Cemental tear: An overlooked finding associated with rapid periodontal destruction. A case series.

Cemental tear is defined as cementum fragment completely or partially detached from the root surface, and it has been associated with localized rapid periodontal breakdown. Although history of trauma and/or attrition may be risk factors, the etiopathology of cemental tear remains unknown. This case series aims to discuss the clinical, radiographic and histopathologic features of cemental tears to aid clinicians in making differential diagnosis. Three teeth from three patients presenting a periradicular lesion underwent an exploratory surgery to determine the cause and provide treatment. Soft and hard tissue biopsies were obtained from each lesion and forwarded for histopathologic evaluation. Two patients received a guided tissue regeneration (GTR) procedure, which allowed the tooth to be retained. One patient received an extraction with simultaneous guided bone regeneration (GBR) due to a hopeless prognosis of the tooth. The results after histopathologic evaluation yielded a final diagnosis of cemental tear for all three patients. Cemental tears may be overlooked, and therefore, they should be included in the differential diagnosis of periapical periodontitis, endodontic-periodontal lesion and vertical root fracture (VRF).

Statistical considerations for noninferiority/equivalence trials in vaccine development.

Noninferioritylequivalence designs are often used in vaccine clinical trials. The goal of these designs is to demonstrate that a new vaccine, or new formulation or regimen of an existing vaccine, is similar in terms of effectiveness to the existing vaccine, while offering such advantages as easier manufacturing, easier administration, lower cost, or improved safety profile. These noninferioritylequivalence designs are particularly useful in four common types of immunogenicity trials: vaccine bridging trials, combination vaccine trials, vaccine concomitant use trials, and vaccine consistency lot trials. In this paper, we give an overview of the key statistical issues and recent developments for noninferioritylequivalence vaccine trials. Specifically, we cover the following topics: (i) selection of study endpoints; (ii) formulation of the null and alternative hypotheses; (iii) determination of the noninferioritylequivalence margin; (iv) selection of efficient statistical methods for the statistical analysis of noninferioritylequivalence vaccine trials, with particular emphasis on adjustment for stratification factors and missing pre-or post-vaccination data; and (v) the calculation of sample size and power.

Childhood vaccination against varicella: persistence of antibody, duration of protection, and vaccine efficacy.

OBJECTIVE: To document the duration of protection afforded by Oka/Merck varicella vaccine over a 7-year period. STUDY DESIGN: The subjects were healthy children 1 to 12 years of age originally enrolled in clinical studies to evaluate the primary immune response to varicella vaccine 6 weeks after vaccination. Each was monitored for antibody persistence, breakthrough infection, and household exposure to varicella to produce estimates of vaccine efficacy. RESULTS: The 6-year cumulative varicella antibody persistence rate was 99.5% (95% CI: 98.9%, 100.0%). The annual breakthrough rate through 7 years ranged from 0.2% to 2.3% per year; the estimated cumulative event rate was 6.5%. Comparison of the observed average annual breakthrough rate with the age-adjusted expected annual incidence rate of varicella in unvaccinated children corresponded to an estimated vaccine efficacy of 93.8% to 94.6%. Eighty vaccinated children were exposed to varicella in the household, resulting in 8 (10%) cases of infection. When compared with the historical attack rate of 86.8% in unvaccinated susceptible persons exposed to varicella in the household, this yields an estimated vaccine efficacy of 88.5% (95% CI: 80.9%, 96.1%). Varicella cases in vaccinated children generally were mild. CONCLUSION: The live attenuated varicella vaccine is highly effective in inducing persistent immunity and long-term protection against breakthrough varicella infection.

Non-parametric estimates of overlap.

Kernel densities provide accurate non-parametric estimates of the overlapping coefficient or the proportion of similar responses (PSR) in two populations. Non-parametric estimates avoid strong assumptions on the shape of the populations, such as normality or equal variance, and possess sampling variation approaching that of parametric estimates. We obtain accurate standard error estimates by bootstrap resampling. We illustrate the practical use of these methods in two examples and use simulations to explore the properties of the estimators under various sampling situations.

Use of an angular transformation for ratio estimation in cost-effectiveness analysis.

Economic evaluations of medical technologies involve a consideration of both costs and clinical benefits, and an increasing number of clinical studies include a specific objective of assessing cost-effectiveness. These studies measure the trade-off between costs and benefits using the cost-effectiveness ratio (CE ratio), which is defined as the net incremental cost per unit of benefit provided by the candidate therapy. In this paper we review the statistical methods which have been proposed for estimating 95 per cent confidence intervals for cost-effectiveness ratios. We show that the use of an angular transformation of the standardized ratio stabilizes the variance of the estimated CE ratio, and provides a clearer interpretation of study results. An estimate of the 95 per cent confidence interval for the CE ratio in the transformed scale is easily made using the jack-knife or bootstrap. The available methods are compared using data from a long term study of mortality in patients with congestive heart failure.

Efficacy estimates from parasite count data that include zero counts.

Because of the positive skewness of parasite distributions and the greater constancy of percentage of response of therapy in animal populations, parasite count data are conventionally transformed logarithmically before combining results from different animals, either all controls or all treated. Observations of zero counts raise difficulties, since the logarithm of zero is not useful. In this study, several types of zero count adjustments are compared. Two systems for assigning values to zero counts were considered: a fixed system, which assigns the same value to all zero counts regardless of the proportion of such counts in a treatment group, and a variable system, which replaces zero counts with a value based on the proportion of zero counts in the group. The values assigned by either system are then adjusted to reflect aliquot size. An evaluation was performed by using 32 compound Poisson lognormal distributions, three sample sizes, and three representatives of each zero count adjustment system. The Poisson lognormal distribution provides a convenient method with which to provide variability greater than Poisson. Expected values of the sample estimate of the (known) population mean were calculated for each of the 576 combinations of these factors, and the bias associated with each combination was derived. The bias associated with the three representatives of the variable adjustment system was similar. The variable adjustment system had a lower overall bias than any representatives of the fixed adjustment system.

A regression-based method for estimating mean treatment cost in the presence of right-censoring.

In many clinical trials and evaluations using medical care administrative databases it is of interest to estimate not only the survival time of a given treatment modality but also the total associated cost. The most widely used estimator for data subject to censoring is the Kaplan-Meier (KM) or product-limit (PL) estimator. The optimality properties of this estimator applied to time-to-event data (consistency, etc.) under the assumptions of random censorship have been established. However, whenever the relationship between cost and survival time includes an error term to account for random differences among patients' costs, the dependency between cumulative treatment cost at the time of censoring and at the survival time results in KM giving biased estimates. A similar phenomenon has previously been noted in the context of estimating quality-adjusted survival time. We propose an estimator for mean cost which exploits the underlying relationship between total treatment cost and survival time. The proposed method utilizes either parametric or nonparametric regression to estimate this relationship and is consistent when this relationship is consistently estimated. We then present simulation results which illustrate the gain in finite-sample efficiency when compared with another recently proposed estimator. The methods are then applied to the estimation of mean cost for two studies where right-censoring was present. The first is the heart failure clinical trial Studies of Left Ventricular Dysfunction (SOLVD). The second is a Health Maintenance Organization (HMO) database study of the cost of ulcer treatment.

Development and evaluation of a standardized questionnaire for identifying adverse events in vaccine clinical trials.

In vaccine trials, diary questionnaires or vaccination report cards (VRCs) are used extensively to collect complaints reported by subjects or guardians following vaccination. These have not been evaluated for accuracy or standardized to facilitate tolerability comparisons among vaccines.Objectives -(1) Develop standardized, age-specific VRCs for collecting self-reported adverse events (AEs) in trials; (2) Evaluate whether complaints elicited by nurse examinations or telephone interviews were missed by VRCs.Methods -Vaccine-trial databases, focus groups, experts and experienced nurses were used to develop paediatric and adolescent/adult VRCs. VRCs were evaluated at four sites. The primary outcome was subjects with AEs missed on the VRC and reported in nurse examinations (for injection-site reactions) or telephone interviews (for systemic complaints).Results -Of 855 subjects, 96.5% completed VRCs. For systemic complaints, 1.5% (12/812) reported both no complaint on VRCs and at least one complaint in telephone interviews. For injection-site reactions, 5.1% (53/1030) of injection sites had both no reaction reported on VRCs and had reactions noted by nurse examination. No missed AEs were rated as severe.Conclusion -The data suggest VRCs provide a practical and reasonably complete method of eliciting complaints following vaccination. Copyright (c) 2000 John Wiley & Sons, Ltd.

Cholesterol reduction yields clinical benefit: impact of statin trials.

BACKGROUND: We determined the effect of incorporating the results of eight recently published trials of Hmg CoA reductase inhibitors ("statins") on the conclusions from our previously published meta-analysis regarding the clinical benefit of cholesterol lowering. METHODS AND RESULTS: We used the same analytic approach as in our previous investigation, separating the specific effects of cholesterol lowering from the effects attributable to the different types of intervention studied. The reductions in coronary heart disease (CHD) and total mortality risk observed for the statins fell near the predictions from our earlier meta-analysis. Including the statin trial findings into the calculations led to a prediction that for every 10 percentage points of cholesterol lowering, CHD mortality risk would be reduced by 15% (P<.001), and total mortality risk would be reduced by 11% (P<.001), as opposed to the values of 13% and 10%, respectively, reported previously. Cholesterol lowering in general and by the statins in particular does not increase non-CHD mortality risk. CONCLUSIONS: Adding the results from the statin trials confirmed our original conclusion that lowering cholesterol is clinically beneficial. The relationships (slope) between cholesterol lowering and reduction in CHD and total mortality risk became stronger, and the standard error of the estimated slopes decreased by about half. Use of statins does not increase non-CHD mortality risk. The effect of the statins on CHD and total mortality risk can be explained by their lipid-lowering ability and appears to be directly proportional to the degree to which they lower lipids.

Cholesterol-reduction intervention study (CRIS): a randomized trial to assess effectiveness and costs in clinical practice.

BACKGROUND: The 1988 US National Cholesterol Education Program Expert Panel Report recommended initial treatment with niacin or bile acid sequestrants, followed by other agents if needed, to lower low-density lipoprotein cholesterol (LDL-C) levels in hypercholesterolemic patients who require drug therapy. It is unknown how the effectiveness and costs of such an approach ("stepped care") compare in typical clinical practice to those of initial therapy with lovastatin. PATIENTS AND METHODS: We randomly assigned 612 patients, aged 20 to 70 years, who met 1988 National Cholesterol Education Program guidelines for drug treatment of elevated LDL-C level and had not previously used cholesterol-lowering medication, to either a stepped-care regimen or initial therapy with lovastatin (both n=306). The study, conducted at Southern California Kaiser Permanente, was designed to approximate typical practice: provider compliance with treatment plans was encouraged but not enforced, and patients paid for medication as they customarily would. RESULTS: At 1 year, the decline in mean LDL-C level was significantly greater among patients assigned to initial treatment with lovastatin (22% vs 15% for stepped care; P<.001), as was the number who attained goal LDL-C level (

Cholesterol reduction yields clinical benefit. A new look at old data.

BACKGROUND: There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years' duration (n = 35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention. METHODS AND RESULTS: The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (P < .002) and total mortality by 10% (P < .03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (P < .01) and total mortality by about 17% (P < .02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (P < .04), non-CHD mortality by about 55% (P < .03), and total mortality by about 33% (P < .01). No specific effects independent of cholesterol lowering were found due to diet (n = 11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1). CONCLUSIONS: The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.

Reduction in burden of illness: a new efficacy measure for prevention trials.

A new efficacy measure is developed for use in prevention trials of interventions which may affect both disease incidence and disease severity. We assign a severity score to each incident case and sum severity scores over all incident cases within each treatment group to create a burden-of-illness score for each treatment group. Efficacy is evaluated by the difference between the burden-of-illness per randomized subject in the two randomized treatment groups. Since the numbers of summands in each burden-of-illness score is a random variable, standard methods of analysis are not directly applicable. The asymptotic distribution and sampling properties of the net reduction in the burden-of-illness score are derived for trials designed to stop either after a fixed length of follow-up or after the occurrence of a fixed number of cases. We illustrate the method with data from a clinical trial of a human rotavirus vaccine.

Effect of finasteride on serum PSA concentration in men with benign prostatic hyperplasia. Results from the North American phase III clinical trial.

Finasteride, a 5-alpha reductase inhibitor recently introduced for the treatment of symptomatic benign prostatic hyperplasia, reduces prostate size and decreases serum PSA concentration. To interpret PSA in men treated with finasteride, it is necessary to take the reduction into account. This article describes the effect of finasteride on the serum PSA concentration in the North American Phase III clinical trial and discusses implications of these findings for the interpretation of serum PSA in men treated with finasteride.

Time-dependent variability in repeated measurements of cholesterol levels: clinical implications for risk misclassification and intervention monitoring.

Intraindividual variability (IIV) in total cholesterol levels based on measurements taken 1 week apart is compared with an estimate based on measurements taken 2 years apart. Single-subject 95% confidence intervals around the mean of two repeated measurements were Xi +/- 21 and +/- 28 mg/dl, respectively, and Xi +/- 30 and +/- 40 mg/dl for a single measurement. Comparing these results with published estimates over varying time intervals shows a trend of decreasing IIV with shorter intervals, suggesting that confidence interval widths based on short-term repeated measurements and those based on longer-term repeated measurements may differ more than previously assumed. The practical consequences are that: (1) the level of misclassification inherent in the National Cholesterol Education Program (NCEP) guidelines may be less than had been estimated; and (2) reliable cholesterol reductions resulting from dietary or other interventions may be somewhat easier to detect. These findings have implications for the cost-effectiveness of cholesterol screening strategies and interventions to reduce cholesterol.

Selection of end points in economic evaluations of coronary-heart-disease interventions.

Economic evaluations of interventions to lower blood pressure or cholesterol have used different outcome measures, or end points, in the denominator. Some have related the costs of interventions to improvements in physiologic end points such as mm Hg reduction in blood pressure. Some have related costs to avoidance of coronary heart disease (CHD) events or gains in life expectancy. Others have measured improvements in outcome in quality-adjusted life years (QALYs) gained. The different end points imply different analytic perspectives and different data requirements. The more ambitious analyses, though potentially more relevant in certain situations, require more controversial assumptions to be made. This paper illustrates the trade-offs of relevance, accuracy, and precision by reference to an evaluation of drug therapy for hypercholesterolemia undertaken in the United Kingdom. Estimates are given of cost per percentage cholesterol reduction, cost per CHD event avoided, cost per CHD-free year gained, cost per life year gained, and cost per quality-adjusted life year gained. In each case the assumptions required and the potential relevance of the estimate are discussed. The main findings are that: 1) some end points cannot be discounted to present values in a meaningful way and hence the timing of costs and outcomes cannot be reflected in the analysis; 2) the incorporation of quality-of-life adjustments for years on drug therapy and years post-CHD events greatly changes the cost-effectiveness ratios; 3) the rate of discount changes the pretreatment level of cholesterol for which cost per life year gained is equivalent to cost per quality-adjusted life year gained.(ABSTRACT TRUNCATED AT 250 WORDS)

Application of the tukey trend test procedure to assess developmental and reproductive toxicity. I. Measurement data.

Developmental and reproductive (DAR) toxicity studies typically include a series of increasing doses of a compound and a zero dose control. Given this framework, Tukey et al. (Biometrics, 41, 295-301, 1985) proposed a procedure (referred to as either the Tukey trend or TCH test procedure) for detecting a nonzero trend in response to increasing doses of the test compound. The procedure considers three candidate dosage scalings to ensure high power against relatively common dose-response patterns and appreciable power against most reasonable patterns. For toxicologic effects with near monotonic dose-response patterns, simulation studies have shown the TCH test to be overall more powerful than pairwise comparison procedures. The TCH test can be applied sequentially, eliminating the highest dose each time a statistically significant trend is observed, until a no-statistical-significance-of-trend dose is reached. This is the highest dose through which there is no statistically trustworthy evidence of the compound's impact on the response. Since DAR toxicity usually exhibits a progressive (monotonic) dose-response, we advocate routine use of Tukey's trend test for the evaluation of treatment effects in these studies. In this article, we discuss the procedure in detail and apply it to fetal body weight, a continuous measurement variable, from a developmental toxicity study.

Tests for qualitative treatment-by-centre interaction using a 'pushback' procedure.

In multicentre clinical trials using a common protocol, the centres are usually regarded as being a fixed factor, thus allowing any treatment-by-centre interaction to be omitted from the error term for the effect of treatment. However, we feel it necessary to use the treatment-by-centre interaction as the error term if there is substantial evidence that the interaction with centres is qualitative instead of quantitative. To make allowance for the estimated uncertainties of the centre means, we propose choosing a reference value (for example, the median of the ordered array of centre means) and converting the individual centre results into standardized deviations from the reference value. The deviations are then reordered, and the results 'pushed back' by amounts appropriate for the corresponding order statistics in a sample from the relevant distribution. The pushed-back standardized deviations are then restored to the original scale. The appearance of opposite signs among the destandardized values for the various centres is then taken as 'substantial evidence' of qualitative interaction. Procedures are presented using, in any combination: (i) Gaussian, or Student's t-distribution; (ii) order-statistic medians or outward 90 per cent points of the corresponding order statistic distributions; (iii) pooling or grouping and pooling the internally estimated standard deviations of the centre means. The use of the least conservative combination--Student's t, outward 90 per cent points, grouping and pooling--is recommended.