Marvin Zelen

A New Design for Randomized Clinical Trials

This paper proposes a new method for planning randomized clinical trials. This method is especially suited to comparison of a best standard or control treatment with an experimental treatment. Patients are allocated into two groups by a random or chance mechanism. Patients in the first group receive standard treatment; those in the second group are asked if they will accept the experimental therapy; if they decline, they receive the best standard treatment. In the analyses of results, all those in the second group, regardless of treatment, are compared with those in the first group. Any loss of statistical efficiency can be overcome by increased numbers. This experimental plan is indeed a randomized clinical trial and has the advantage that, before providing consent, a patient will know whether an experimental treatment is to be used.

L-Phenylalanine Mustard (L-PAM) in the Management of Primary Breast Cancer

Abstract Prolonged L-phenylalanine mustard (L-PAM) administration as an adjuvant to mastectomy in the management of patients with primary breast cancer and pathologically positive axillary nodes was evaluated by a prospective, randomized, clinical trial. Treatment failures occurred in 22 per cent of 108 patients receiving placebo and 9.7 per cent of 103 women given L-PAM (p = 0.01). A statistically significant difference (p = 0.02) existed in favor of L-PAM relative to disease-free interval. In premenopausal women, the difference with respect to disease-free interval of treated and control groups was highly significant (p = 0.008). A treatment failure occurred in 30 per cent of premenopausal patients receiving placebo and 3 per cent of those treated with L-PAM (p = 0.008). Whereas a similar trend was observed in postmenopausal patients, the difference is not statistically significant. Thus, L-PAM has been demonstrated to be effective in the treatment of women with primary breast cancer, particularly those...

Rethinking centrality: Methods and examples☆

Abstract A new model of centrality is proposed for networks. The centrality measure is based on the “information” contained in all possible paths between pairs of points. The method does not require path enumeration and is not limited to the shortest paths or geodesies. We apply this measure to two examples: a network of homosexual men diagnosed with AIDS, and observations on a colony of baboons. Comparisons are made with “betweenness” and “closeness” centrality measures. The processes by which structural changes in networks occur over time are also discussed.

EFFECTS OF MAMMOGRAPHY SCREENING UNDER DIFFERENT SCREENING SCHEDULES: MODEL ESTIMATES OF POTENTIAL BENEFITS AND HARMS

To inform the USPSTF recommendations about breast cancer screening, Mandelblatt and colleagues developed 6 models of breast cancer incidence and mortality in the United States and estimated benefit...

Effect of Screening Mammography on Breast-Cancer Mortality in Norway

BACKGROUND A challenge in quantifying the effect of screening mammography on breast-cancer mortality is to provide valid comparison groups. The use of historical control subjects does not take into account chronologic trends associated with advances in breast-cancer awareness and treatment. METHODS The Norwegian breast-cancer screening program was started in 1996 and expanded geographically during the subsequent 9 years. Women between the ages of 50 and 69 years were offered screening mammography every 2 years. We compared the incidence-based rates of death from breast cancer in four groups: two groups of women who from 1996 through 2005 were living in counties with screening (screening group) or without screening (nonscreening group); and two historical-comparison groups that from 1986 through 1995 mirrored the current groups. RESULTS We analyzed data from 40,075 women with breast cancer. The rate of death was reduced by 7.2 deaths per 100,000 person-years in the screening group as compared with the historical screening group (rate ratio, 0.72; 95% confidence interval [CI], 0.63 to 0.81) and by 4.8 deaths per 100,000 person-years in the nonscreening group as compared with the historical nonscreening group (rate ratio, 0.82; 95% CI, 0.71 to 0.93; P<0.001 for both comparisons), for a relative reduction in mortality of 10% in the screening group (P=0.13). Thus, the difference in the reduction in mortality between the current and historical groups that could be attributed to screening alone was 2.4 deaths per 100,000 person-years, or a third of the total reduction of 7.2 deaths. CONCLUSIONS The availability of screening mammography was associated with a reduction in the rate of death from breast cancer, but the screening itself accounted for only about a third of the total reduction. (Funded by the Cancer Registry of Norway and the Research Council of Norway.)

Estimation of exponential survival probabilities with concomitant information.

Concomitant information on a l)atients condition often accompanies survival time information. This paper presents a method of estimating survival distributions when the survival times are asstumed to follow simple exponential distributions, with a different parameter for eacli patient. The parameter associated with each patients distribution is functionially related to the concomitant variates. The parameters are estimated by the method of maximum likelihood. An illustration of the method using acute leukemia survival data is given.

An analysis of contaminated well water and health effects in Woburn, Massachusetts

Abstract In 1979, two of the eight municipal wells servicing Woburn, Massachusetts, were discovered to be contaminated with several chlorinated organics. Shortly afterwards, the town was found to have an elevated rate of childhood leukemia. Using recent information about the space—time distribution of water from the two contaminated wells, we find positive statistical associations between access to this water and the incidence rates of childhood leukemia, perinatal deaths (1970–1982), two of five categories of congenital anomalies, and two of nine categories of childhood disorders. We find no associations with spontaneous abortions, low birth weight, or the other categories of congenital anomalies and childhood disorders. This article discussed these results and other features of the data relevant to their interpretation.

Participation of community hospitals in clinical trials: analysis of five years of experience in the Eastern Cooperative Oncology Group.

The Eastern Cooperative Oncology Group (ECOG) initiated a program in 1976 to involve community hospitals in multi-institutional clinical trials. The community hospitals can be characterized as generally having no tradition of participating in clinical trials of cancer therapy, whereas the ECOG member institutions are university hospitals or major treatment centers. More than 100 community hospitals participated in 97 randomized trials involving 4506 patients from November 1976 through February 1981. Comparisons between the community hospitals and the ECOG member institutions indicate that the quality of participation was similar, as measured by rates of ineligibility, compliance with the protocol, and submission of data. Objective measures of outcome, such as survival, response, and toxicity, were also comparable. We conclude that under the mechanism adopted by the ECOG, it is possible to include community hospitals in clinical trials of cancer therapy without reducing the quality of the data or compromising the therapeutic outcomes.

Scheduling Periodic Examinations for the Early Detection of Disease: Applications to Breast Cancer

Abstract This article develops and extends previous investigations on stochastic models for selecting examination schedules targeted at earlier diagnosis of chronic diseases. The general aim is to provide guidelines for public health programs in the choice of examination schedules. The main features of such schedules are the initial age to begin a scheduled examination program, the intervals between subsequent examinations, and the number of examinations. Our basic model consists of three health states: a disease-free or nondetectable state; a preclinical state, in which an individual has disease but is asymptomatic and is unaware of it; and a clinical state in which the disease has been diagnosed by routine methods. The aim of early detection programs is to identify individuals in a preclinical local state, which may result in higher cure rates or longer survival. We introduce two basic ideas that either individually or together can lead to satisfactory examinations schedules. The threshold method constr...

The use of prognostic factors in predicting survival for breast cancer patients

Abstract There were 375 cases in the series of breast cancer patients diagnosed from 1921 to 1953 at the Yale-New Haven Medical Center for which information was available for the following four variables: axillary lymph node status, nuclear grade, sinus histiocytosis and tumor size. Patients were classified according to a favorable or unfavorable status with respect to each of these four variables. With one exception, the survival distribution for the 16 resulting groups of patients could be reasonably approximated by a simple exponential distribution. This implies that the mortality rate can be used for analytical purposes as a summary of the survival pattern for a group of cases. Using statistical methods for analyzing factorial experiments, we found that each of the four variables influenced survival and that the order of importance was axillary node status, tumor size, sinus histiocytosis and nuclear grade. No interaction was judged important. Based on an assumption of exponential survival, a mathematical model was developed which made meaningful survival prediction possible (by taking disease status at time of mastectomy into account). The mathematical model was further used for ranking combinations of conditions of the four variables in order of prognostic importance.