Faculty Bibliography

According to FDA regulations, a combination drug is not efficacious unless each component contributes to the claimed effects. For a univariate endpoint, this implies that the combination at specific doses must be superior to each of its components at the same doses. More demanding is the property of synergy, in which the effect of the combination must be superior to the effect expected based on those of its components. If it is equal to those effects, it is additive, and if it is inferior, it is antagonistic. We give regions in the combination dose plane where these concepts are well defined. If the effect of the combination is greater than the greatest effect achievable by any of its components it is therapeutically synergistic. A combination can be antagonistic, yet its components can still contribute to the claimed effects. If it is additive, synergistic or therapeutically synergistic, its components must contribute to the claimed effects. We relate these concepts and provide designs and sequential procedures for determining whether a combination is therapeutically synergistic, synergistic, additive, antagonistic and contributing or antagonistic and non-contributing

In contrast to classical capture recapture methods, the single-sample method of Laska, Meisner, and Siegel (1988) (LMS) enables estimation of the size of a population, N*, on the basis of a single survey. For example, it may be desired to estimate the unduplicated number of individuals served by a mental health center during the last year on the basis of a 1-week sample. The time since each of the sampled individuals last engaged in the activity that defines the population is ascertained. The LMS estimator of N* and its unbiasedness property are motivated in a simple way, and an improved LMS estimator is introduced if additional information is available. An empirical assessment of the procedure is made using mental health service data for which the true population size is known. The performance of the extended LMS estimator is a substantial improvement over the standard LMS estimator

We demonstrate that average cost-effectiveness ratios (CERs) play an important role in the evaluation of the cost-effectiveness of treatments. Criticisms of the usefulness of CERs derive mostly from the context of resource allocation under a constrained budget in which some decisions are based on incremental CERs. However, we show that in many cases, these decision rules are equivalent to decision rules on CERs. This follows for mutually exclusive treatments first, because a treatment is eliminated by extended dominance if and only if there is a mixed treatment with a smaller CER, where the mixing parameter lies in a certain interval. Second, after elimination of treatments by dominance and by extended dominance, resources can be allocated in order of increasing CERs. Moreover, the CER is a parameter that characterizes clinical and economical properties of a treatment independent of its comparators

BACKGROUND: Information on patterns and correlates of the violent behaviour of individuals with schizophrenia is largely limited to populations in developed countries. Data from a World Health Organization epidemiological study of schizophrenia and related disorders, the Determinants of Outcome of Severe Mental Disorders (DOSMD), presented an opportunity to study patterns of violence across multinational settings. METHOD: Centres in 10 countries participated in the DOSMD study. An incidence sample of 1017 patients with schizophrenia who had their first-in-lifetime contact with a helping agency as a result of their psychotic symptoms was obtained. Data were available on their history of violent behaviour, substance use, and demographics. RESULTS: The occurrence rate of assault in the entire cohort was 20.6 per hundred, but the rate was three times higher in the developing countries (31.5 per hundred) than in developed countries (10.5 per hundred). History of assault was associated with positive symptoms, such as excitement and auditory hallucinations, and with serious alcohol problems. CONCLUSIONS: The cultural context and the specific characteristics of the disease in individuals with schizophrenia may interactively affect rates of violent behaviour

Methods for statistical inference for cost-effectiveness (C/E) ratios for individual treatment and for incremental cost-effectiveness (delta C/ delta E) ratios when two treatments are compared are presented. In a lemma, we relate the relative magnitude of two C/E ratios to the delta C/ delta E ratio. We describe a statistical procedure to test for dominance, or admissibility, that can be used to eliminate an inferior treatment. The one-sided Bonferroni's confidence interval procedure is generalized to the two-sided case. The method requires only that two confidence intervals be available, one for cost and one for effectiveness. We describe Fieller-based confidence intervals and show them to be shorter than Bonferroni intervals. When distribution assumptions hold and variance and covariance estimates are available, Fieller intervals are preferable. However, Bonferroni intervals can be applied in more diverse situations and are easier to calculate. A simple Bonferroni based technique, and a likelihood ratio statistic given by Siegel, Laska and Meisner, for testing the null hypothesis that the C/E ratios of two treatments are equal is presented. The approaches are applied to the data from a phase II clinical trial of a new treatment for sepsis considered previously by others

A statistical framework is presented for examining cost and effect data on competing interventions obtained from an RCT or from an observational study. Parameters of the join distribution of costs and effects or a regression function linking costs and effects are used to define cost-effectiveness (c-e) measures. Several new c-e measures are proposed that utilize the linkage between costs and effects on the patient level. These measures reflect perspectives that are different from those of the commonly used measures, such as the ratio of expected cost to expected effect, and they can lead to different relative rankings of the interventions. The cost-effectiveness of interventions are assessed statistically in a two stage procedure that first eliminates clearly inferior interventions. Members of the remaining admissible set are then rank ordered according to a c-e preference measure. Statistical techniques, particularly in the multivariate normal case, are given for several commonly used c-e measures. These techniques provide methods for obtaining confidence intervals, for testing the hypothesis of admissibility and for the equality of interventions, and for ranking interventions. The ideas are illustrated for a hypothetical clinical trial of antipsychotic agents for community-based persons with mental illness

An unexpected finding of the International Pilot Study of Schizophrenia, launched by the World Health Organization (WHO) in 1967, was that patients in countries outside Europe and the United States have a more favourable short- and medium-term course of the disease than those seen in developed countries. Since then, WHO has intensified its schizophrenia research programme and has initiated a set of international studies that have confirmed these initial findings and explored possible reasons for such differences in the course and outcome of schizophrenia. While such work has provided important findings and has generated additional pertinent hypotheses, it did not explain the differences in outcome. The present paper describes a new initiative in which approximately 2500 subjects involved in previous WHO multicentre schizophrenia studies are being followed up for between 15 and 25 years after initial examination. Nineteen research centres in 16 countries are taking part in this work. The research methodology is described

Each of K mental health programmes reports the number of patients served in a year. The sum of these numbers, y, is an overcount because some patients are seen in more than one programme. Health care planners need to know the unduplicated number served by the mental health system. Thus, there is an unknown number, M, of distinct individuals who appear on one or more of K lists; some appear on multiple lists and the duplicates are not readily identifiable. Let X be the number of lists on which a randomly selected individual appears. When E(X) is known, y/E(X) is the natural estimator of M. We assume that we know the number of programmes, Xi, used by the ith individual in a random sample of recipients of service. Here, the intuitive estimator, Y/X has desirable statistical properties. We give confidence interval estimators for M. We apply the method to estimate the number of individuals served in 1991 by the mental health programmes in New York State

OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences