mammography are associated with an increased risk of breast cancer. PURPOSE: The purpose of the present study was to determine whether the adoption of a low-fat, high-carbohydrate diet for 2 years would reduce breast density. METHODS: Women with radiologic densities in more than 50% of the breast area on mammography were recruited and randomly allocated to an intervention group taught to reduce intake of dietary fat (mean, 21% of calories) and increase complex carbohydrate (mean, 61% of calories) or to a control group (mean, 32% of calories from fat and 50% of calories from carbohydrates). Mammographic images from 817 subjects were taken at baseline and compared with those taken 2 years after random allocation by use of a quantitative image analysis system, without knowledge of the dietary group of the subjects or of the sequence in which pairs of images had been taken. The effects of the intervention on the mammographic features of breast area, area of dense tissues in the breast, and the percent of the breast occupied by dense tissue were examined using t tests. Multiple regression was used to examine these effects while accounting for age at trial entry, weight change, and menopausal status. RESULTS: After 2 years, the total area of the breast was reduced by an average of 233.7 mm2 (2.4%) (95% confidence interval [CI] = 106.9-360.6) in the intervention group compared with an average increase of 26.3 mm2 (0.3%) (95% CI = -108.0-160.5) in the control group (P = .01). The area of density was reduced by 374.4 mm2 (6.1%) (95% CI = 235.1-513.8) in the intervention group compared with an average of 127.7 mm2 (2.1%) (95% CI = 8.6-246.7) in the control group (P = .01). Weight loss was associated with a reduction in breast area. The effect of the intervention on breast area was only marginally statistically significant after weight change, menopausal status, and age at trial entry were taken into account (P = .06). Greater weight loss and becoming postmenopausal were associated with statistically significant reductions in the area of density on the mammographic image at 2 years (P = .04 and P<.001, respectively). Age at entry into the trial was marginally significant in the same direction (P = .06). The effect of the intervention on area of density remained statistically significant after controlling for weight loss, age at entry, and menopausal status (P = .03). The change in the percentage of dense tissue in the mammographic image was not significantly different between the two groups (P = .71). CONCLUSIONS AND IMPLICATIONS: These results show that after 2 years, a low-fat, high-carbohydrate diet reduced the area of mammographic density, a radiographic feature of the breast that is a risk factor for breast cancer. Longer observation of a larger number of subjects will be required to determine whether these effects are associated with changes in risk of breast cancer.

Adult↗
PubMed1997

Comparison of evidence for linkage from different analytic methods.

In a randomly chosen replicate of extended pedigrees from GAW10, we conducted robust multipoint genome scans for linkage using a dense marker map. For analysis of the quantitative traits, we selected sibships from the pedigrees, and for analysis of disease status, small families of affected relatives were selected. Lod-score likelihood analyses were conducted in the full pedigrees and in the affected relative families for selected regions. We located a flanking marker for MG1 on chromosome 5, and identified marker regions including MG2, MG4, and MG5 on chromosomes 8 and 9. The analytic methods were consistent for the major gene with a strong effect; false positive errors on chromosomes 1 and 10 could have been eliminated by requiring evidence from more than one method.

Female↗
PubMed1996

Explanatory analyses of randomized studies.

This paper considers randomized interventions which do not completely determine an intended determinant of response, and which may also manipulate additional, possibly unobserved, variables influencing response. The example we use throughout this paper is counseling for a low-fat diet for breast cancer prevention, where the intervention is counseling and dietary fat is hypothesized to reduce breast cancer risk. We use additive linear models to derive conditions and assumptions for considering fat to be the sole explanation of an observed treatment effect. A modified experimental design which supports stronger conclusions about causality is proposed.

Biometry↗
PubMed1995

Mammographic densities as a criterion for entry to a clinical trial of breast cancer prevention.

The most convincing evidence that a factor such as dietary fat is causally related to breast cancer would be obtained from a randomised controlled trial in which exposure to dietary fat intake was systematically varied. A limitation of randomised controlled trials of breast cancer prevention, however, is the large sample size required to detect plausible reductions in risk resulting from the intervention. We describe here experience over a period of 9 years with the use of one risk factor for breast cancer as a criterion for entry to a clinical trial of breast cancer prevention. The risk factor used was the presence of extensive densities in the breast tissue on mammography, which has been found by several investigators to be strongly associated with risk of breast cancer. Using this criterion for selection, 1800 subjects of mean age 46 years were enrolled between 1982 and 1986, and again between 1988 and the present. Throughout this period, the point estimate of annual invasive cancer incidence was approximately 6 per 1000 per year. The observed cancer incidence has been consistently 4-5 times the incidence expected from age-specific breast cancer incidence data for women living in Ontario. These data show that the selection of subjects for a clinical trial of breast cancer prevention using the criterion of extensive breast parenchymal densities does identify a group at substantially increased risk of breast cancer. Use of this criterion for the selection of subjects can substantially reduce the sample size required for a clinical trial of a preventive strategy.

Adult↗
PubMed1995

Plasma lipids, lipoproteins, and familial breast cancer.

We have examined the relationship between plasma lipids, lipoproteins, and a family history of breast cancer. We measured the plasma lipids and lipoproteins in unaffected female members of the nuclear family of women with familial breast cancer and compared them with those of the female members of the nuclear family of women with sporadic breast cancer. A mean number of 3.3 relatives of mean age 35 years were studied in 23 pairs of familial and sporadic breast cancer families. After adjustment in multivariate analysis for variables that either differed between high and low risk families, or were significantly associated with plasma levels or lipoproteins, statistically significant differences were found in plasma levels of total cholesterol, low density lipoprotein cholesterol, and apoprotein B, all of which were lower in familial breast cancer than in sporadic breast cancer families. These data suggest that inherited factors associated with breast cancer risk may play a role in determining plasma lipid and lipoprotein levels and that lipid regulatory genes should be considered in this context.

Adult↗
PubMed1995

Interpreting the standardized difference.

An interpretation of the standardized difference is given which assists in judging the importance of such a difference. This is useful for designing two sample studies when information on mean difference or standard deviation is unavailable.

Biometry↗
PubMed1994

Accuracy of family cancer history in breast cancer patients.

We assessed the validity of information reported by patients with breast cancer on cancer in first- and second-degree relatives. In Toronto, Canada, 165 patients completed mailed questionnaires about cancer in relatives and were then interviewed in person. Their reports were compared with relatives' hospital records, cancer registry or death records for presence of cancer, site and age at diagnosis. Questionnaire and interview reports agreed with records for 82-96% of reports on first-degree and 48-80% on second-degree relatives. Proband reports of cancer sites in first-degree relatives were generally accurate (breast 99%, ovary 100%, prostate 85%, colon 93%). Reports of cancer sites in second-degree relatives were accurate for prostate cancer but only for 85% of breast and 72% of colon cancers. Age at diagnosis of breast cancer was correct in 92% of cases in first-degree and 54% in second-degree relatives. The interview contributed additional information about the presence of cancer in second-degree relatives, and the site and age at diagnosis in first- and second-degree relatives. In a similar population the questionnaire alone should yield adequate data for identifying families that warrant further investigation.

Adult↗
PubMed1992

Dietary fat and breast cancer risk: the feasibility of a clinical trial of breast cancer prevention.

Animal experimental evidence and human ecological data suggest that dietary fat intake is related to breast cancer risk. Epidemiological studies within countries have given inconsistent results but are limited by the restricted range of dietary intake found in Western populations and by error in the measurement of fat consumption. Experimental evidence, derived from controlled clinical trials in which the range of fat intake is increased beyond that seen in most Western populations, is capable of overcoming this limitation of observational epidemiology, and would provide the strongest evidence available concerning the relationship of dietary fat intake to breast cancer risk. Further, such trials are the only means likely to answer the question of whether breast cancer risk in high-risk subjects can be modified by changing dietary fat intake. We describe here several aspects of the feasibility of an experimental approach to this problem, including the identification of subjects at increased risk for breast cancer, and the demonstration that such subjects will enter a clinical trial of dietary fat reduction and comply with a low-fat diet. It is shown that subjects can be recruited and retained in such trials, that satisfactory dietary compliance can be achieved over at least 24 mon and that the subjects selected are at demonstrably increased risk of breast cancer. This finding indicates that it is feasible to test the dietary fat-breast cancer hypothesis experimentally by means of a clinical trial.

Adult↗
PubMed1992

The risk of breast cancer associated with mammographic parenchymal patterns: a meta-analysis of the published literature to examine the effect of method of classification.

The appearance of the breast parenchyma as seen on mammography is known to vary between individuals. The evidence is reviewed that some of the sources of this variation, namely, the densities referred to as "dysplasia", are related to breast cancer risk. We have carried out a meta-analysis of the published literature to determine the magnitude of the risk of breast cancer associated with mammographic densities by calculating summary odds ratios for studies grouped according to their design and the method used to classify mammographic parenchymal patterns. This has shown that subjects with mammographic densities have an increased risk of breast cancer relative to those without densities. Of the studies that used Wolfe's method of classification, cohort studies (n = 8) had a summary odds ratio of 5.19 (95% CI, 3.6 to 7.48); case control studies (n = 13) had a summary odds ratio of 1.8 (95% CI, 1.5 to 2.13); and prevalence surveys had a summary odds ratio of 0.54 (95% CI, 0.4 to 0.7). Other methods of classification, using quantitative estimates of the proportion of the breast occupied by densities, gave substantially higher odds ratios than Wolfe's system. The ability to recognize individuals within the population at different risks for breast cancer could be exploited in studies of potential etiological factors.

Breast↗
PubMed1991

Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate.

One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.

Adolescent↗
PubMed1990

Quantitative changes in dietary fat intake and serum cholesterol in women: results from a randomized, controlled trial.

We compared observed and predicted changes in serum cholesterol in women with mammographic dysplasia who participated for 12 mo in a randomized, controlled trial of a low-fat, high-carbohydrate diet, in which total fat intake was reduced from an average of 37% of calories to 21% and carbohydrate intake increased from 44% to 52% of calories. Changes observed in serum cholesterol were greater than those predicted (by the formulas of Hegsted and Keys) for subjects with initial serum cholesterol values in the upper tertile of the population, were not significantly different from those predicted for subjects with baseline values in the middle tertile, and were significantly less than those predicted for subjects with initial values in the lower tertile. These results show that the usefulness of serum cholesterol as a marker of change in dietary fat intake in women depends on the distribution of serum cholesterol values in the population studied.

Adult↗