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Barnett S Kramer

Publications and source records attributed to Barnett S Kramer.

At least 19 recordsLinked to original sources
PubMed2007

Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial.

OBJECTIVE: To determine patterns of repeat prostate biopsy in a cohort of men undergoing prostate cancer screening who have a negative initial biopsy. SUBJECTS AND METHODS: The Prostate, Colorectal, Lung, and Ovarian (PLCO) cancer screening trial is an ongoing study the prostate component of which consists of six annual screens with measurements of prostate-specific antigen (PSA) level and a digital rectal examination (DRE). The diagnostic follow-up of positive screening results is done by the subject's healthcare provider outside the purview of the PLCO. We analysed the experience of repeat biopsy in men in the PLCO with an initial negative biopsy. Men were divided by indication for initial biopsy into those with suspicious PSA levels and those with suspicious DRE findings. RESULTS: The probability of having a repeat biopsy within 3 years of initial biopsy was 43% for 1736 men with suspicious PSA levels and 13% for 1025 men with suspicious DRE findings. Rates of third and fourth biopsy after a previous negative biopsy were similar to the initial repeat biopsy rate in PSA-positive men. Most men had a repeat biopsy only after having an additional round of screening. The PSA level and PSA velocity determined after initial biopsy were independent risk factors for a repeat biopsy, both in PSA-positive and DRE-positive men. High-grade prostatic intraepithelial neoplasia was a risk factor for repeat biopsy before any repeat PSA or DRE testing. CONCLUSION: The experience of this cohort should be generally representative of patterns of care for repeat biopsy in men undergoing periodic screening. These data can provide context to the debate over optimum practices for repeat biopsy.

Aged↗
PubMed2006

Clinical cancer advances 2006: major research advances in cancer treatment, prevention, and screening--a report from the American Society of Clinical Oncology.

A MESSAGE FROM ASCO's PRESIDENT For the second consecutive year, the American Society of Clinical Oncology (ASCO) is publishing Clinical Cancer Advances: Major Research Advances in Cancer Treatment, Prevention, and Screening, an annual review of the most significant cancer research presented or published over the past year. ASCO developed this report to demonstrate the enormous progress being made on the front lines of cancer research today. The report is intended to give all those with an interest in cancer care-the general public, cancer patients and physicians, policymakers, oncologists, and other medical professionals-an accessible summary of the year's most important cancer research advances. These pages report on new targeted therapies that are improving survival and response rates in hard-to-treat cancers such as kidney cancer, HER-2-positive breast cancer, head and neck cancer, and chronic myelogenous leukemia; the FDA's approval of the world's first preventive vaccine for human papillomavirus (HPV), which has the potential to dramatically reduce the global burden of cervical cancer; and advances in the fast-growing field of personalized medicine, including a new lung cancer test that could help physicians better target treatments and predict prognosis. These advances are only part of the landscape. Survival rates are on the rise, the number of cancer deaths in the United States began declining for the first time since 1930, and new research is showing that the rates of certain common cancers, such as those of the breast and colon, have stabilized, and may have even begun to decline. However, cancer research still faces a number of major obstacles. At a time of extraordinary scientific potential, declining federal funding of cancer research threatens to stall or even reverse recent progress. Such funding cuts have already led to fewer clinical trials, fewer talented young physicians entering the field, and a growing bottleneck of basic science discoveries waiting to be "translated" into useful therapies and diagnostics. In addition to highlighting the major research advances over the past year, this report also identifies key barriers to accelerating the pace of cancer research and outlines ASCO's recommendations for overcoming them. Despite these and other challenges, there is much good news on the front lines of cancer research. This report demonstrates the essential role of clinical cancer research in finding new and better ways to treat, diagnose, and prevent a group of diseases that strike half of men and one-third of women in the United States.

Breast Neoplasms↗
PubMed2006

Identifying genes that contribute most to good classification in microarrays.

BACKGROUND: The goal of most microarray studies is either the identification of genes that are most differentially expressed or the creation of a good classification rule. The disadvantage of the former is that it ignores the importance of gene interactions; the disadvantage of the latter is that it often does not provide a sufficient focus for further investigation because many genes may be included by chance. Our strategy is to search for classification rules that perform well with few genes and, if they are found, identify genes that occur relatively frequently under multiple random validation (random splits into training and test samples). RESULTS: We analyzed data from four published studies related to cancer. For classification we used a filter with a nearest centroid rule that is easy to implement and has been previously shown to perform well. To comprehensively measure classification performance we used receiver operating characteristic curves. In the three data sets with good classification performance, the classification rules for 5 genes were only slightly worse than for 20 or 50 genes and somewhat better than for 1 gene. In two of these data sets, one or two genes had relatively high frequencies not noticeable with rules involving 20 or 50 genes: desmin for classifying colon cancer versus normal tissue; and zyxin and secretory granule proteoglycan genes for classifying two types of leukemia. CONCLUSION: Using multiple random validation, investigators should look for classification rules that perform well with few genes and select, for further study, genes with relatively high frequencies of occurrence in these classification rules.

Colonic Neoplasms↗
PubMed2006

Prostate volume and prostate-specific antigen levels in men enrolled in a large screening trial.

OBJECTIVES: Prostate volume correlates both with prostate-specific antigen (PSA) values and with the presence of benign prostatic hyperplasia (BPH). Here we examine the relationship between prostate volume and PSA level in a large, geographically diverse sample of men undergoing prostate cancer screening. METHODS: We followed 35,323 men enrolled in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Each man was screened with digital rectal examination (DRE) and PSA levels for up to 4 years. Prostate volume was estimated by DRE performed by trained examiners at the PLCO sites. Linear and logistic regression was used to assess the effect of prostate volume and age on PSA levels. Regression coefficients were adjusted for the effect of prostate volume measurement error. RESULTS: Prostate volume estimated by DRE showed considerable measurement error. Averaging volume over screening visits and accounting for examiner bias greatly reduced this error. Linear regression analysis showed a slope of 0.030/cm3 of log PSA on prostate volume when correcting for measurement error (95% confidence interval [CI], 0.029 to 0.031). Age was independently associated with (log) PSA, with a slope of 0.022 per year. Logistic regression analysis of the risk of having an elevated PSA value (exceeding 4 ng/mL) showed an odds ratio of 1.9 (95% CI, 1.8 to 2.0) associated with a 10 cm3 increase in prostate volume. The correlation of log PSA and prostate volume was 0.37. Prostate volume was not correlated with body mass index and showed weak correlation (r = 0.14) with age. CONCLUSIONS: Prostate volume and age are independently associated with increased PSA levels in a population of men undergoing screening.

Aged↗
PubMed2006

Prostate specific antigen changes as related to the initial prostate specific antigen: data from the prostate, lung, colorectal and ovarian cancer screening trial.

PURPOSE: Annual screening with PSA, although of unproven benefit, is currently used for prostate cancer early detection. A large fraction of screened men have low (less than 2 ng/ml) initial PSA. The yield over time of positive PSA screens (ie more than 4 ng/ml) in these men has not been well characterized in large cohorts in the United States. MATERIALS AND METHODS: Men in the screening arm of the PLCO received baseline PSA and annual tests for 5 years. 30,495 of these men had baseline PSA 4 ng/ml or less. We estimated the cumulative probability of converting to PSA greater than 4 at years 1 through 5 as a function of baseline PSA. RESULTS: Among men with baseline PSA less than 1 ng/ml, 1.5% converted by year 5 (95% CI 1.2-1.7). Among men with baseline PSA of 1.0 to 1.99 ng/ml, 1.2% (95% CI 0.9-1.3) and 7.4% (95% CI 6.8-8.1) converted by year 1 and 5, respectively. A total of 33.5% and 79% of men with initial PSA of 2.0 to 2.99 and 3.0 to 4.0, respectively, converted by year 5. Of men with baseline PSA less than 1 ng/ml converting to PSA more than 4 ng/ml, 8% were diagnosed with cancer within 2 years of conversion. About 10% of men with baseline PSA less than 1 ng/ml and negative baseline DRE had a positive DRE within 3 years. CONCLUSIONS: For men choosing PSA screening, screening every 5 years for baseline PSA less than 1 ng/ml and every 2 years for PSA 1 to 2 ng/ml could result in a 50% reduction in PSA tests and in less than 1.5% of men missing earlier positive screens, but with an unknown effect on prostate cancer mortality.

Aged↗
PubMed2006

Evaluating markers for the early detection of cancer: overview of study designs and methods.

BACKGROUND: The field of cancer biomarker development has been evolving rapidly. New developments both in the biologic and statistical realms are providing increasing opportunities for evaluation of markers for both early detection and diagnosis of cancer. PURPOSE: To review the major conceptual and methodological issues in cancer biomarker evaluation, with an emphasis on recent developments in statistical methods together with practical recommendations. METHODS: We organized this review by type of study: preliminary performance, retrospective performance, prospective performance and cancer screening evaluation. RESULTS: For each type of study, we discuss methodologic issues, provide examples and discuss strengths and limitations. CONCLUSION: Preliminary performance studies are useful for quickly winnowing down the number of candidate markers; however their results may not apply to the ultimate target population, asymptomatic subjects. If stored specimens from cohort studies with clinical cancer endpoints are available, retrospective studies provide a quick and valid way to evaluate performance of the markers or changes in the markers prior to the onset of clinical symptoms. Prospective studies have a restricted role because they require large sample sizes, and, if the endpoint is cancer on biopsy, there may be bias due to overdiagnosis. Cancer screening studies require very large sample sizes and long follow-up, but are necessary for evaluating the marker as a trigger of early intervention.

Biomarkers, Tumor↗
PubMed2005

Simple adjustments for randomized trials with nonrandomly missing or censored outcomes arising from informative covariates.

In randomized trials with missing or censored outcomes, standard maximum likelihood estimates of the effect of intervention on outcome are based on the assumption that the missing-data mechanism is ignorable. This assumption is violated if there is an unobserved baseline covariate that is informative, namely a baseline covariate associated with both outcome and the probability that the outcome is missing or censored. Incorporating informative covariates in the analysis has the desirable result of ameliorating the violation of this assumption. Although this idea of including informative covariates is recognized in the statistics literature, it is not appreciated in the literature on randomized trials. Moreover, to our knowledge, there has been no discussion on how to incorporate informative covariates into a general likelihood-based analysis with partially missing outcomes to estimate the quantities of interest. Our contribution is a simple likelihood-based approach for using informative covariates to estimate the effect of intervention on a partially missing outcome in a randomized trial. The first step is to create a propensity-to-be-missing score for each randomization group and divide the scores into a small number of strata based on quantiles. The second step is to compute stratum-specific estimates of outcome derived from a likelihood-analysis conditional on the informative covariates, so that the missing-data mechanism is ignorable. The third step is to average the stratum-specific estimates and compute the estimated effect of intervention on outcome. We discuss the computations for univariate, survival, and longitudinal outcomes, and present an application involving a randomized study of dual versus triple combinations of HIV-1 reverse transcriptase inhibitors.

Acquired Immunodeficiency Syndrome↗
PubMed2005

Prostate Cancer Screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial: findings from the initial screening round of a randomized trial.

BACKGROUND: The benefit of screening for prostate cancer using prostate-specific antigen (PSA) testing and digital rectal examination (DRE) is uncertain and is under evaluation in a randomized prospective trial, the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Although the final results are several years away, the initial round of screening is complete. We describe the population enrolled in the PLCO trial, their baseline PSA and DRE screening results, and diagnostic follow-up results during the first year of follow-up. METHODS: A total of 38,350 men were randomly assigned to the screening arm of the PLCO trial from November 1993 through June 2001. Men were advised to seek diagnostic follow-up from their primary care provider if their DRE was suspicious for cancer and/or if their serum PSA level was higher than 4 ng/mL. PLCO trial staff obtained records related to diagnostic follow-up. RESULTS: Compliance with both screening tests was high (more than 89%). At screening, 7.5% of men had a positive DRE (i.e., suspicious for cancer) and 7.9% had a PSA level higher than 4 ng/mL. Of the men with positive screening tests, 74.2% underwent additional diagnostic testing, and 31.5% underwent a prostatic biopsy within 1 year. Overall, 1.4% of the men in the screening arm were diagnosed with prostate cancer, the majority of whom had clinically localized cancer. These compliance, biopsy, and cancer detection rates appear to be representative of contemporary practice patterns. CONCLUSION: The PLCO trial is evaluating PSA- and DRE-based screening for prostate cancer in a clinically valid manner. Whether such screening will result in a reduction of prostate cancer mortality cannot be answered until the randomized comparison is completed.

Aged↗
PubMed2005

Cancer screening in theory and in practice.

Improvements in technology have led to a number of tests that can be used to suggest that a patient has a cancer. Advances in cancer biology and medical imaging have led to a number of cancer screening tests. Cancer screening is commonly advocated, but its complexity is often lost in guidelines that have sound-bite quality. It is commonly viewed as of no harm, when in fact there are harms associated with every known screening test. Indeed, many screening experts believe a screening test should only be used when the potential for benefit clearly outweighs the potential for harm. Cancer screening principles are classically within the realm of the epidemiologist. As more screening tests are developed, these principles have become more relevant to the practicing clinician. What is known and what is unknown about screening is distinctly different from what is believed by the public and many practicing clinicians. Many tests have both screening and diagnostic uses, and it is only the context in which these are used that determines whether they are screening or diagnostic. A screening test is done on asymptomatic individuals who receive the test principally because they are of the age or sex at risk for the cancer. A diagnostic test is done on an individual because of clinical suspicion of disease.

Adult↗
PubMed2005

Diagnostic procedures after a positive spiral computed tomography lung carcinoma screen.

BACKGROUND: Low-radiation dose spiral computed tomography (LDCT) currently is being evaluated as a screening modality for lung carcinoma in a randomized trial. Although several diagnostic algorithms for the workup of positive LDCT screens have been proposed, to the authors' knowledge there is no widely accepted standard to date and there are few nationwide data concerning how such diagnostic workups are actually being performed outside a research protocol setting. METHODS: The Lung Screening Study (LSS) was a multicenter feasibility trial that randomized 1660 subjects to undergo LDCT and an equivalent number to undergo chest X-ray. Subjects with positive screens were referred to their own health care providers for diagnostic follow-up; LSS did not specify a diagnostic algorithm. LSS collected and abstracted medical records regarding procedures employed in the diagnostic workup of positive screens. RESULTS: Of the 522 subjects with a positive LDCT screen at baseline or at Year One, 12% underwent biopsy. Biopsy was less likely to be performed in subjects with 4-9-mm nodules (5%) than in subjects with nodules measuring 10+ mm (25%) or in subjects with no nodules but other suspicious findings (15%). Among 63% of the subjects who underwent chest CT on follow-up, the median time between screening and first follow-up chest CT was 82 days. Only a minority of subjects received diagnostic workups that were consistent with published algorithms. CONCLUSIONS: The data from the current study represent the experience of subjects followed by their health care providers in five different U.S. metropolitan areas and one rural area. As such, they provide some indication of practices in the U.S. with regard to the diagnostic workup of patients with positive spiral CT screens.

Algorithms↗
PubMed2005

Final results of the Lung Screening Study, a randomized feasibility study of spiral CT versus chest X-ray screening for lung cancer.

The Lung Screening Study (LSS) was a pilot study designed to assess the feasibility of conducting a large scale randomized controlled trial (RCT) of low radiation dose spiral computed tomography (LDCT) versus chest X-ray (CXR) for lung cancer screening. Baseline results of LSS have been previously reported. Here, we report on the findings at the year one screen and on the final results of the LSS study. A total of 1660 subjects were randomized to the LDCT arm and 1658 to the CXR arm. Compliance with screening declined from 96% at baseline to 86% at year one in the LDCT arm and declined from 93% at baseline to 80% at year one in the CXR arm. Positivity rates for the year one screen were 25.8% for LDCT and 8.7% for CXR. Cancer yield was significantly less at year one for LDCT, 0.57%, than at baseline, 1.9%; cancer yield for CXR increased from 0.45% at baseline to 0.68% at year one. Forty lung cancers in the LDCT arm and 20 in the CXR arm were diagnosed over the study period. Stage I cancers comprised 48% of cases in the LDCT arm and 40% in the CXR arm. A total of 16 stage III-IV cancers were observed in the LDCT arm versus nine in the CXR arm. The LSS has established the feasibility of a RCT comparing annual spiral CT to chest X-ray for lung cancer screening.

Aged↗
PubMed2005

Prostate biopsy following a positive screen in the prostate, lung, colorectal and ovarian cancer screening trial.

PURPOSE: The benefit of prostate specific antigen (PSA) and digital rectal examination (DRE) screening for prostate cancer is under evaluation in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Followup of positive screens in PLCO is done by subject personal physicians and it is outside of trial control. We describe the pattern of prostate biopsy in men with positive screens in PLCO. MATERIALS AND METHODS: We examined all men with positive baseline PSA or DRE screens and men with positive post-baseline screens occurring by December 2000. RESULTS: Of 2,717 men with positive PSA (greater than 4 ng/ml) at baseline 41% and 64% underwent biopsy within 1 and 3 years, respectively. A screening PSA of 7 to 10 and greater than 10 ng/ml at baseline was associated with significantly higher biopsy rates (HR 1.9 and 2.6, respectively) compared to PSA 4 to 7 ng/ml. The 1,793 in men whom the first positive PSA was after baseline had a lower overall biopsy rate (50% within 3 years). Furthermore, PSA above 7 ng/ml were not associated with higher biopsy rates in this group. The 4,449 men with positive DRE screens and negative PSA had a 3-year biopsy rate of 27%. Men with positive DRE at diagnostic followup had a biopsy rate of around 90%. However, few men, even of those with positive DRE screens, had positive diagnostic DREs. CONCLUSIONS: : These biopsy rates following positive PSA and DRE screens are likely to be representative of national rates. These results suggest that PLCO is evaluating the effects of screening in a contemporary and robust manner.

Aged↗
PubMed2005

Simple maximum likelihood estimates of efficacy in randomized trials and before-and-after studies, with implications for meta-analysis.

Efficacy, which we define as the effect of receiving intervention on health outcomes among a group of subjects, is the quantity of interest for many investigators. In contrast, intent-to-treat analyses in randomized trials and their analogue for observational before-and-after studies compare outcomes between randomization groups or before-and-after time periods. When there is switching of interventions, estimates based on intent-to-treat are biased for estimating efficacy. By constructing a model based on potential outcomes, one can make reasonable assumptions to estimate efficacy under 'all-or-none' switching of interventions in which switching occurs immediately after randomization or at the start of the time period. This paper reviews the basic methodology, with emphasis on simple maximum likelihood estimates that arise with completely observed outcomes, partially missing binary outcomes, and discrete-time survival outcomes. Particular attention is paid to estimating efficacy in meta-analysis, where the interpretation is much more straightforward than with intent-to-treat analyses.

Likelihood Functions↗
PubMed2004

The fallacy of enrolling only high-risk subjects in cancer prevention trials: is there a "free lunch"?

BACKGROUND: There is a common belief that most cancer prevention trials should be restricted to high-risk subjects in order to increase statistical power. This strategy is appropriate if the ultimate target population is subjects at the same high-risk. However if the target population is the general population, three assumptions may underlie the decision to enroll high-risk subject instead of average-risk subjects from the general population: higher statistical power for the same sample size, lower costs for the same power and type I error, and a correct ratio of benefits to harms. We critically investigate the plausibility of these assumptions. METHODS: We considered each assumption in the context of a simple example. We investigated statistical power for fixed sample size when the investigators assume that relative risk is invariant over risk group, but when, in reality, risk difference is invariant over risk groups. We investigated possible costs when a trial of high-risk subjects has the same power and type I error as a larger trial of average-risk subjects from the general population. We investigated the ratios of benefit to harms when extrapolating from high-risk to average-risk subjects. RESULTS: Appearances here are misleading. First, the increase in statistical power with a trial of high-risk subjects rather than the same number of average-risk subjects from the general population assumes that the relative risk is the same for high-risk and average-risk subjects. However, if the absolute risk difference rather than the relative risk were the same, the power can be less with the high-risk subjects. In the analysis of data from a cancer prevention trial, we found that invariance of absolute risk difference over risk groups was nearly as plausible as invariance of relative risk over risk groups. Therefore a priori assumptions of constant relative risk across risk groups are not robust, limiting extrapolation of estimates of benefit to the general population. Second, a trial of high-risk subjects may cost more than a larger trial of average risk subjects with the same power and type I error because of additional recruitment and diagnostic testing to identify high-risk subjects. Third, the ratio of benefits to harms may be more favorable in high-risk persons than in average-risk persons in the general population, which means that extrapolating this ratio to the general population would be misleading. Thus there is no free lunch when using a trial of high-risk subjects to extrapolate results to the general population. CONCLUSION: Unless the intervention is targeted to only high-risk subjects, cancer prevention trials should be implemented in the general population.

Confidence Intervals↗
PubMed2004

Estimating the cumulative risk of a false-positive test in a repeated screening program.

The goal of screening tests for a chronic disease such as cancer is early detection and treatment with a consequent reduction in mortality from the disease. Screening tests, however, might produce false positive and false-negative results. With an increasing number of screening tests, it is clear that the risk of a false-positive screen, a finding with potentially significant emotional, financial, and health costs, also increases. Elmore et al. (1998, New England Journal of Medicine 338, 1089-1096), Christiansen et al. (2000, Journal of the National Cancer Institute 92, 1657-1666), and Gelfand and Wang (2000, Statistics in Medicine 19, 1865-1879) investigated this problem under the somewhat unrealistic assumption that the choice of making the decision to drop out at the kth screen does not depend upon the results of the earlier k - 1 screens. In this article we obtain sufficient and necessary conditions for their assumption to hold and use one of them to provide a method for testing the validity of the assumption. A new model which does not depend on their assumption is introduced. The maximum likelihood estimator of the cumulative risk of receiving a false-positive screen under the new model is derived and its asymptotic normality is proved. The extension of the new model by incorporating covariate information is also considered. We apply our testing method and the new model to data from the breast cancer screening trial of the Health Insurance Plan of Greater New York.

Adult↗
PubMed2004

Development tracks for cancer prevention markers.

We provide a general framework for describing various roles for biomarkers in cancer prevention research (early detection, surrogate endpoint, and cohort identification for primary prevention) and the phases in their evaluation.

Biomarkers, Tumor↗