Alan J. Gross

META-ANALYSIS IN EPIDEMIOLOGY, WITH SPECIAL REFERENCE TO STUDIES OF THE ASSOCIATION BETWEEN EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE AND LUNG CANCER : A CRITIQUE

Meta-analysis, a set of statistical tools for combining and integrating the results of independent studies of a given scientific issue, can be useful when the stringent conditions under which such integration is valid are met. In this report we point out the difficulties in obtaining sound meta-analyses of either controlled clinical trials or epidemiological studies. We demonstrate that hastily or improperly designed meta-analyses can lead to results that may not be scientifically valid. We note that much care is typically taken when meta-analysis is applied to the results of clinical trials. The Food and Drug Administration, for example, requires strict adherence to the principles we discuss in this paper before it allows a drugs sponsor to use a meta-analysis of separate clinical studies in support of a New Drug Application. Such care does not always carry over to epidemiological studies, as demonstrated by the 1986 report of the National Research Council concerning the purported association between exposure to environmental tobacco smoke and the risk of lung cancer. On the basis of a meta-analysis of 13 studies, 10 of which were retrospective and the remaining 3 prospective in nature, the Council concluded that non-smokers who are exposed to environmental tobacco smoke are at greater risk of acquiring lung cancer than non-smokers not so exposed. In our opinion, this conclusion in unwarranted given the poor quality of the studies on which it is based.

The measurement of environmental tobacco smoke in 585 office environments

Abstract In order to provide information on levels of environmental tobacco smoke (ETS) in office environments during 1989, a total of 585 offices was sampled for a number of factors, including respirable suspended particles (RSP), nicotine, carbon monoxide, carbon dioxide, room size, average number of room occupants, and number of cigarettes consumed. Each data set was collected over a one-hour sampling period. Discriminant analysis of the data collected showed a group of rooms used for light smoking (59.9% of total smoking rooms) was not significantly different from the nonsmoking rooms, in terms of the variables which contributed to the predictive ability of the model (RSP and nicotine). These light-smoking rooms overlapped somewhat with the heavy-smoking rooms, suggesting other variables not measured here might contribute to this model, such as air change rates or outside air intake volumes. This leads to the possibility that a range of smoker densities could be established inside which indoor air quality will not be significantly affected, thus reflecting the American Society of Heating, Refrigerating and Air Conditioning Engineers (ASHRAE) Standard 62-89, which shows that with good ventilation acceptable air quality can be maintained with moderate amounts of smoking. Statistical analysis also showed overall levels of ETS in offices to be considerably lower than estimated in work ten years previously, and that carbon monoxide is only weakly influenced by smoking activity. Carbon dioxide measurements taken in each room did not correlate significantly with RSP, nicotine, or carbon monoxide, and there were significant relationships between smoker density, RSP, and nicotine, respectively.

Improvement in Antiepileptic Drug Levels Following Reduction of Intervals Between Clinic Visits

Summary: Antiepileptic drug levels (AEDLs) may reflect how well patients adhere to prescribed medical regimens. Of 30 patients on stable drug regimens AEDLs were increased in 33% by decreasing clinic visit intervals from a mean of 3.4 months to 1.1 months. The testing situation was applied to patients who had AEDLs in the “therapeutic range”(n= 15) as well as those with one or more AEDLs below “therapeutic range” (n= 15). In the latter group 73% of patients showed improvement in AEDLs. Although a less reliable parameter, verbally reported seizure frequencies were also improved. Overall, the reduction in clinic visit interval could be expected to yield improvement in 46 to 80% (confidence interval = 95%). These patients responded equally well to physician and non‐physician practitioners. This technique may be useful as an intervening measure for those patients who are noncompliant.

The risk of lung cancer in nonsmokers in the United States and its reported association with environmental tobacco smoke

Abstract Is environmental tobacco smoke (ETS) causally related to lung cancer? In this study, 29 case-control and three cohort studies involving exposed and unexposed female smokers (as defined herein, an exposed individual is a never-smoker married to a smoker and an unexposed individual is a never-smoker married to a never-smoker) and nine case-control and two cohort studies involving exposed and unexposed male smokers, in which presence or absence of lung cancer is the specified outcome, are reviewed. It is pointed out that any attempt to make inferences toward such a causal relationship must account for the fundamental differences in these studies, which took place on three continents over 15 years and involved many differences in individual study design as well as in study subjects. Since this has largely not been done, the only conclusion that sensibly can be drawn from these studies is that the conclusion of a causal relationship is currently not supported by the data. This is certainly true when an attempt is made to apply a world-wide risk ratio to the U.S. population, as was done in the U.S. Surgeon Generals report (1986).

The Barlow-Scheuer Reliability Growth Model from a Bayesian Viewpoint

A model resembling the Barlow-Scheuer reliability growth model [I] is examined from a Bayesian perspective. A Dirichlet prior distribution is assumed on the three parameters of the model, i.e. the probability of an inherent failure, the probability of an assignable-cause failure, and the probability of success. The model assumes that a subsystem is tested in independent stages. At each stage, the posterior distribution is a Dirichlet distribution, or a mixture of Dirichlet distributions, depending on whether the investigator can identify with certainty which of the assignable-failure causes are removed when those discovered during testing are corrected. Methodology is developed for estimating reliability at the end of each stage of testing and for obtaining lower and upper bounds for system reliability. The Barlow-Scheuer data are reexamined using the approach developed herein.

The correlation coefficient between the smallest and largest observations when (N-1) of the n observations are iid exponentially distributed

A random sample of size n is obtained from two exponential populations in the following manner: (n-1) observations are selected from one of these populations and a single observation is selected from the other population. The correlation coefficient for Y1and Yn, the first and n-th order statistics is obtained. More ngenerally, it is shown in the course of the derivation that Yj-Yi is independent of YK-Y1 for all i, j, l and k such that I < j < l < k. This result is weil known when all the observations are iid exponentially distributed.

Oral cancer and smokeless tobacco: Literature review and meta-analysis

Abstract The use of smokeless tobacco (SLT) is considered as a major risk factor for oral cancer. In this paper, a detailed review is provided on the major results of the available published analytic epidemiological studies on the hypothetical association between the risk of oral cancer and the use of SLT. Meta-analysis is then used to summarize the major findings of these studies. It is observed from our literature survey and meta-analysis that the quality and major findings of the studies reviewed are quite variable.

Heterozygote detection through bleomycin-induced G2 chromatid breakage in dyskeratosis congenita families

We determined the mean number of chromatid breaks per cell (b/c) in the bleomycin-treated lymphocytes of 10 patients with dyskeratosis congenita (DC) and 26 of their relatives to ascertain whether bleomycin sensitivity would distinguish DC heterozygotes from normal individuals. We observed a significantly higher mean number of chromatid b/c in DC patients and obligate heterozygotes (patients versus controls, p less than 0.0001; heterozygotes versus controls, p = 0.0076, Mann-Whitney rank-sum test). Unequivocal heterozygote detection was not possible owing to overlap of the b/c values of patients, heterozygotes, and controls, but our findings provided strong evidence of a link between autosomal recessive as well as X-linked recessive DC mutations and bleomycin sensitivity in homozygous, hemizygous, and heterozygous individuals.

Antibiotics and return visits for respiratory illness : A comparison of pooled versus hierarchical statistical methods

BACKGROUND Antibiotic prescribing for respiratory illness has been associated with small reductions in return visits in an analysis of a large practice-based network. In this study, we apply hierarchical analytical methods that account for the clustering of patients by practices to identify whether antibiotic prescribing by primary care physicians reduces subsequent visits for 6 acute respiratory illnesses-upper respiratory infection, pharyngitis, bronchitis, otitis media, sinusitis, and cough. METHODS The study data came from 318 family physicians and internists in 45 practices in the Practice Partner Research Network from January 1995 through December 1996, with 255,564 active patients. Patients treated with antibiotics were compared with those who were not on the frequency of revisit within the next 14 days. A simple pooling model and 3 hierarchical statistical models (fixed-effects, random-effects, and Bayesian) were used to compare the odds-ratios for return visits. RESULTS Statistically significant results were found only for bronchitis and sinusitis by the hierarchical models, but the simple pooling model produced statistically significant results for all study conditions. CONCLUSION We conclude that antibiotics may reduce return visits for patients with bronchitis and sinusitis, but not for patients with other respiratory illness (upper respiratory infection, pharyngitis, otitis media, or cough). Studies of large clinical databases should use methods of analysis that account for the grouping of patients by practice to avoid false positive associations (type I errors.)

Flow in Coronary Artery Bypass Grafts to Totally and Partially Occluded Left Anterior Descending Coronary Arteries

Flow was determined by electromagnetic flowmeter in vein bypass grafts in 20 patients with a totally occluded left anterior descending (LAD) coronary artery and on 61 patients with a partially occluded LAD. The median flow in LAD grafts was 14.5 ml/min with total LAD occlusion, and 40 ml/min with partial LAD occlusion (p less than 0.001). In cases of total LAD occlusion, the presence of mild or moderate anteroseptal wall dysfunction was associated with more satisfactory flow than was the case with severe anteroseptal wall dysfunction (p less than 0.02). Flows over 25 ml/min were found only when the LAD distal to total occlusion was 1.5 mm or greater. Unsatisfactory flows were consistently found with total LAD occlusion, poor ventricular function, and a distal LAD less than 1.5 mm. Repeat catheterizations to determine an unsatisfactory patency rate under these conditions would be necessary to alter our policy of grafting all suitable vessels beyond a total occlusion.