Biomedical subjects

L S Freedman

Publications and source records attributed to L S Freedman.

At least 37 records · Page 2Linked to original sources

PubMed1998

Measurement error and dietary intake.

This chapter reviews work of Carroll, Freedman, Kipnis, and Li (1998) on the statistical analysis of the relationship between dietary intake and health outcomes. In the area of nutritional epidemiology, there is some evidence from biomarker studies that the usual statistical model for dietary measurements may break down due to two causes: (a) systematic biases depending on a person's body mass index; and (b) an additional random component of bias, so that the error structure is the same as a one-way random effects model. We investigate this problem, in the context of (1) the estimation of the distribution of usual nutrient intake; (2) estimating the correlation between a nutrient instrument and usual nutrient intake; and (3) estimating the true relative risk from an estimated relative risk using the error-prone covariate. While systematic bias due to body mass index appears to have little effect, the additional random effect in the variance structure is shown to have a potentially important impact on overall results, both on corrections for relative risk estimates and in estimating the distribution usual of nutrient intake. Our results point to a need for new experiments aimed at estimation of a crucial parameter.

Bias↗

PubMed1998

Conditional logistic regression with sandwich estimators: application to a meta-analysis.

Motivated by a meta-analysis of animal experiments on the effect of dietary fat and total caloric intake on mammary tumorigenesis, we explore the use of sandwich estimators of variance with conditional logistic regression. Classical conditional logistic regression assumes that the parameters are fixed effects across all clusters, while the sandwich estimator gives appropriate inferences for either fixed effects or random effects. However, inference using the standard Wald test with the sandwich estimator requires that each parameter is estimated using information from a large number of clusters. Since our example violates this condition, we introduce two modifications to the standard Wald test. First, we reduce the bias of the empirical variance estimator (the middle of the sandwich) by using standardized residuals. Second, we approximately account for the variance of these estimators by using the t-distribution instead of the normal distribution, where the degrees of freedom are estimated using Satterthwaite's approximation. Through simulations, we show that these sandwich estimators perform almost as well as classical estimators when the true effects are fixed and much better than the classical estimators when the true effects are random. We achieve simulated nominal coverage for these sandwich estimators even when some parameters are estimated from a small number of clusters.

Animals↗

PubMed1998

An evaluation of rectal mucosal proliferation measure variability sources in the polyp prevention trial: can we detect informative differences among individuals' proliferation measures amid the noise?

We assessed components of total variability of bromodeoxyuridine (BrdUrd) and proliferating cell nuclear antigen (PCNA) assays of rectal mucosal proliferation in a subset of 390 participants from the U. S. National Cancer Institute's multicenter Polyp Prevention Trial. Biopsies were blindly double-scored by two technicians. For those participants for whom at least one evaluable biopsy was obtained, a mean of 2.0 and 2.6 biopsies, and 6.2 and 8.7 crypts/biopsy were evaluated, respectively, with the BrdUrd and PCNA assays. Factors such as clinical center, scorer, and month of biopsy collection significantly affected the observed values of the labeling index (LI) and proliferative height (PH). Therefore, it is essential to control or adjust for these variables in proliferation studies. Sources of random variation for LI and PH measures remaining after the aforementioned factors include between-participant variation and several sources of within-participant variation, including variation over time, between biopsies, and between multiple measurements on the same biopsy. Both LI and PH measurements exhibited substantial variability over time, between biopsies, and from reading-to-reading of the same biopsy. When other sources of variability have been accounted for, the PCNA LI seems to have little between-participant variation. This brings into question its utility as a marker in colorectal cancer studies. The PCNA PH showed significant between-participant variability and may hold some promise as a useful marker in colorectal cancer studies. Results for BrdUrd were less conclusive. The BrdUrd LI showed marginally significant between-participant variation, whereas the corresponding variation for PH was nonsignificant.

Adult↗

PubMed1997

Effect of measurement error on energy-adjustment models in nutritional epidemiology.

The use and interpretation of energy-adjustment regression models in nutritional epidemiology has been vigorously debated recently. There has been little discussion, however, regarding the effect of dietary measurement error on the performance of such models. Contrary to conventional assumptions invoked in the standard treatment of the effect of measurement error in regression analysis, reporting errors in dietary studies are usually biased, correlated with true nutrient intakes and with each other, heteroscedastic, and nonnormally distributed. Methods developed in this paper allow for this more complex error structure and are therefore more appropriate for dietary data. For practical illustration, these methods are applied to data from the Women's Health Trial Vanguard Study. The results demonstrate considerable shrinkage in the magnitude of the estimated main exposure effect in energy-adjustment models due to attenuation of the true effect and contamination from the effect of an adjusting covariate. In most cases, this shrinkage causes a sharply reduced statistical power of the corresponding significance test in comparison with measurement without error. These results emphasize the need to understand the measurement error properties of dietary instruments through validation/calibration studies and, where possible, to correct for the impact of measurement error when applying energy-adjustment models.

Aged↗

PubMed1997

Effect of different types and amounts of fat on the development of mammary tumors in rodents: a review.

We performed a meta-analysis on data extracted from 97 reports of experiments, involving a total of 12,803 mice or rats, studying the effect on mammary tumor incidence of different types of dietary fatty acids. Fatty acids were categorized into saturated, monounsaturated, n-6 polyunsaturated, and n-3 polyunsaturated. We modeled the relation between tumor incidence and percentage of total calories from these fatty acids using conditional logistic regression and allowing for varying effects between experiments, and for each fatty acid we estimated the effect of substituting the fatty acid calories for nonfat calories. Our results show that n-6 polyunsaturated fatty acids (PUFAs) have a strong tumor-enhancing effect and that saturated fats have a weaker tumor-enhancing effect. The n-3 PUFAs have a small protective effect that is not statistically significant. There is no significant effect of monounsaturated fats. n-6 PUFAs have a stronger tumor-enhancing effect at levels under 4% of total calories, but an effect is still present at intake levels greater than 4% of calories. In addition, when the intake of n-6 PUFAs is at least 4% of calories, the n-6 PUFA effect remains stronger than the saturated fat effect.

Animals↗

PubMed1997

Breast cancer clusters in the northeast United States: a geographic analysis.

High breast cancer mortality rates have been reported in the northeastern part of the United States, with recent attention focused on Long Island, New York. In this study, the authors investigate whether the high breast cancer mortality is evenly spread over the Northeast, in the sense that any observed clusters of deaths can be explained by chance alone, or whether there are clusters of statistical significance. Demographic data and age-specific breast cancer mortality rates for women were obtained for all 244 counties in 11 northeastern states and for the District of Columbia for 1988-1992. A recently developed spatial scan statistic is used, which searches for clusters of cases without specifying their size or location ahead of time, and which tests for their statistical significance while adjusting for the multiple testing inherent in such a procedure. The basic analysis is adjusted for age, with further analyses examining how the results are affected by incorporating race, urbanicity, and parity as confounding variables. There is a statistically significant and geographically broad cluster of breast cancer deaths in the New York City-Philadelphia, Pennsylvania, metropolitan area (p = 0.0001), which has a 7.4% higher mortality rate than the rest of the Northeast. The cluster remains significant when race, urbanicity, and/or parity are included as confounding variables. Four smaller subclusters within this area are also significant on their own strength: Philadelphia with suburbs (p = 0.0001), Long Island (p = 0.0001), central New Jersey (p = 0.0001), and northeastern New Jersey (p = 0.0001). The elevated breast cancer mortality on Long Island might be viewed less as a unique local phenomenon and more as part of a more general situation involving large parts of the New York City-Philadelphia metropolitan area. The several known and hypothesized risk factors for which we could not adjust and that may explain the detected cluster are most notably age at first birth, age at menarche, age at menopause, breastfeeding, genetic mutations, and environmental factors.

Breast Neoplasms↗

PubMed1997

The efficiency of the matched-pairs design of the Community Intervention Trial for Smoking Cessation (COMMIT).

The Community Intervention Trial for Smoking Cessation (COMMIT) was a randomized trial to evaluate the effects of a community-wide smoking cessation intervention on smoking behavior. The statistical design involved 22 pair-matched communities and the randomization of one community in each of the 11 pairs to the intervention, with the other community in the pair acting as a comparison. Communities were matched on the basis of their geographical proximity and similarity of demographic composition. In this paper, we use the data on the rates of quitting smoking among cohorts of heavy and light/moderate smokers in each community to estimate the gains in efficiency achieved by the matched-pairs design compared to an unmatched randomized trial. We find evidence of some gain in efficiency, although the data are not extensive enough to give estimates of efficiency gain that have good precision.

Analysis of Variance↗

PubMed1997

Register of dietary assessment calibration-validation studies: a status report.

A register of dietary assessment calibration-validation studies was created to improve communication between investigators, avoid duplication of effort, and identify gaps in knowledge. Calibration-validation studies were defined as investigations in which the participants completed at least two different dietary measurements. A questionnaire soliciting descriptive information about such studies was widely distributed. Completed questionnaires were received from October 1993 through September 1994 and the data from them were entered into a computer database. Preliminary individual reports were mailed to all contributors in September 1994 for revision or updating. Responses received by the end of October 1994 were incorporated into the database. A status report was published in December 1994. The report includes descriptions of 84 studies, 15 summary tables, and 6 reference indexes. Of the 84 studies included, 44 (52%) were conducted in North America, 35 (42%) in Europe, 2 (2%) in South America, 2 (2%) in Asia, and 1 (1%) in Australia. Sixty-three of the 84 studies (75%) used food-frequency questionnaires, 52 (62%) used food records, 35 (42%) used one or more dietary recalls, 11 (13%) used biological measures, and 8 (10%) used diet histories. Plans for maintaining and updating the register are being developed.

Biomarkers↗

PubMed1997

Statistical design of calibration studies.

We investigated some design aspects of calibration studies. The specific situation addressed was one in which a large group is evaluated with a food-frequency questionnaire and a smaller calibration study is conducted through use of repeated food records or recalls, with the subjects in the calibration study constituting a random sample of those in the large group. In designing a calibration study, one may use large sample sizes and few food records per individual or smaller samples and more records per subject. Neither strategy is always preferable. Instead, the optimal method for a given study depends on the survey instrument used (24-h recalls or multiple-day food records) and the variables of interest.

Computer Simulation↗

PubMed1997

Elevated serum phenytoin concentrations associated with coadministration of sertraline.

The hepatic cytochrome P450 enzyme system is involved in the metabolism of numerous drugs. Specific enzymes are associated with the metabolism of specific drugs. The potential for drug interactions arises when one drug inhibits or induces the enzyme(s) responsible for metabolism of another drug given concurrently. Most psychotropics are metabolized by these enzymes. Clinically significant drug interactions are reported between the selective serotonin reuptake inhibitors and other psychotropics. Specifically, interactions between fluoxetine and phenytoin are reported with substantial elevations of phenytoin concentrations. Phenytoin is metabolized by the CYP2C subfamily, and fluoxetine is known to inhibit this subfamily. Similarly, sertraline also inhibits the CYP2C subfamily, but no case reports to date have been identified. To minimize and prevent these interactions, one must be aware of the P450 enzymes involved in drug metabolism. The significance of these interactions seems to rely both on the concentration of the drug at the enzyme and its potency for inhibiting the enzyme. Frequent monitoring of serum concentrations of drugs with a narrow therapeutic range would be appropriate when a potential inhibitor is added. This article describes an apparently similar interaction between sertraline and phenytoin in two elderly patients, which resulted in elevated phenytoin concentrations without symptoms of toxicity.

Aged↗

PubMed1997

Bayesian design and analysis of two x two factorial clinical trials.

The 2 x 2 factorial design has been advocated for improving the efficiency of clinical trials. Most such trials are designed on the assumption that there is no interaction between the levels of the factors and outcome. This assumption is often problematic, however, because interactions are usually possible in clinical trials and the sample sizes often used provide little power in testing for interactions. We consider the use of Bayesian methods for the design and analysis of 2 x 2 factorial clinical trials. This approach avoids the need to dichotomize one's assumptions that interactions either do or do not exist and provides a flexible approach to the design and analysis of such clinical trials. Exact results are developed for balanced factorial designs with normal response. Approximations are then presented for factorial designs based on the logistic model for binary response or the proportional hazards model for time-to-event data. The resulting approximate posterior distributions are normal and hence no extensive computations are required. Suggestions for specification of prior distributions are presented.

Antineoplastic Agents, Phytogenic↗

PubMed1997

Using and interpreting surrogate end-points in cancer research.

Researchers have proposed a broad range of molecular, cellular and histological markers as surrogate end-points for cancer (SECs). The effect of an intervention on a 'valid' SEC is concordant with its effect on cancer incidence. The validity of a potential SEC is determined primarily by the extent to which the marker is a necessary event on the causal pathway to cancer. Colorectal adenomatous polyp formation is an example of a reasonably valid SEC because these lesions are obligate precursors of most large bowel malignancies. However, the existence of a plausible major alternative causal pathway--one bypassing the potential SEC--weakens inferences from that marker to cancer. Moreover, unless the pathway to cancer operates nearly exclusively through the SEC, an SEC that is valid for one intervention or exposure may not be valid for another. Metabolic, ecological, observational epidemiological and intervention studies may yield data that are useful in revealing these causal interrelations of intervention (exposure), SEC and cancer. Empirical studies of three questions are pertinent: (1) What is the relation of the SEC to cancer? (2) What is the relation of the intervention (exposure) to the SEC? (3) To what extent does the SEC mediate the relation between the intervention (exposure) and cancer? Data on SEC measurement error are important in ascertaining the extent to which marker results have been attenuated by such error. It is essential to carry out these studies to evaluate potential SECs (such as epithelial cell hyperproliferation) with plausible major alternative pathways to cancer. At the present time, definitive evidence on etiology and prevention will emerge only from studies with cancer end-points or SECs that are, by and large, necessary steps on the causal pathway to malignant disease.

Adenomatous Polyposis Coli↗

PubMed1996

Alpha-Tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance.

BACKGROUND: Experimental and epidemiologic investigations suggest that alpha-tocopherol (the most prevalent chemical form of vitamin E found in vegetable oils, seeds, grains, nuts, and other foods) and beta-carotene (a plant pigment and major precursor of vitamin A found in many yellow, orange, and dark-green, leafy vegetables and some fruit) might reduce the risk of cancer, particularly lung cancer. The initial findings of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC Study) indicated, however, that lung cancer incidence was increased among participants who received beta-carotene as a supplement. Similar results were recently reported by the Beta-Carotene and Retinol Efficacy Trial (CARET), which tested a combination of beta-carotene and vitamin A. PURPOSE: We examined the effects of alpha-tocopherol and beta-carotene supplementation on the incidence of lung cancer across subgroups of participants in the ATBC Study defined by base-line characteristics (e.g., age, number of cigarettes smoked, dietary or serum vitamin status, and alcohol consumption), by study compliance, and in relation to clinical factors, such as disease stage and histologic type. Our primary purpose was to determine whether the pattern of intervention effects across subgroups could facilitate further interpretation of the main ATBC Study results and shed light on potential mechanisms of action and relevance to other populations. METHODS: A total of 29,133 men aged 50-69 years who smoked five or more cigarettes daily were randomly assigned to receive alpha-tocopherol (50 mg), beta-carotene (20 mg), alpha-tocopherol and beta-carotene, or a placebo daily for 5-8 years (median, 6.1 years). Data regarding smoking and other risk factors for lung cancer and dietary factors were obtained at study entry, along with measurements of serum levels of alpha-tocopherol and beta-carotene. Incident cases of lung cancer (n = 894) were identified through the Finnish Cancer Registry and death certificates. Each lung cancer diagnosis was independently confirmed, and histology or cytology was available for 94% of the cases. Intervention effects were evaluated by use of survival analysis and proportional hazards models. All P values were derived from two-sided statistical tests. RESULTS: No overall effect was observed for lung cancer from alpha-tocopherol supplementation (relative risk [RR] = 0.99; 95% confidence interval [CI] = 0.87-1.13; P = .86, logrank test). beta-Carotene supplementation was associated with increased lung cancer risk (RR = 1.16; 95% CI = 1.02-1.33; P = .02, logrank test). The beta-carotene effect appeared stronger, but not substantially different, in participants who smoked at least 20 cigarettes daily (RR = 1.25; 95% CI = 1.07-1.46) compared with those who smoked five to 19 cigarettes daily (RR = 0.97; 95% CI = 0.76-1.23) and in those with a higher alcohol intake (> or = 11 g of ethanol/day [just under one drink per day]; RR = 1.35; 95% CI = 1.01-1.81) compared with those with a lower intake (RR = 1.03; 95% CI = 0.85-1.24). CONCLUSIONS: Supplementation with alpha-tocopherol or beta-carotene does not prevent lung cancer in older men who smoke. beta-Carotene supplementation at pharmacologic levels may modestly increase lung cancer incidence in cigarette smokers, and this effect may be associated with heavier smoking and higher alcohol intake. IMPLICATIONS: While the most direct way to reduce lung cancer risk is not to smoke tobacco, smokers should avoid high-dose beta-carotene supplementation.

Age Factors↗

PubMed1996

Use of semiquantitative food frequency questionnaires to estimate the distribution of usual intake.

The authors consider whether semiquantitative food frequency questionnaires can be used to survey a population to estimate the distribution of usual intake. They take as an assumption that, if they were possible to obtain, the mean of many food records or recalls would be an accurate representation of an individual's usual diet. They then assume that nutrient intake as measured by a questionnaire follows a linear regression model when regressed against the usual intake of that nutrient. If the coefficients in this regression relation were known, then the distribution of usual intake could be constructed from the responses to the questionnaire. Since one generally does not know the values of the coefficients, they need to be estimated from a calibration study in which respondents complete the questionnaire together with multiple food records or recalls. This can be done either through an internal subset of the data or through an independent external study. With an internal substudy, the authors find that food frequency questionnaires typically provide little information about the distribution of usual intake in addition to that obtained from the multiple records or recalls in the substudy. When the substudy is external, if it is small then having very large numbers of subjects completing food frequency questionnaires in the survey is no more efficient than having a few subjects completing food records or recalls. However, if the external substudy is large and accurately characterizes the relation between the questionnaire response and usual intake, food frequency questionnaires can provide a cost-efficient way of estimating the distribution of usual intake. These results do not apply to the different problem of correcting relative risks for the effects of measurement error.

Bias↗

PubMed1996

Urbanicity-related trends in lung cancer mortality in US counties: white females and white males, 1970-1987.

BACKGROUND: The effect of urbanization on age-adjusted lung cancer mortality rates in US counties is investigated. The data come from National Cancer Institute, and urban trends are estimated in time periods 1970-1979 and 1980-1987, for both white males and white females. To account for possibly different gradients in different parts of the country, the 48 contiguous states are divided into seven regions. METHODS: A measure of urbanness, urbanicity, is defined and is used to stratify counties. A multiplicative model is proposed that relates county mortality rates to urbanicity. The residuals from this multiplicative model serve as age- and urban-adjusted rates. RESULTS: Urban-rural gradients are significant for nearly all regions for both white males and white females, diminishing slightly in the latter time period for white males but becoming stronger for white females. CONCLUSIONS: The age- and urban-adjusted rates may be used in mapping to investigate geographical patterns that remain after removal of the urban factor.

Female↗

PubMed1996

The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years of follow up.

PURPOSE: We determined the role, if any, of 1 and 5 instillations of intravesical mitomycin C in the treatment of newly diagnosed superficial bladder cancer. MATERIALS AND METHODS: A multicenter randomized clinical trial was done involving 502 patients with newly diagnosed superficial bladder cancer. After complete transurethral resection patients with newly diagnosed superficial bladder cancer. After complete resection patients were randomized into 1 of 3 treatment arms: no further treatment, 1 instillation of mitomycin C at resection and 1 instillation at resection and at 3-month intervals for 1 year (total 5 instillations). The dose of mitomycin C used was 40 mg./40 ml. water. End points were interval to first superficial recurrence, recurrence rate (defined as the number of positive cystoscopies per year) and progression-free interval rate (progression defined as the development of muscle invasive or metastatic disease, or death from bladder cancer). RESULTS: After median followup of 7 years 1 and 5 instillations of mitomycin C resulted in decreased recurrence rates and increased recurrence-free interval. The benefit of mitomycin C was observed in patients at low, medium and high risk for subsequent recurrence. There was suggestive but not conclusive evidence that 5 instillations of mitomycin C offered a slight advantage over 1 instillation. CONCLUSIONS: Our analysis confirms the positive benefit of mitomycin C to decrease the number of subsequent recurrences and increase the recurrence-free interval.

Administration, Intravesical↗

PubMed1996

Surrogate end points in cancer research: a critique.

Studies using surrogate end points of malignant disease may be smaller, shorter, and less expensive than studies with incident cancer end points. Researchers have proposed a broad range of histological, cellular, and molecular markers as surrogate end points for cancer (SECs). We define a valid SEC as follows: the effect of an intervention on (or the association of a risk factor with) the SEC is concordant with its effect on (or association with) incident cancer. Adenomatous polyps and persistent human papillomavirus infections are examples of reasonably valid SECs (for colorectal and cervical cancer, respectively) because these markers are necessary precursors of most of these malignancies. Inferences from other potential SECs, however, are problematic if there exist major alternative causal pathways to malignancy bypassing the SEC. Furthermore, in such circumstances, an SEC that is valid for one intervention or exposure may not be valid for another. Even for those end points without such major alternative pathways, an intervention could differentially affect two intermediate markers on the same pathway, thus disturbing the concordance between its effect on a given SEC and its effect on cancer. Thus, an understanding of the causal structure underlying the relations of interventions/exposures, potential SECs, and cancer is critical in evaluating SECs. Three questions are pertinent to elucidating this structure: (a) What is the relation of the SEC to cancer? (b) What is the relation of the intervention/exposure to the SEC? and (c) To what extent doses the SEC mediate the relation between the intervention/exposure and cancer? Ecological, metabolic, observational epidemiological, and intervention studies may provide data relevant to one or more of these questions. Data on SEC variability are critical in evaluating whether marker findings have been attenuated by random sources of intra-individual variation. We emphasize the importance of conducting studies, especially SEC-cancer and intervention/exposure-SEC-cancer mediation studies, to evaluate problematic SECs such as epithelial cell hyperproliferation. For some time to come, hard and policy-relevant evidence on cancer etiology and prevention will emerge only from studies with cancer end points or, at a somewhat lower level of certainty, SECs that are (for the most part) obligatory steps on the causal pathway to malignant disease.

Biomarkers, Tumor↗

PubMed1996

The polyp prevention trial I: rationale, design, recruitment, and baseline participant characteristics.

The Polyp Prevention Trial (PPT) is a multicenter randomized controlled trial examining the effect of a low-fat (20% of total energy intake), high-fiber (18 g/1000 kcal), high-vegetable and -fruit (5-8 daily servings) dietary pattern on the recurrence of adenomatous polyps of the large bowel, precursors of most colorectal malignancies. Eligibility criteria include one or more adenomas removed within 6 months of randomization; complete nonsurgical polyp removal and complete colonic examination to the cecum at the qualifying colonoscopy: age 35 years of more; no history of colorectal cancer, inflammatory bowel disease, or large bowel resection; and satisfactory completion of a food frequency questionnaire and 4-day food record. Of approximately 38,277 potential participants with one or more polyps recently resected, investigators at eight clinical centers randomized 2,079 (5.4%; 1,037 in the intervention and 1,042 in the control arm) between June 1991 and January 1994, making the PPT the largest adenoma recurrence trial ever conducted. Of PPT participants, 35% are women and 10% are minorities. At study entry, participants averaged 61.4 years of age; 14% of them smoked, and 22% used aspirin. At the baseline colonoscopy, 35% of participants had two or more adenomas, and 29% had at least one large (> of = 1 cm) adenoma. Demographic, behavioral, dietary, and clinical characteristics are comparable across the two study arms. Participants have repeat colonoscopies after 1 (T(1)) and 4 (T(4)) years of follow-up. The primary end point is adenoma recurrence; secondary end points include number, size, location, and histology of adenomas. All resected lesions are reviewed centrally by gastrointestinal pathologists. The trial provides 90% power to detect a reduction of 24% in the annual adenoma recurrence rate. The primary analytic period, on which sample size calculations were based is 3 years (T(1) to T(4)), which permits a 1-year lag time for the intervention to work and allows a more definitive clearing of lesions at T(1), given that at least 10-15% of polyps may be missed at baseline. The final (T(4)) colonoscopies are expected to be completed in early 1998.

Adenoma↗