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Biomedical subjects

L S Freedman

Publications and source records attributed to L S Freedman.

At least 19 recordsLinked to original sources
PubMed1992

The future of prognostic factors in outcome prediction for patients with cancer.

The anatomic description of the extent of tumor spread (tumor staging) assists clinical management, facilitates communication among physicians, is an essential part of randomized controlled trials, and may help in the counseling patients and their families. However, in recent years, additional "prognostic factors" have been defined, many of which assess or reflect the biologic behavior of malignant neoplasms. Other measures of tumor biochemistry address the natural history of neoplastic development and often are included in a discussion of new prognostic factors. This review article summarizes current knowledge and thinking related to tumor prognostic factors in four areas by providing: (1) a definition and principles of anatomic spread of tumor (staging) and some suggestions for improvement, (2) a description of some examples of additional factors of prognostic significance, (3) some statistical methods to evaluate prognostic factors, and (4) an examination of the possible future of summary statements of outcome (i.e., prognostic indexes).

Biomarkers↗
PubMed1992

Sample size for studying intermediate endpoints within intervention trails or observational studies.

An intermediate endpoint is a biologic event or marker that is a precursor to a given health outcome. Examples of potential intermediate endpoints include serum cholesterol for coronary heart disease, endogenous steroid hormones for breast cancer, and CD4 count for acquired immunodeficiency syndrome. When one is studying a potential intermediate endpoint in the context of an intervention trial, five types of questions may be investigated: 1) Does the intervention affect the intermediate endpoint? 2) Is the intermediate endpoint associated with prognostic or risk factors? 3) Is the intermediate endpoint associated with the main outcome? 4) Is the intervention effect on the main outcome mediated by the intermediate endpoint? 5) Are the prognostic or risk factor effects mediated by the intermediate endpoint? In this paper, the authors show that each of these questions had different sample size requirements, and they illustrate their point with a discussion of an ancillary study of large bowel epithelial proliferation in the National Cancer Institute's Polyp Prevention Trial. The same methods may be used in an observational study, in which case questions 2, 3, and 5 are relevant. However, much larger numbers than those used in the Polyp Prevention Trial example will be required when the main outcome is rare.

Colonic Polyps↗
PubMed1992

The study of markers of biological effect in cancer prevention research trials.

Biological markers may provide a valuable tool for the development of cancer prevention agents, for monitoring patient compliance to a selected intervention, or for further defining the carcinogenic process. This discussion focuses on markers of biological effect and the rationale for their use in cancer prevention trials. Recent studies with biological markers are investigating their incorporation into phase-I, -II, and -III chemoprevention clinical trial designs. Their use in clinical studies is expected to increase the number of agents that may be evaluated and to provide valuable information on the biological effectiveness of agents, doses, and schedules. Markers may also provide information to help in selecting high-risk groups for prevention research, and to indicate the pathways inhibited and the stage of carcinogenesis affected. Such information may prove of crucial importance in strengthening the rationale for long-term trials and other ancillary research. Biomarker research for colon carcinogenesis is discussed, including examples of a number of recent trials that may influence future progress in this area of prevention research. A crucial step in this process is marker validation as an aspect of major prospective observational and intervention studies where cancer incidence is the endpoint. We cannot be fully confident of markers as intermediate endpoints until the evidence from clinical trials is sufficiently strong to support major public health initiatives for prevention.

Antineoplastic Agents↗
PubMed1992

Statistical validation of intermediate endpoints for chronic diseases.

We discuss the implementation of a criterion due to Prentice for the statistical validation of intermediate endpoints for chronic disease. The criterion involves examining in a cohort or intervention study whether an exposure or intervention effect, adjusted for the intermediate endpoint, is reduced to zero. For example, to examine whether serum cholesterol level is an intermediate endpoint for coronary heart disease (CHD), we may investigate the effect of the cholesterol lowering drug cholestyramine on CHD incidence adjusted for serum cholesterol levels. We show that use of this criterion will usually demand some form of model selection. When the unadjusted exposure or treatment effect is less than four times its standard error, the analysis can usually lead only to a weak form of validation, a conclusion that the data are not inconsistent with the validation criterion. More significant unadjusted exposure effects offer the potential for stronger types of validation statement such as 'the intermediate endpoint explains at least 50 per cent (or 75 per cent) of the exposure effect'.

Biomarkers↗
PubMed1992

Application of Bayesian statistics to decision making during a clinical trial.

We describe the application of Bayesian methods to the monitoring and analysis of a trial of treatment for patients with advanced colorectal carcinoma. We discuss the choice of prior distribution and justify the use of a truncated normal distribution with a probability mass at zero difference. The stopping rule, based on the trials of the posterior distribution and a chosen range of equivalence, yields an upper boundary very close to the Pocock group sequential boundary. The Bayes stopping rule is quite sensitive to the amount of probability mass at zero in the prior distribution.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Statistical validation of intermediate markers of precancer for use as endpoints in chemoprevention trials.

Using an intermediate marker of precancer as an endpoint for evaluating agents that may prevent cancer involves a presumption that the modification of the marker will be accompanied by a modification of cancer incidence. This presumption can hold only if the marker is on or very closely linked to a causal pathway. Epidemiologists have discussed the nature of evidence required to infer causal relationships, and we briefly survey their work. Studies relating exposure (E) to marker (M) provide only indirect evidence for causality. Those relating marker (M) to disease (D) are more relevant. We propose a new validation criterion based on an analysis of the three-way relationship of exposure (E), marker (M) and disease (D). We discuss the level of evidence required for using intermediate markers as endpoints for Phase II and Phase III trials, and propose very stringent criteria for Phase III trials. For Phase II trials, we propose less stringent criteria, but still recommend that the marker (M) should have been shown to have a strong association with disease (D).

Anticarcinogenic Agents↗
PubMed1992

Randomized, placebo-controlled, double-blind study of low-dose oral interferon-alpha in HIV-1 antibody positive patients.

One hundred forty-nine patients of private physicians in Toronto, Canada, who were positive for human immunodeficiency virus (HIV), medically stable, and had CD4 cell counts of < 700 cells/mm3 participated in a randomized, double-blind trial of placebo versus low-dose (50 U) versus high-dose (100 U) oral interferon-alpha. Treatment allocation was balanced according to baseline CD4 cell count and history of prior antiviral therapy. Patients were observed at 4 and 8 weeks for assessment of adverse events and several measures of disease status, including CD4 cell count, beta 2-microglobulin, weight, and Karnofsky score. We detected neither short-term benefits nor adverse effects from oral interferon-alpha therapy.

Administration, Oral↗
PubMed1992

The impact of stopping rules on heterogeneity of results in overviews of clinical trials.

This paper explores the extent to which application of statistical stopping rules in clinical trials can create an artificial heterogeneity of treatment effects in overviews (meta-analyses) of related trials. For illustration, we concentrate on overviews of identically designed group sequential trials, using either fixed nominal or O'Brien and Fleming two-sided boundaries. Some analytic results are obtained for two-group designs and simulation studies are otherwise used, with the following overall findings. The use of stopping rules leads to biased estimates of treatment effect so that the assessment of heterogeneity of results in an overview of trials, some of which have used stopping rules, is confounded by this bias. If the true treatment effect being studied is small, as is often the case, then artificial heterogeneity is introduced, thus increasing the Type I error rate in the test of homogeneity. This could lead to erroneous use of a random effects model, producing exaggerated estimates and confidence intervals. However, if the true mean effect is large, then between-trial heterogeneity may be underestimated. When undertaking or interpreting overviews, one should ascertain whether stopping rules have been used (either formally or informally) and should consider whether their use might account for any heterogeneity found.

Analysis of Variance↗
PubMed1991

Relationship among outcome, stage of disease, and histologic grade for 22,616 cases of breast cancer. The basis for a prognostic index.

Survival rates for 22,616 cases of breast cancer listed in the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute were stratified on outcome according to the histologic grade and stage of disease. Two different staging systems, "local, regional, and distant" and a modified American Joint Committee on Cancer (AJCC) system adopted for SEER were used. Relative survival rates were calculated at 5 and 10 years. Patients who were assigned Stage II, Grade 1 had the same survival as those assigned Stage I, Grade 3. Their survival was better than patients assigned Stage I, Grade 4. The 5-year relative survival rate for patients listed as Stage I, Grade 1 was 99% and for patients listed as Stage I, Grade 2, it was 98%. At 10 years, the survival rate of patients assigned Stage I, Grade 1 was 95%. Patients with histologic Grade 1 tumors less than 2 cm in size and with positive axillary lymph nodes had a 5-year survival rate of 99%. As breast tumors increased in size, the histologic grade also increased. The results suggest that in linking histologic grade with stage of disease, the staging system should also be considered. Histologic grade when used in conjunction with stage of disease can improve the prediction of outcome. Our results also indicate that a prognostic index can be created for breast cancer using a combination of stage of disease and histologic grade. The data suggest that only three grades are needed for breast cancer.

Adult↗
PubMed1991

Estimating the relation between dietary intake obtained from a food frequency questionnaire and true average intake.

Knowledge of the regression relation between dietary intake reported on a food frequency questionnaire and true average intake is useful in interpreting results from nutritional epidemiologic studies and in planning such studies. Studies which validate a questionnaire against a food record may be used to estimate this regression relation provided the food record is completed by each subject on at least two occasions. Using data collected from women aged 45-69 years during 1985-1986 in the pilot study of the Women's Health Trial, the authors show how variation in diet over time and intraindividual correlation between a questionnaire and food record obtained close together in time affects the estimation of the regression. The authors' method provides estimates of the regression slope and the questionnaire "bias" that are corrected for these effects, together with standard errors. A computer program in the SAS language, for carrying out the analysis, is provided.

Aged↗
PubMed1991

Using replicate observations in observer agreement studies with binary assessments.

By introducing replicate observations into observer agreement studies, one can obtain better measures of observer agreement than heretofore possible. New methodology based on the analysis of latent variables allows a separation of within- and between-observer variation for binary measures of assessment among pairs of observers. Maximum likelihood estimation and hypothesis testing are discussed. The methodology is illustrated using data on the assessment of dysplasia by pathologists.

Biometry↗
PubMed1990

Validation of intermediate end points in cancer research.

Investigations using intermediate end points as cancer surrogates are quicker, smaller, and less expensive than studies that use malignancy as the end point. We present a strategy for determining whether a given biomarker is a valid intermediate end point between an exposure and incidence of cancer. Candidate intermediate end points may be selected from case series, ecologic studies, and animal experiments. Prospective cohort and sometimes case-control studies may be used to quantify the intermediate end point-cancer association. The most appropriate measure of this association is the attributable proportion. The intermediate end point is a valid cancer surrogate if the attributable proportion is close to 1.0, but not if it is close to 0. Usually, the attributable proportion is close to neither 1.0 nor 0; in this case, valid surrogacy requires that the intermediate end point mediate an established exposure-cancer relation. This would in turn imply that the exposure effect would vanish if adjusted for the intermediate end point. We discuss the relative advantages of intervention and observational studies for the validation of intermediate end points. This validation strategy also may be applied to intermediate end points for adverse reproductive outcomes and chronic diseases other than cancer.

Biomarkers, Tumor↗
PubMed1990

Analysis of dietary fat, calories, body weight, and the development of mammary tumors in rats and mice: a review.

We have extracted from the literature data from 100 animal experiments, involving 7838 rats and mice, which compared the effects of different levels of dietary fat and/or calorie intake on the development of mammary tumors. Both higher calorie intake (P less than 0.0001) and higher fat intake (P less than 0.0001) independently increased mammary tumor incidence in Sprague-Dawley rats and in mice, as judged from analyses combining ad libitum feeding experiments and restricted feeding experiments. The effect of fat was two thirds the magnitude of the calorie effect in both Sprague-Dawley rats and mice. In ad libitum feeding experiments, a modest but significant (P less than 0.0001) average increase in body weight was found in animals fed high fat diets. However, these differences in body weight did not correspond to differences in mammary tumor incidence. The effect of log body weight on the log odds of tumor incidence was not significant (P = 0.16), while dietary fat intake significantly increased tumor incidence (P less than 0.0001). The collection of animal experimental data supports the hypothesis that, in mammary tumor development, there is a specific enhancing effect of dietary fat, as well as a general enhancing effect of calories.

Animals↗
PubMed1990

A stratified Wilcoxon-type test for trend.

We propose an extension of Cuzick's non-parametric Wilcoxon-like trend test for situations when the observations can be grouped into strata which are thought to be related to the outcome. We illustrate its use in two examples from cancer epidemiology.

Antibodies, Monoclonal↗