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Objectives: To assess incidence and preventability of adverse drug events (ADEs) and potential ADEs. To analyze preventable events to develop prevention strategies., Design: Prospective cohort study., Participants: All 4031 adult admissions to a stratified random sample of 11 medical and surgical units in two tertiary care hospitals over a 6-month period. Units included two medical and three surgical intensive care units and four medical and two surgical general care units., Main Outcome Measures: Adverse drug events and potential ADEs., Methods: Incidents were detected by stimulated self-report by nurses and pharmacists and by daily review of all charts by nurse investigators. Incidents were subsequently classified by two independent reviewers as to whether they represented ADEs or potential ADEs and as to severity and preventability., Results: Over 6 months, 247 ADEs and 194 potential ADEs were identified. Extrapolated event rates were 6.5 ADEs and 5.5 potential ADEs per 100 nonobstetrical admissions, for mean numbers per hospital per year of approximately 1900 ADEs and 1600 potential ADEs. Of all ADEs, 1% were fatal (none preventable), 12% life-threatening, 30% serious, and 57% significant. Twenty-eight percent were judged preventable. Of the life-threatening and serious ADEs, 42% were preventable, compared with 18% of significant ADEs. Errors resulting in preventable ADEs occurred most often at the stages of ordering (56%) and administration (34%); transcription (6%) and dispensing errors (4%) were less common. Errors were much more likely to be intercepted if the error occurred earlier in the process: 48% at the ordering stage vs 0% at the administration stage., Conclusion: Adverse drug events were common and often preventable; serious ADEs were more likely to be preventable. Most resulted from errors at the ordering stage, but many also occurred at the administration stage. Prevention strategies should target both stages of the drug delivery process.

This paper proposes the use of two-factor models (age-period and age-cohort models) to estimate age, period, and cohort effects on pulmonary function by using the data collected in a 24-year longitudinal study in the Netherlands from 1965 to 1990. The analysis included 18,363 pulmonary function measurements on 6,148 subjects aged 20-54 years at the initial visit. The subjects were grouped into four birth cohorts (before 1923, 1923-1934, 1935-1946, and after 1946) and four survey periods (1965-1972, 1973-1978, 1979-1984, and 1985-1990). In the age-cohort model, the decrement in forced expiratory volume in 1 second (FEV1) associated with a yearly increase in age was 28.3 +/- 3.7 ml/year for a man 176 cm tall and 16.0 +/- 1.9 ml/year for a woman 163 cm tall. The estimated acceleration of decline with aging was significant for both men (beta = -0.212; standard error = 0.079 ml) and women (beta = -0.346; standard error = 0.058 ml). Compared with that of the cohort born before 1923, the average level of FEV1 was estimated to increase by 156, 277, and 379 ml, respectively, for the three younger cohorts in men (p = 0.01) and by 133, 213, and 328 ml for the three younger cohorts in women (p < 0.01). In the age-period model, the estimated linear age effect on FEV1 was 36.2 +/- 4.2 ml/year for a man and 30.5 +/- 2.3 ml/year for a woman. The age quadratic term was significant for women, but not for men. Average FEV1 was estimated to be increased by 141, 169, and 250 ml, respectively, for the periods 1973-1978, 1979-1984, and 1985-1990 in men and by 131, 138, and 219 ml in women. These period effects were significant for both men and women. In summary, this study applied the two-factor models to estimate cross-sectional and longitudinal effects of aging on FEV1 and demonstrated significant period and cohort effects, which could be attributed in part to changes in air pollutants, respiratory infections, vaccinations, types of cigarettes, diet, and lifestyles over time.

In this paper, we describe a likelihood-based method for analysing balanced but incomplete longitudinal binary responses that are assumed to be missing at random. Following the approach outlined in Zhao and Prentice (1990, Biometrika 77, 642-648), we focus on "marginal models" in which the marginal expectation of the response variable is related to a set of covariates. The association between binary responses is modelled in terms of conditional log odds-ratios. We describe a set of scoring equations for jointly estimating both the marginal parameters and the conditional association parameters. An outline of the EM algorithm used to obtain the maximum likelihood estimates is presented. This approach yields valid and efficient estimates when the responses are missing at random, but not necessarily missing completely at random. An example, using data from the Muscatine Coronary Risk Factor Study, is presented to illustrate this methodology.

Moment methods for analyzing repeated binary responses have been proposed by Liang and Zeger (1986, Biometrika 73, 13-22), and extended by Prentice (1988, Biometrics 44, 1033-1048). In their generalized estimating equations (GEE), both Liang and Zeger (1986) and Prentice (1988) estimate the parameters associated with the expected value of an individual's vector of binary responses as well as the correlations between pairs of binary responses. In this paper, we discuss one-step estimators, i.e., estimators obtained from one step of the generalized estimating equations, and compare their performance to that of the fully iterated estimators in small samples. In simulations, we find the performance of the one-step estimator to be qualitatively similar to that of the fully iterated estimator. When the sample size is small and the association between binary responses is high, we recommend using the one-step estimator to circumvent convergence problems associated with the fully iterated GEE algorithm. Furthermore, we find the GEE methods to be more efficient than ordinary logistic regression with variance correction for estimating the effect of a time-varying covariate.

In this paper, we describe a two-step weighted least squares method for analyzing repeated categorical outcomes when some individuals are not observed at all times of follow-up. Other weighted least squares methods for analyzing repeated measures data with missing responses have previously been proposed by Koch, Imrey, and Reinfurt (1972, Biometrics 28, 663-692) and Woolson and Clarke (1984, Journal of the Royal Statistical Society, Series A 147, 87-99). These methods give consistent estimators if the responses are missing completely at random, as discussed in Rubin (1976, Biometrika 63, 581-592). We propose a two-step method that will give consistent results under the weaker condition of missing at random, and compare it with the other two methods.

The crossover design is a type of longitudinal study with subjects receiving different treatments in different time periods. When carry-over effects are absent, the usual crossover design is structured so that all the information about treatment effects is contained in the within-subject contrasts; standard analyses are based on these within-subject contrasts and ignore any between-subject information. With carry-over effects present these standard analyses can be very inefficient, especially for suboptimal designs. We describe alternative approaches based on methods for the analysis of longitudinal data.

We explore the deterrent effect of the tort system by assessing physician perceptions of the risk of being sued and the impact of those perceptions on their own practice. The data are from a mailed survey conducted in 1989 of a random sample of physicians who were practicing in New York State in 1984. The survey results were compared to the actual risk of suit using the between-group (Wald) test and logistic regression methods. We also surveyed physicians about practice changes undertaken in the last ten years, factors influencing practice standards, and the costs of being sued and included these in the analysis. On average, physicians estimate that 19.5 out of one hundred of their colleagues will be sued in a given year, approximately three times the actual rate, with significant differences by specialty, location, and suit history. Perceived risk is associated with self-reported changes in test-ordering frequency and reduction in practice scope. The median number of days lost from practice to defend a malpractice suit was three to five, and 6 percent of the physicians surveyed incurred some out-of-pocket expenses. These findings suggest that physicians respond to the messages sent by litigation in a manner consistent with the deterrent theory of tort litigation.

The analysis of serial measurements obtained in longitudinal studies plays an increasingly prominent role in applied research. The last few years have seen the development of many new techniques for carrying out analyses, including computer software. These methods can be used in a variety of standard problems, including repeated measures and cross-over designs, as well as growth curve analyses. We review these new methods, their application, and available computer packages. Data from a longitudinal study of lung function is used to illustrate the methods.

Tracking of blood pressure in adolescent boys is investigated using a mathematical model that corresponds to progression along a constant percentile. A more general analysis, based on the method of principal components, is also proposed that determines various alternative tracks or patterns that are most prevalent in the longitudinal blood pressure data. The degree of tracking along a constant percentile curve for systolic pressure was moderately high, as evidenced by a tracking index of .78 explaining 81% of the variance, but less strong for diastolic (tracking index of .60) where tracking along a percentile explained 66% of the variance. The value of the more general analysis of blood pressure patterns may lie in the assessment of adolescent risk factors for elevated adult blood pressure. Using adolescent patterns determined by either statistical model, adult systolic at age 38 was predicted (R2 = .22) by the concept of a systolic fixed percentile curve in adolescence, and similarly for diastolic (R2 = .21). However, the more general analysis based on longitudinal principal components further suggests that boys who have a larger than usual systolic peak at age 14 years, which is near the time of the adolescent physical growth spurt in these boys, may be more likely to have higher systolic pressures at age 38. Because the adult data were incomplete and highly unbalanced, these findings were obtained using random-effects models for longitudinal data.

Background and Methods: By matching the medical records of a random sample of 31,429 patients hospitalized in New York State in 1984 with statewide data on medical-malpractice claims, we identified patients who had filed claims against physicians and hospitals. These results were then compared with our findings, based on a review of the same medical records, regarding the incidence of injuries to patients caused by medical management (adverse events)., Results: We identified 47 malpractice claims among 30,195 patients' records located on our initial visits to the hospitals, and 4 claims among 580 additional records located during follow-up visits. The overall rate of claims per discharge (weighted) was 0.13 percent (95 percent confidence interval, 0.076 to 0.18 percent). Of the 280 patients who had adverse events caused by medical negligence as defined by the study protocol, 8 filed malpractice claims (weighted rate, 1.53 percent; 95 percent confidence interval, 0 to 3.2 percent). By contrast, our estimate of the statewide ratio of adverse events caused by negligence (27,179) to malpractice claims (3570) is 7.6 to 1. This relative frequency overstates the chances that a negligent adverse event will produce a claim, however, because most of the events for which claims were made in the sample did not meet our definition of adverse events due to negligence., Conclusions: Medical-malpractice litigation infrequently compensates patients injured by medical negligence and rarely identifies, and holds providers accountable for, substandard care.

To explore the epidemiology of adverse events (AEs), which were defined as injuries due to medical treatment, and that subset of AEs caused by negligence, we studied interhospital variation in these outcomes in a sample of 31,000 medical records drawn from a random selection of 51 hospitals in New York in 1984. We found a substantial variation in both AE rates (0.2% to 7.9%; mean, 3.2%) and the percentage of AEs due to negligence (1% to 60%; mean, 24.9%) among hospitals. Univariate analyses of AEs revealed that primary teaching institutions had significantly higher rates (4.1%) and rural hospitals had significantly lower ones (1.0%). The percentage of AEs due to negligence was lower in primary teaching (10.7%) and for-profit (9.5%) hospitals and was significantly higher in hospitals with predominantly (greater than 80%) minority patients who had been discharged (37%). These findings were corroborated by multivariate analysis. Our results suggest that AEs and negligence are not randomly distributed and that certain types of hospitals have significantly higher rates of injuries due to substandard care. These observations may represent an important improvement on existing measures of quality because they take into account the fact that some hospitals' populations may be at risk of suffering a poor outcome.

Background: As part of an interdisciplinary study of medical injury and malpractice litigation, we estimated the incidence of adverse events, defined as injuries caused by medical management, and of the subgroup of such injuries that resulted from negligent or substandard care., Methods: We reviewed 30,121 randomly selected records from 51 randomly selected acute care, nonpsychiatric hospitals in New York State in 1984. We then developed population estimates of injuries and computed rates according to the age and sex of the patients as well as the specialties of the physicians., Results: Adverse events occurred in 3.7 percent of the hospitalizations (95 percent confidence interval, 3.2 to 4.2), and 27.6 percent of the adverse events were due to negligence (95 percent confidence interval, 22.5 to 32.6). Although 70.5 percent of the adverse events gave rise to disability lasting less than six months, 2.6 percent caused permanently disabling injuries and 13.6 percent led to death. The percentage of adverse events attributable to negligence increased in the categories of more severe injuries (Wald test chi 2 = 21.04, P less than 0.0001). Using weighted totals, we estimated that among the 2,671,863 patients discharged from New York hospitals in 1984 there were 98,609 adverse events and 27,179 adverse events involving negligence. Rates of adverse events rose with age (P less than 0.0001). The percentage of adverse events due to negligence was markedly higher among the elderly (P less than 0.01). There were significant differences in rates of adverse events among categories of clinical specialties (P less than 0.0001), but no differences in the percentage due to negligence., Conclusions: There is a substantial amount of injury to patients from medical management, and many injuries are the result of substandard care.

Background: In a sample of 30,195 randomly selected hospital records, we identified 1133 patients (3.7 percent) with disabling injuries caused by medical treatment. We report here an analysis of these adverse events and their relation to error, negligence, and disability., Methods: Two physician-reviewers independently identified the adverse events and evaluated them with respect to negligence, errors in management, and extent of disability. One of the authors classified each event according to type of injury. We tested the significance of differences in rates of negligence and disability among categories with at least 30 adverse events., Results: Drug complications were the most common type of adverse event (19 percent), followed by wound infections (14 percent) and technical complications (13 percent). Nearly half the adverse events (48 percent) were associated with an operation. Adverse events during surgery were less likely to be caused by negligence (17 percent) than nonsurgical ones (37 percent). The proportion of adverse events due to negligence was highest for diagnostic mishaps (75 percent), noninvasive therapeutic mishaps ("errors of omission") (77 percent), and events occurring in the emergency room (70 percent). Errors in management were identified for 58 percent of the adverse events, among which nearly half were attributed to negligence., Conclusions: Although the prevention of many adverse events must await improvements in medical knowledge, the high proportion that are due to management errors suggests that many others are potentially preventable now. Reducing the incidence of these events will require identifying their causes and developing methods to prevent error or reduce its effects.

We discuss maximum likelihood methods for analysing binary responses measured at two times, such as in a cross-over design. We construct a 2 x 2 table for each individual with cell probabilities corresponding to the cross-classification of the responses at the two times; the underlying likelihood for each individual is multinomial with four cells. The three dimensional parameter space of the multinomial distribution is completely specified by the two marginal probabilities of success of the 2 x 2 table and an association parameter between the binary responses at the two times. We examine a logistic model for the marginal probabilities of the 2 x 2 table for individual i; the association parameters we consider are either the correlation coefficient, the odds ratio or the relative risk. Simulations show that the parameter estimates for the logistic regression model for the marginal probabilities are not very sensitive to the parameters used to describe the association between the binary responses at the two times. Thus, we suggest choosing the measure of association for ease of interpretation.

This article deals with the extension of the pretest-posttest clinical trial to the longitudinal data setting. We assume that a baseline (or pretest) measurement is taken on all individuals, who are then randomized, without regard to baseline values, to a treatment group. Repeated measurements are taken postrandomization at specified times. Our objective is to estimate the average rate of change (or slope) in the experimental groups and the differences in the slopes. Our focus is on the optimal use of the baseline measurements in the analysis. We contrast two different approaches:--a multivariate one that regards the entire vector of responses (including the baseline) as random outcomes and a univariate one that uses each individual's least squares slope as an outcome. Our multivariate approach is essentially a generalization of Stanek's Seemingly Unrelated Regression (SUR) estimator for the pretest-posttest design. The multivariate approach is natural to apply in this setting, and optimal if the assumed model is correct. However, the most efficient estimator requires assuming that the baseline mean parameters are the same for all experimental groups. Although this assumption is reasonable in the randomized setting, the resulting multivariate estimator uses postrandomization data as a covariate; if the assumed linear model is not correct, this can lead to distortions in the estimated treatment effect. We propose instead a reduced form multivariate estimator that may be somewhat less efficient, but protects against model misspecification.

Metallocluster extrusion requirements, interspecies MoFe-protein primary sequence comparisons and comparison of the primary sequences of the MoFe-protein subunits with each other have been used to assign potential P-cluster (Fe-S cluster) domains within the MoFe protein. In each alpha-beta unit of the MoFe protein, alpha-subunit domains, which include potential Fe-S cluster ligands Cys-62, His-83, Cys-88 and Cys-154, and beta-subunit domains, which include potential Fe-S cluster ligands Cys-70, His-90, Cys-95 and Cys-153, are proposed to comprise nearly equivalent P-cluster environments located adjacent to each other in the native protein. As an approach to test this model and to probe the functional properties of the P clusters, amino acid residue substitutions were placed at the alpha-subunit Cys-62, His-83, Cys-88 and Cys-154 positions by site-directed mutagenesis of the Azotobacter vinelandii nifD gene. The diazotrophic growth rates, MoFe-protein acetylene-reduction activities, and whole-cell S = 3/2 electron paramagnetic resonance spectra of these mutants were examined. Results of these experiments show that MoFe-protein alpha-subunit residues, Cys-62 and Cys-154, are probably essential for MoFe-protein activity but that His-83 and Cys-88 residues are not. These results indicate either that His-83 and Cys-88 do not provide essential P-cluster ligands or that a new cluster-ligand arrangement is formed in their absence.

Astemizole, a new histamine H1 receptor antagonist, was tested in a double-blind cross-over comparison study with chlorpheniramine maleate, a very effective conventional H1 antagonist, in patients with chronic allergic rhinitis. Astemizole was found to be equally effective, yet there was a significant decrease in the side effects of sleepiness (P less than .01) and dry mouth (P less than .05). Astemizole has a completely different structure and binding curves from terfenadine. It is approved for clinical use in the United Kingdom, Canada, and many European countries.

Models for the analysis of longitudinal data must recognize the relationship between serial observations on the same unit. Multivariate models with general covariance structure are often difficult to apply to highly unbalanced data, whereas two-stage random-effects models can be used easily. In two-stage models, the probability distributions for the response vectors of different individuals belong to a single family, but some random-effects parameters vary across individuals, with a distribution specified at the second stage. A general family of models is discussed, which includes both growth models and repeated-measures models as special cases. A unified approach to fitting these models, based on a combination of empirical Bayes and maximum likelihood estimation of model parameters and using the EM algorithm, is discussed. Two examples are taken from a current epidemiological study of the health effects of air pollution.

Considerable controversy exists about the relative risk of thyroid cancer following exposure to external radiation compared to the risk after exposure to internally deposited 131I. The human epidemiological data are equivocal, and studies are not directly comparable owing to differing ages at exposure, dose ranges, and periods of follow-up. Limited experimental data at low dose ranges support the hypothesis of equal potency in animals. This report utilizes a relative potency model to reconcile data from different sources, and to provide an estimate of thyroid cancer risk following human exposure to 131I. We utilize data from epidemiological studies of external radiation and 131I exposure in humans and data from an experimental animal study. This analysis shows that the data provide no compelling evidence to suggest that the risks accompanying external radiation or 131I exposure are different.

A model for analysing longitudinal growth data with covariates is proposed. It assumes that the data for each individual follow a nonlinear growth model, with parameters unique to that individual. The parameters of individuals are assumed to vary in the population, with the population mean of each parameter dependent upon covariates. Several simple, two-stage methods of estimation are described and compared for making inferences about the effects of covariates upon growth. We also present a method of model validation for nonlinear models. These two-stage methods solve the inference problem we encounter when performing multiple cross-sectional analyses of the effects of covariates along the age scale. In addition, these two-stage methods permit us to study the effects of covariates upon growth rate, or other, possibly nonlinear, growth parameters. We find that some methods are better than others at reproducing the covariate effects observed in a series of age-specific analyses of the data.

A 5.7-year prospective study of 1380 patients treated for psoriasis with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA) revealed that after adjustment for exposures to ionizing radiation and topical tar preparations, the risk that cutaneous squamous-cell carcinoma would develop at least 22 months after the first exposure to PUVA was 12.8 times higher in patients exposed to a high dose than in those exposed to a low dose (95 per cent confidence interval, 5.8 to 28.5). No substantial dose-related increase was noted for basal-cell carcinoma. The dose-dependent risk of cutaneous squamous-cell carcinoma suggests that PUVA can act as an independent carcinogen. In our study, morbidity associated with these tumors has been limited, but further follow-up is needed. Meanwhile, patients treated with PUVA should be followed closely for the possible development of cutaneous squamous-cell carcinoma.

This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.

The electronystagmographic findings for 116 patients with unilateral idiopathic sudden hearing loss (ISHL) were analyzed. For the purpose of the study, three groups were formed: patients with normal electronystagmographic (ENG) findings; patients with mild to moderate vestibular injuries consisting of spontaneous horizontal nystagmus or directional preponderance; and patients with severe vestibular injuries indicated by reduced vestibular responses, including paresis of the semicircular canal or lack of response to caloric testing. Clinical and audiologic findings were compared. High correlations were found between both subjective vertigo and abnormal ENG findings and the presence of profound hearing loss at the onset of ISHL. There was an inverse relationship between recovery from ISHL and the ENG findings, namely, as the severity of the vestibular injury increased, the percentage of patients who achieved recovery decreased. Patients with abnormal ENGs had a greater mean hearing loss at onset of ISHL and less mean recovery of hearing than did patients who had normal ENG findings. In addition, patients who had abnormal ENG findings recovered less fully from hearing loss in the high frequencies than from those in the low frequencies owing to the proximity of the basilar turn of the cochlea to the vestibular sense organ.

Although lidocaine prophylaxis reduces the incidence of ventricular fibrillation during acute myocardial infarction (AMI), randomized control trials (RCTs) have not demonstrated any significant mortality effect of this therapy. We conducted a meta-analysis of 14 RCTs of lidocaine prophylaxis during AMI to detect any mortality effect. Six prehospital- and eight hospital-phase RCTs that randomized totals of 7656 and 1407 patients, respectively, were selected and reviewed in a blinded fashion. Mortality data were evaluated according to therapy type, reporting interval, and patient category. The prehospital-phase RCTs showed no meaningful mortality effect (risk difference, 0.0184; 95% confidence interval, -0.048 to +0.012). The hospital-phase RCTs showed a statistically significant increase in mortality during the treatment period for lidocaine recipients (risk difference, 0.029; 95% confidence interval, +0.004 to +0.055). These results confirm that lidocaine administered to monitored patients during the prehospital phase of AMI will not reduce mortality by a clinically important amount and suggest that lidocaine administered in the hospital phase of monitored, uncomplicated AMI may increase mortality among recipients with proved AMI.

The probability of recovery from idiopathic sudden hearing loss depends on many factors, including patient age, presence of vertigo, audiogram type at diagnosis, and electronystagmographic test results. The authors present a model for calculating the probability of patient recovery based on the combined effects of risk factors determined for these variables. Data collected from 123 patients with "profound" or "moderate" sudden hearing losses are used to illustrate the model. Interrelationships among the prognostic factors and their relative importances in predicting hearing recovery are discussed.

Double-blind studies were conducted for the treatment of idiopathic sudden hearing loss (ISHL) with oral steroids. The condition was defined as not less than a 30-dB loss over three contiguous frequencies in three days or less. Follow-up audiograms were obtained four weeks and three months later. Specific audiologic guidelines for the assessment of hearing recovery were used to ensure objectivity. Steroids had a statistically significant effect on the recovery of hearing in patients with moderate hearing losses. The nature of the hearing loss and its susceptibility to improvement with steroid therapy lend support to the hypothesis that viral cochlitis is the primary cause of ISHL.

When observations are made repeatedly over time on the same experimental units, unbalanced patterns of observations are a common occurrence. This complication makes standard analyses more difficult or inappropriate to implement, means loss of efficiency, and may introduce bias into the results as well. Some possible approaches to dealing with missing data include complete case analyses, univariate analyses with adjustments for variance estimates, two-step analyses, and likelihood based approaches. Likelihood approaches can be further categorized as to whether or not an explicit model is introduced for the non-response mechanism. This paper will review the use of likelihood based analyses for longitudinal data with missing responses, both from the point of view of ease of implementation and appropriateness in view of the non-response mechanism. Models for both measured and dichotomous outcome data will be discussed. The appropriateness of some non-likelihood based analyses is briefly considered.

We compare two statistical methods for combining event rates from several studies. Both methods treat each study as a separate stratum. The Peto-modified Mantel-Haenszel (Peto) method estimates a combined odds ratio assuming homogeneity across strata and provides a test for heterogeneity. The DerSimonian and Laird modified Cochran method (D&L) produces a weighted average of rate differences, where the weights allow for among-study variability. We analyse 22 meta-analyses from ten reports by both methods. The pooled estimates are divided by their standard errors to produce a Z-statistic. A t-test comparing Z-statistics from all 22 studies suggests that the D&L method tends to be more conservative [d(Peto - D&L) = 0.29, t = 2.53, p = 0.02]. For a subset of 14 non-heterogeneous studies, the difference is smaller and non-significant (d = 0.09, t = 0.72, p = 0.49). The results from the methods correlate well (r = 0.66 for all 22 studies, r = 0.95 for 14 non-heterogeneous studies). Thus, the presence of heterogeneity influences our conclusion. We discuss the statistical and scientific implications of these findings.

The relationship between viral seroconversions and idiopathic sudden hearing loss (ISHL) is studied. Compared with our control group, the incidence of viral seroconversions is greater among ISHL patients, both for single and multiple viral infections. There was a significantly greater number of patients with seroconversions to mumps, rubeola, varicella-zoster, cytomegalovirus, and influenza B. We were unable to find a relationship between viral seroconversion and type or degree of hearing loss, vertigo, or chance for recovery. The incidences of viral conversion and sudden hearing loss track one another closely, suggesting that viral infection is a major cause of ISHL. During this 3-year study in Boston, ISHL was most prevalent in the spring.

Azotobacter vinelandii genes contained within the major nif-cluster and designated orf6, nifU, nifS, nifV, orf7, orf8, nifW, nifZ, nifM, and orf9 are organized into at least two overlapping transcriptional units. Nitrogenase derepressed crude extracts of Azotobacter vinelandii mutant strains having individual deletions located within nifU, nifS, nifV, nifW, nifZ, or nifM were examined for nitrogenase component protein activities. The results of these experiments indicated that, in A. vinelandii, the nifU, nifS and nifM gene products are required for the full activation or the catalytic stability of the nitrogenase Fe protein. Deletion of the nifV gene resulted in lower MoFe protein activity, probably resulting from the accumulation of an altered FeMo-cofactor. The nifW and nifZ gene products were required for the full activation or catalytic stability of the MoFe protein. Deletion of nifZ alone or nifM alone did not appear to affect FeMo-cofactor biosynthesis. However, deletion of both nifZ and nifM eleminated either FeMo-cofactor biosynthesis or the insertion of FeMo-cofactor into the apo-MoFe protein. Other genes contained within the nifUSVWZM gene cluster (orf6, orf7, orf8, and orf9) were not required for Mo-dependent diazotrophic growth.

We investigated respiratory mucosa cilia ultrastructure in patients homozygous for the gene for Kartagener's syndrome (KS) and patients apparently phenotypic for KS who had bronchiectasis and sinusitis but without situs inversus. Parents, as obligate carriers of the recessive KS gene, were also evaluated among other control groups. The four patients with KS had significantly fewer cilia outer dynein arms than normal subjects or parents of patients with KS. Two of five patients apparently phenotypic for KS demonstrated distinctive ultrastructural changes. No other subjects demonstrated explicit ultrastructural abnormalities. Internal control specimens showed that the number of outer dynein arms was consistent within a subject compared with variation between subjects. The outer dynein arm serves as a dependable ultrastructural marker. Carriers of KS do not demonstrate distinctive morphologic cilia abnormalities. Not every patient with chronic bronchiectasis and sinusitis demonstrates abnormal cilia ultrastructure.

To evaluate a process for identifying adverse events through review of medical records, multiple reviews of 360 medical records from two teaching hospital were performed. The data from these multiple reviews provided information about the validity and reliability of our two-phase review process. In particular, it was found that the initial phase, involving review of the medical records by medical-record-room administrators using explicit criteria, was valid, with a sensitivity of 84% and negative predictive value of 92%. Results also showed that the second phase, involving judgments by physicians guided by an adverse event analysis form, was reliable (Spearman Brown Rm = 0.78, m = 2) and demonstrated construct validity when compared with a review by a set of senior physicians employing a different method of review (Kappa = 0.57). In addition, it was found that these cases classified as difficult to judge from causation were judged less reliable (Rm = 0.48, for difficult case, Rm = 0.65, for other cases, m = 1). These results indicate that a two-step review process of medical records can produce judgments about adverse events that are both reliable and valid.

The Special Supplemental Food Program for Women, Infants and Children (WIC) provides food supplements and nutrition counseling to pregnant and lactating women and children up to age 5 who are at nutritional risk. The purpose of this study was to determine the effects of the program on the growth of infants. Retrospective longitudinal anthropometric data were obtained on 906 WIC and 1001 non-WIC infants from birth to 18 months of age. A new methodology was developed that addressed two factors in longitudinal studies frequently confounded with program impact: 1) regression to the mean and 2) expected growth. Regression analyses indicated that children who were on WIC between 6 and 18 months of age were growing at greater than expected rates. The most persistent program effect was at 6 months of age, after the children had been on the program for an average of 4 months. The study indicated that data routinely collected by the program can be used for evaluation purposes.

The Ames test is widely used in the screening of chemicals and compounds for potential carcinogenic effect. There is, however, considerable inter-laboratory variability in results from this assay. Using data from the RTI Collaborative Study of the EPA Ames Test Protocol, we show that their reported standard errors of estimates of mutagenicity fall far short of capturing day-to-day or laboratory-to-laboratory variation. We estimate the factors by which the standard errors must be inflated to account for these sources of variation. The laboratory protocol and previous studies suggest that much of this variation may be caused by factors that are relatively constant within days (e.g. technician, incubation temperature, S9 liver homogenate preparation) but vary over days and across laboratories. Therefore, such variation might be reduced through use of a reference compound tested on the same day and under the same conditions as the test chemical. This conjecture was, however, not supported by analyses that considered the positive control compound and a pure chemical as possible reference assays.

This paper presents a general mixed model for the analysis of serial dichotomous responses provided by a panel of study participants. Each subject's serial responses are assumed to arise from a logistic model, but with regression coefficients that vary between subjects. The logistic regression parameters are assumed to be normally distributed in the population. Inference is based upon maximum likelihood estimation of fixed effects and variance components, and empirical Bayes estimation of random effects. Exact solutions are analytically and computationally infeasible, but an approximation based on the mode of the posterior distribution of the random parameters is proposed, and is implemented by means of the EM algorithm. This approximate method is compared with a simpler two-step method proposed by Korn and Whittemore (1979, Biometrics 35, 795-804), using data from a panel study of asthmatics originally described in that paper. One advantage of the estimation strategy described here is the ability to use all of the data, including that from subjects with insufficient data to permit fitting of a separate logistic regression model, as required by the Korn and Whittemore method. However, the new method is computationally intensive.