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Guidelines are suggested for determining efficacy of products to supplement scaling and root planing in professional, non-surgical treatment of adult periodontitis. They result from an extended process including a conference on clinical trials in gingivitis and periodontitis, a subsequent workshop, and commentary from industrial, academic, professional and governmental members of the periodontal research community on two drafts. Recommendations are made in the broad areas of basic study design, subject and periodontal site selection, clinical management, choice of outcome variables, statistical summarization and analysis, and criteria for acceptance. Prominent dissenting views, with justifications for positions taken here, are also provided. Groundwork is laid for possible future guidelines addressing products for primary prevention or over-the-counter uses, or for determining superiority or equivalence of competing products. However, issues are identified which require further exploration before responsible and widely acceptable recommendations can be made in these areas. The guidelines suggested here are meant to form the basis of an evolving document rather than a static standard. It is suggested that they be reviewed frequently in the light of improvement in the technology available for periodontal research, and the emergence of products representing new approaches to periodontal therapy.

This paper presents suggested revisions to the American Dental Association's 1985 guidelines for acceptance of anti-gingivitis chemotherapeutic agents. The areas of study design, choice and quality control of clinical gingivitis measurements, statistical analysis, and minimum strength of effect, are addressed. The revisions articulate certain aspects of study design which were implicit in the 1985 guidelines, clarify language on cross-over designs and independence of studies, and recommend use of a United States population in at least one trial supporting a product. Separate recording and analysis of a product's effect on gingival bleeding is proposed, and quality control of clinical measurements receives enhanced emphasis. Modestly elaborated statistical reporting guidelines and strengthened approval criteria, based on size of estimated effect as well as statistical significance, are advocated.

Aspects of the design and analysis of periodontal clinical trials are surveyed from a biostatistical perspective. Design issues discussed include protocol preparation, subject selection and its documentation, randomization, problems associated with the sample versus population paradigm in sampling of microbes and gingival fluid constituents, quality control, cross-over and split-mouth versus parallel-arm designs, blinding, and multicenter trials. Analytic discussion deals with the definition and choice of analytic unit, appropriate methods for the analysis of data from multiple sites within the same subject, the nature and application of randomization tests, interim analyses, subgroup analyses, and multiple comparison issues. Examples are provided to illustrate the feasibility of analyzing site-specific data while accounting for intra-subject correlation, which represents the increased similarity of sites chosen from the same mouth as compared to sites from different patients. J Periodontol 1992; 63:1124-1140., (© 1992 American Academy of Periodontology.)

Subsequent to the American Dental Association Symposium on Intra-oral Studies, held in Chicago in September, 1990, the Council on Dental Therapeutics decided that further consideration should be given to statistical issues relating to intra-oral models. The authors accepted the request of Council staff to assist in the development of Guidelines concerning the validity, reliability, and combinability of data obtained from these models. The ensuing work in this area, which began in the fall of 1990 and has continued to date, has thus far focused on the tissue of validity. The purpose of the present paper is to provide the interested community at large with an update on the progress made thus far, and to provide some perspective as to where all of the work in this area may eventually be leading. It is anticipated that a more comprehensive and definitive report will be produced at the completion of this process.

Factors affecting inter- and intra-examiner variability for probing pocket depth and periodontal attachment level were studied on a sample of 20 patients, each given six full-month examinations, two by each of 3 examiners. The major determinant of both dimensions of variability was the degree of periodontal destruction, measured as either pocket depth or level of attachment: the greater the degree of destruction, the greater the disagreements within and between examiners. Differences in variability were generally minor between sites on anterior and sites on posterior teeth, between midsites and proximal sites, and between sites on the facial and sites on the lingual surface. When differences were found between the average variances for different kinds of sites, they may have been due to corresponding differences between the average depths, and not to any inherently greater difficulty in measuring one kind of site than another.

Various statistical properties of the plaque index, the gingival index, and the whole-mouth averages of pocket depth and attachment level measurements were examined using data from a 4-year randomized trial of 80 patients with a history of treated periodontal disease. Departures from normality were assessed by the median of the standardized distribution, by the coefficients of skewness and kurtosis, and by the Kolmogorov goodness-of-fit test. The relative precisions of probing pocket depth and of attachment level were measured, as were correlations between repeated measurements over time for the four clinical measures. The distribution of the plaque index was far from normal, but the distribution of its logarithm was more nearly normal. The distributions of the other clinical measures were effectively normal to varying degrees of approximation. With only rare exceptions, correlations between repeated measurements on the same clinical variable remained relatively constant no matter how far apart in time the measurements were made, at least up to 4 years. The whole-mouth mean of the attachment level measurements seemed to be relatively more precise than the whole-mouth mean of the pocket depth measurements.

Sixty-six dental students, randomly assigned to one of three examiners, were scored initially for gingivitis using the Columbia gingival index (GI). After four weekly prophylaxes, gingival scores for all teeth were recorded at day 0. Following prophylaxes, all subjects were randomly assigned one of three mouthwash formulations. Gingival scores were taken on the full mouth after three weeks and again after six weeks. Pearson product moment correlation coefficients (r) were obtained for the gingivitis index from six selected teeth (partial score) with the full mouth score, usually based on 24 to 28 teeth. GI scores obtained from partial recording on the six selected teeth correlated very well with scores obtained from full mouth examinations. A special study was set up to obtain independent GI readings for the six target teeth and for the full mouth. GI scores obtained by independent examinations of the six selected teeth also correlated well with the full mouth scores, although not as well as when the partial scores were derived from the full mouth scores. Partial scores should only be compared with partial scores obtained from evaluating the same teeth and not with full mouth scores, in clinical trials or epidemiologic surveys.

Twenty-four normal healthy patients were scored for plaque by four examiners with different professional backgrounds and different levels of training. Each patient was examined twice by each examiner according to a predetermined random assignment with the assumption of no change in state. All four examiners scored higher on the second examination and there was no apparent consistent relationship between professional background and level of training in the plaque scoring.

Fifty subjects enrolled in a double-blind clinical trial to test the effectiveness of a solution of carbamide peroxide in 10% glycerol upon healing time and pain relief of recurrent aphthous stomatitis. No apparent difference was experienced in either duration of healing or pain relief between the 25 subjects who received the active medication and the 25 subjects who received a placebo.

Data from the Veterans Administration Dental Longitudinal Study of 736 men each examined four times were analyzed to determine how representative the six "Ramfjord Teeth" (RT) were of the rest of the dentition for epidemiologic studies of gingivitis and periodontitis. Correlation coefficients were calculated between scores for gingival inflammation generated by the RT and scores for the teeth in the rest of the mouth; the correlation coefficients between the two scores tended to be high. Sensitivity, specificity and predictive values were calculated for periodontal pathology classified on the basis of the pocket depths of the six RT. Reliance on the RT resulted in systematic underestimation of the prevalence and incidence of deep periodontal pockets. The RT are more than adequately representative of the rest of the dentition for epidemiologic studies of gingivitis, but are inadequate surrogates of the rest of the mouth for epidemiologic studies of periodontitis.

It is most important that the proper design of a clinical trial be developed prior to the start of the study. Such a design is one that will not tend to find a treatment to be effective when it really is ineffective, and will not tend to miss a good treatment when it really is effective. The questions to be answered by a clinical trial must be decided in advance and will help determine the design. Trials should take into consideration how the agent is to be used: carefully controlled, ordinary use, subject or professionally applied, etc. The double-blind parallel randomized trial is preferred to the double blind cross-over design, except possibly for a professionally applied treatment which does not leach into the saliva or affect the oral microflora. Blocking or stratification tends to increase the efficiency of a clinical trial, and also may produce more information on the agent's effectiveness. Stratification is preferred to blocking, particularly when subjects enter the trial serially over time. Subjects should be stratified by age, sex and baseline level of plaque or gingivitis. Stratification permits a check on whether the effect of treatment is atypically strong or weak for certain types of patients. Where possible, the same examiner should examine the same patients throughout the study. Examiners should be self-calibrated to reduce intra-examiner error. Plaque and gingivitis trials should be at least of 6 months duration and may be preventive or therapeutic in nature. The preferred statistical analysis when 2 treatments are being compared is a comparison of mean changes in plaque or gingivitis scores by the independent sample t-test. An analysis of covariance using the baseline scores as the covariate may improve power somewhat. When pairwise t-tests are performed in comparing several treatments, multiple comparison criteria are indicated. Parametric rather than nonparametric tests are preferred since they usually have more power. The square root of whole mouth means in gingivitis clinical trials is the preferred transformation to obtain greater power and to produce approximately normal distributions.

Logistic analysis methodology is being increasingly used in the analysis of categorical data from the biomedical sciences. We describe how the relationships between a dichotomous outcome variable and several qualitative classificatory or experimental variables can be modeled in a format similar to that used for quantitative data. The technique of weighted least squares is used to estimate the underlying parameters in the model and to perform various tests of statistical significance. The methodology is illustrated using data from a randomized dental anaesthetic study comparing three local anaesthetic solutions under two operative procedures. The similarities between the logistic analysis of dichotomous data and the analysis of variance applied to quantitative data are stressed.

Ridit analysis is presented as an appropriate method of analyzing dental clinical data which fall somewhere between the purely categorical (e.g., improved vs. not improved) and the bona fide quantitative (e.g., mg % salivary calcium) scales of measurement. The key feature of the method is the estimation of the probability that a randomly-selected patient from one treatment group is "better-off" than a randomly-selected patient from another. Methods are presented for testing statistical significance and constructing confidence intervals. The method is illustrated on data from a comparative clinical trial of ibuprofen, aspirin and placebo in the relief of post-extraction pain. There were no significant differences in efficacy among the active treatments, but each was significantly superior to placebo.

Replicate measurements of probing depth and attachment level were made by three examiners on the six Ramfjord teeth of 34 patients. Within-mouth correlations were high for single measurements, and yet higher for means across replicate measurements. Inter- and intra-examiner variability were both found to be low relative to between-patient variability. Conclusions are that the low within-mouth correlations reported by others may be the result of poor reliability, and that it is inappropriate to take the individual site as the unit of statistical analysis in clinical studies of periodontitis.

Inter- and intra-examiner variability in scoring supragingival plaque using the Turesky modification of the Quigley-Hein method was analyzed for four examiners each examining 24 patients twice. There was no evidence of systematic differences between the dentists and dental hygienists or between the more experienced and less experienced examiners in their mean scores, in the variability of their scores, or in the precision of their scores. The major sources of extraneous variation in the scores were measurement error, inter-examiner variation (not accounted for by professional training or experience), and a failure of examiners to apply their scoring criteria uniformly to all patients.

116 subjects were recruited from a population of patients previously treated for adult periodontitis and maintained in periodontal health by means of periodic prophylaxes every 3-6 months. The subjects were divided into a control (C) and a test (T) group. A total of 33 patients in the T group and 47 in the C group completed the 4-year study. The C subjects were examined every 6 months and given a prophylaxis every 3 months. The patients in the T group were examined at similar intervals, but prophylaxes were administered according to the individualized scheme of Listgarten and Shiffter, on the basis of a differential microscopic count of subgingival bacterial morphotypes. Recurrent periodontitis was defined as an increase in probing depth of 3 mm or more from baseline measurements. Teeth so affected were sampled microbiologically when the diagnosis of recurrent disease was made and "exited" from the study for treatment. A control microbial sample was taken at the same time from a previously-defined pooled sample of non-affected surfaces with comparatively high, but stable probing depths. During a 4-year period, more than half of the subjects developed at least one recurrence of disease, and one-third of the subjects had 2 or more recurrences of periodontitis. Disease recurred on approximal surfaces 81% and on orovestibular surfaces 19% of the time. There were no significant differences in the rate of disease recurrence between the C and the T group, even though recall intervals in the T group at the 4-year examination averaged 19.4 months and an average of 30.6 months had elapsed since the previous prophylaxis. Both groups exhibited similar plaque index and gingival index scores, similar probing depth and attachment level measurements, and similar proportions of different bacterial morphotypes during the 4-year study. However, differences were noted between examinations for both groups with respect to most of these criteria. This study provides 4-year longitudinal data on the clinical and certain microbiological characteristics of a population of adult patients previously treated for moderate to advanced periodontitis, and subsequently placed on periodontal maintenance. The results indicate that some of these patients may remain in good periodontal health despite the lack of regular tri-monthly recall visits, and that microscopic monitoring of the subgingival microbiota may be of value in identifying these individuals.(ABSTRACT TRUNCATED AT 400 WORDS)

Using a data set from the Forsyth Dental Center consisting of repeated measurements of periodontal attachment level on 22 patients over 1 year, we performed correlation analyses at 4 time points (baseline, 1 month, 6 months and 9 months) for 3 units of measurement (sites, teeth and quadrants). Values of the intraclass correlation coefficient were obtained for the cross-sectional measurements and for changes from baseline. The values were positive and often of appreciable magnitude, indicating that measurements of attachment level and of change in attachment level within the same mouth are positively correlated. Taking sites rather than patients as the units of statistical analysis in comparative clinical trials in periodontology will therefore tend to produce underestimated standard errors and overstated statistical significance.

A statistical model is given for representing the several components of variability present in measurements (e.g., DMFS scores) given by examiners to patients. Methods for making inferences about the intraclass correlation coefficient of reliability are presented and illustrated on a real set of data. The proper analysis of data from a reliability study is shown to depend on the planned design and analysis of the clinical or field trial to be conducted following the reliability trial.

An index (PMGI) that combines the Massler-Schour (PMA) and Löe-Silness (GI) indices for non-invasive scoring of gingivitis was applied in 2 independent comparative clinical studies. 4 statistical transformations of the scores of individual papillary and marginal units were analyzed: the whole-mouth mean, its square root, the proportion of units judged to be inflamed, and its arc sin transformation. According to the criteria of how closely the transformations produced approximately normal distributions, and of how successful they were in detecting treatment differences, the square root transformation performed the best.