Specific statistical considerations relevantto the design and analysis of gingivitis trials demonstrating

Simulation studies were conducted to address specific statistical issues which arise in the design and analysis of gingivitis studies whose principal aim is the demonstration of superiority or equivalence of one product to another. The effects of measurement scale, using differences or ratios of group means, particular statistical test produces and specific rules demonstrating superiority or equivalence were investigated. An alternative concept to equivalence—denoted “least as good”—was also defined and evaluated. For a wide class of possible distributions of gingivitis scores, characterized by specific gamma distributions, the student-t test applied to means of subject GI gingivitis scores proved to be the most powerful of the test produces considered, having statistical properties quite similar to the randomization or permutation test procedure. Transformations of subject GI mean gingivitis scores did not produce an advantage in demonstrating either superiority or equivalence, and in some cases made it more difficult. Little difference was observed in test results when using the difference in group means as compared with using the ratio of group means for demonstrating either equivalence or superiority. The clinically significant rule produced the lowest false-positive rates for products slightly better than the active control, and similar false-positive and -negative rates as the statistically significant rule for products clearly superior to the active control. Demonstration of product equivalence will require more subjects per group than demonstrating product superiority, the size of this difference being a function of the definition of superiority that is accepted. Showing that the 90% confidence interval for 100*R is completely contained within the [90%, 110%] interval is the preferred method of demonstrating equivalence today, although much more research needs to be done to improve methods for demonstrating product equivalence. The “least as good” alternative to “equivalence” makes it easier to demonstrate “equivalence” for products slightly better than the active control product, but both experience great difficulty in demonstrating equivalence for lest products not quite as good as the active control.     

Biological and measurement issues critical to design of gingivitis trials

Chronic plaque-induced gingivitis is usually of little consequence, thus the concern about prevention and treatment must stem from the belief that pre-existing gingivitis is necessary for periodontitis to develop. When clinical signs of gingivitis are present, an inflammatory infiltrate can be found upon histological evaluation. When clinical signs are absent, however, significant inflammation may still be present within the gingival tissues. Therefore, multiple clinical evaluations should be made, with special attention given to the visually inaccessible midinterdental area. The "gold standard" for evaluation of gingivitis is histological evaluation and other measurements should be evaluated against this standard. The significance of clinical severity measurements of gingivitis is not well-understood relative to onset of periodontitis; therefore, it is suggested that consideration be given to gingival evaluations based on the presence or absence of clinical signs of inflammation. Furthermore, equivalency and superb ority of antigingivitis agents or devices should be predicated, at least in part, on their ability to prevent the onset of periodontitis.     

Design and analysis of plaque and gingivitis clinical trials

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.     

Variability of gingival bleeding in experimental gingivitis trials

Gingival bleeding is a difficult parameter to assess in experimental trials. The Confirmed Bleeding Day was recently developed as a measurement for this purpose. It was observed that considerable variations existed between the measurements made in a pilot study and an experimental trial, and these variations were subjected to a statistical analysis. The reasons for the variations are discussed, and recommendations made for the design of experimental trials involving gingival bleeding.     

Diagnostic considerations concerning a case of an unusual gingivitis

A young woman presented a severe gingivitis that wouldn't respond to antibiotics prescribed by her general practitioner. Thorough clinical examination showed atypical gingival inflammation. In such unusual cases a careful anamnesis is essential in determining appropriate continued diagnostic procedures. Eventually, acute myeloid leukaemia was diagnosed. Since the diagnosis of gingival disease primarily lies with the dentist, it is important to be able to consider any unusual aspects of gingivitis within a dental office.     

Experimental gingivitis studies: effects of triclosan and triclosan-containing dentifrices on dental plaque and gingivitis in three-week randomized controlled clinical trials

A recently reported six-month gingivitis study demonstrated that in subjects with gingivitis, a triclosan/pyrophosphate dentifrice provided supragingival plaque control. The level of plaque reduction was comparable with that reported for other triclosan-containing dentifrices; however, no reductions in gingivitis were observed for triclosan/pyrophosphate relative to the negative control. One possible explanation of this result is that the Hawthorne effect in the study was too great to allow the detection of a treatment benefit for the triclosan product. In order to further explore the relevance of these results, three independent clinical studies were undertaken utilizing designs based on a 21-day experimental gingivitis model in which Hawthorne effects are minimized, in part due to the absence of toothbrushing. In each model, a pre-study prophylaxis was followed by a three-week period of oral hygiene instruction to establish optimum baseline gingival health in study participants. The studies varied in enrollment; 120, 33 and 32 subjects completed treatment on studies 1, 2, and 3, respectively. In study 1, test articles were dentifrice products (0.28% triclosan/5% pyrophosphate/0.145% sodium fluoride, 0.2% triclosan/0.5% zinc citrate/0.112% sodium fluoride, 0.145% sodium fluoride and 0.15% sodium monofluorophosphate) applied neat and undiluted via a performed tooth shield (that prevents mechanical tooth-brushing at the test sites in the oral cavity) in a partial mouth design. In study 2, test articles were also dentifrice products (0.28% triclosan/5% pyrophosphate/0.243% sodium fluoride, 0.3% triclosan/2% Gantrez copolymer/0.24% sodium fluoride and 0.243% sodium fluoride) but administered to subjects in the form of 1:3 aqueous slurry rinses. Lastly, in study 3, test articles were all mouthrinses (0.12% chlorhexidine, 0.045% triclosan in ethanol plus respective vehicle placebos). Clinical assessments to quantify the test articles' effects on the development of plaque and gingivitis were conducted at baseline (studies 1, 2 and 3), day 7 (studies 2 and 3), day 14 (studies 2 and 3) and day 21 (studies 1, 2 and 3). In study 1, no statistically significant treatment effects were observed between the test articles and controls for plaque or gingivitis development. In study 2, no statistically significant treatment effects were observed at any time point between test products for the development of gingivitis. At days 7 and 14, there were no significant differences between test products and control for plaque development as well. At day 21, the group rinsing with the triclosan/pyrophosphate/sodium fluoride slurry had significantly less plaque accumulation than the group rinsing with the triclosan/copolymer/sodium fluoride slurry (p < 0.05); however, neither of the groups using test products containing triclosan was significantly different for plaque development from the group using the sodium fluoride control test article. In addition, aspartate aminotransferase activity in gingival crevicular fluid was assayed at days 0 and 21; no between-group differences were found at either of these time points, though day 21 AST activities were higher than those at baseline. In study 3, statistically significant treatment differences in plaque regrowth and gingivitis were observed at day 21 for the chlorhexidine rinse versus all other rinses (p < 0.05). No other statistically significant treatment effects were observed between test compounds at any other time points. The results benchmark the anti-plaque and anti-gingivitis benefit for a range of triclosan-based product forms against positive and negative controls in a three different experimental gingivitis models, a design considered predictive of clinical efficacy in longer-term investigations. It is concluded that dentifrice products containing triclosan do not possess sufficient antimicrobial activity to suppress plaque and gingivitis development in the absence of normal oral hygiene, and that relative to chlorhexidine, triclosan itself offers only modest efficacy for the prevention of plaque accumulation and therefore the delayed onset of gingivitis.     

Prosthodontic research design from the standpoint of statistical analysis: learning and knowing the research design

For any kind of research, "Research Design" is the most important. The design is used to structure the research, to show how all of the major parts of the research project. It is necessary for all the researchers to begin the research after planning research design for what is the main theme, what is the background and reference, what kind of data is needed, and what kind of analysis is needed. It seems to be a roundabout route, but, in fact, it will be a shortcut. The research methods must be appropriate to the objectives of the study. Regarding the hypothesis-testing research that is the traditional style of the research, the research design based on statistics is undoubtedly necessary considering that the research basically proves "a hypothesis" with data and statistics theory. On the subject of the clinical trial, which is the clinical version of the hypothesis-testing research, the statistical method must be mentioned in a clinical trial planning. This report describes the basis of the research design for a prosthodontics study.