Randomized controlled trials: what are they and who needs them?

Dentistry is rapidly entering a new era of evidence-based practice, and society is demanding prevention and treatment that has been proven to be effective in terms of meaningful health outcomes. Practitioners, individual patients and the public need randomized controlled trials because they provide the highest level of scientific evidence to change clinical practice and inform public health policy. Well-designed randomized controlled trials are conceptually simple but deceptively complex to design, implement and translate into clinical practice. Randomized controlled trials are fundamentally different from observational clinical research because they randomly assign volunteers to receive test or control interventions, they are prospective and the success of the test intervention is based on a meaningful clinical outcome that is specified before the trial begins. To be successful, randomized controlled trials must be carefully designed and powered to answer a specific question that will be generalizable to the population under study. Randomized controlled trials can be designed to evaluate efficacy, effectiveness, superiority, equivalence or noninferiority. Prominent issues and challenges in designing and conducting randomized controlled trials include carefully defining enrollment criteria, establishing an organizational infrastructure, use of a data-coordinating center, developing a manual of procedures, obtaining informed consent, recruiting and ensuring the safety of volunteer subjects, ensuring data quality, analysis and publication of trial outcomes, and translating results into clinical practice.

Effect of partial recording protocols on severity estimates of periodontal disease.

OBJECTIVES: The study aim was to assess bias magnitudes of periodontal disease severity estimates for specific partial recording protocols (PRPs) in epidemiological studies. MATERIAL AND METHODS: Estimates of mean clinical attachment loss (MCAL) and mean probing pocket depth (MPPD) were derived for 20 different PRPs using full-mouth periodontal data from 1437 dentate Brazilian subjects 14-103 years old having at least four teeth. Biases, relative biases and intra-class correlations for all PRPs were evaluated. Graphical methods were used to assess how well the PRP-based estimates agreed with full-mouth scores across levels of disease. RESULTS: Slightly higher levels of disease were evidenced on lingual than on buccal sites. Seven multi-site PRPs and the Ramfjörd PRP produced small biases in MPPD (-0.17 to 0.04 mm) and MCAL with relative biases under 8% and 4% in absolute value for MPPD and MCAL, respectively. Biases for full- and random half-mouth-based PRPs were similar. The three-site random half-mouth MB-B-DL and the Ramfjörd PRPs produced the smallest biases, with relative biases <3% in absolute value for MPPD and MCAL. CONCLUSIONS: Bias for MPPD or MCAL estimates varies by site type, number of sites per tooth and number of quadrants included in the PRP.

Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HCT) is frequently complicated by severe infections and graft-vs-host disease (GVHD). Saliva contains many components of adaptive and innate immune response crucial for local host defenses. Changes in salivary constituents could reflect systemic processes such as immune reconstitution and development of GVHD that occur posttransplant. This study was an initial evaluation of salivary protein changes that occur after allo-HCT. PATIENTS AND METHODS: Serially collected saliva samples from 41 patients undergoing allo-HCT were evaluated. Changes in salivary proteome were initially examined by SELDI-TOF mass spectrometry. Individual protein changes were identified by 2-dimensional differential in-gel electrophoresis (2D-DIGE) with subsequent MS/MS sequencing and ELISA. RESULTS: Significant increases and decreases in multiple salivary proteins that lasted at least 2 months posttransplant were detected by SELDI-TOF mass spectrometry. Lactoferrin and secretory leukocyte protease inhibitor demonstrated elevations 1 month post-HCT that persisted at least 6 months. Secretory IgA (sIgA) levels were decreased 1 month posttransplant, with recovery at approximately 6 months. Levels of salivary beta(2)-microglobulin were elevated at 6 months and correlated with sIgA levels. CONCLUSION: Allo-HCT is associated with long-term changes in several salivary proteins important for innate immune responses. These results support further studies on the association of salivary proteins with posttransplant complications including infections and GVHD.

Amalgam exposure and neurological function.

Concerns regarding the safety of silver-mercury amalgam fillings continue to be raised in the absence of any direct evidence of harm. The widespread population exposure to amalgam mandated that a thorough investigation be conducted of its potential effects on the nervous system. The National Institute of Dental and Craniofacial Research and U.S. Air Force investigators collaborated in the ongoing Air Force Health Study (AFHS) of Vietnam era veterans. The primary study question involved adverse health effects associated with exposure to herbicides or dioxin. An assessment of exposure to dental amalgam fillings was added to the 1997-1998 health examination to investigate possible associations between amalgam exposure and neurological abnormalities. Our study population consisted of 1663 dentate AFHS participants, comprised of 986 AFHS controls and 677 Ranch Hand veterans who were exposed to dioxin in Vietnam. Two hundred and fifty-two of the participants had confirmed diabetes mellitus. Study outcomes included clinical neurological signs, vibrotactile thresholds, and summary variables for different levels of peripheral neuropathy. A limitation of our study is that our database did not include more sensitive continuous measures such as nerve conduction studies. No significant associations were found between amalgam exposure and clinical neurological signs of abnormal tremor, coordination, station or gait, strength, sensation, or muscle stretch reflexes or for any level of peripheral neuropathy among our study participants. A statistically significant association was detected between amalgam exposure and the continuous vibrotactile sensation response for the combined non-diabetic participants and separately for non-diabetic AFHS controls. No significant association in this measure was detectable for non-diabetic Ranch Hand veterans or among the combined diabetic participants. The association is a sub-clinical finding that was not associated with symptoms, clinically evident signs of neuropathy, or any functional impairment. Overall, we found no association between amalgam exposure and neurological signs or clinically evident peripheral neuropathy. Our findings do not support the hypothesis that exposure to amalgam produces adverse, clinically evident neurological effects.

Effect of partial recording protocols on estimates of prevalence of periodontal disease.

BACKGROUND: The aim of this study was to assess the degree of underreporting in the estimates of prevalence of periodontal attachment loss due to different partial recording protocols (PRP) in epidemiological studies, and to derive a correction factor to adjust for this bias. METHODS: The study sample included 1,460 dentate persons 14 to 103 years old who were examined clinically to assess the clinical attachment loss at six sites per tooth. Seven PRP based on full-mouth or half-mouth designs were assessed, and the bias and sensitivity in the assessment of attachment loss prevalence for these protocols were assessed. RESULTS: All partial protocols underestimated the prevalence of attachment loss. Bias estimates for any full-mouth PRP were smaller than those for the corresponding site-combination PRP for the half-mouth design. The PRP using the mesio-buccal (MB), mid-buccal (B), and disto-lingual (DL) sites of teeth in all four quadrants showed the smallest bias and highest sensitivity of prevalence estimates among the seven PRP evaluated, uniformly across the range of attachment loss severity level. The three site PRP incorporating the DL site produced less bias than the three site PRP including the disto-buccal (DB) site. There was a 3% to 12% gain in sensitivity for 2 to 5 mm attachment loss thresholds for the three site half-mouth PRP compared with the two site MB, B half-mouth PRP. CONCLUSIONS: The bias in the assessment of attachment loss is influenced by the partial recording design and the type and number of sites assessed, and is also influenced by the severity of attachment loss in the study population. These factors should be considered when selecting a partial recording method in large surveys. Furthermore, inflation factors designed to adjust for the bias due to the use of partial systems should be calculated and reported so that comparisons of results with other surveys are more meaningful.

Trends in income-related inequality in untreated caries among children in the United States: findings from NHANES I, NHANES III, and NHANES 1999-2004.

OBJECTIVE: The goal of this analysis was to describe income-related inequality in untreated caries among children in the United States over time. METHODS: The analysis focuses on children ages 2-12 years in three nationally representative U.S. surveys: the National Health and Nutrition Examination Survey (NHANES) 1971-1974, NHANES 1988-1994, and NHANES 1999-2004. The outcome of interest is untreated dental caries. Various methods are employed to measure absolute and relative inequality within each survey such as pair-wise comparisons, measures of association (odds ratios), and three summary measures of overall inequality: the slope index of inequality, the relative index of inequality, and the concentration index. Inequality trends are then assessed by comparing these estimates across the three surveys. RESULTS: Inequality was present in each of the three surveys analyzed. Whether measured on an absolute or relative scale, untreated caries disproportionately affected those with lower income. Trend analysis shows that, despite population-wide reductions in untreated caries between NHANES I and NHANES III, overall absolute inequality slightly increased, while overall relative inequality significantly increased. Between NHANES III and NHANES 1999-2004, both absolute and relative inequality tended to decrease; however, these changes were not statistically significant. CONCLUSIONS: Socioeconomic inequality in oral health is an important measure of progress in overall population health and a key input to inform health policies. This analysis shows the presence of socioeconomic inequality in oral health in the American child population, as well as changes in its magnitude over time. Further research is needed to determine the factors related to these changes and their relative contribution to inequality trends.

Dental characteristics of fibrous dysplasia and McCune-Albright syndrome.

OBJECTIVE: Fibrous dysplasia (FD) is a skeletal disorder often associated with McCune-Albright syndrome, a rare multisystem disorder caused by GNAS1 gene mutation. FD frequently affects the craniofacial bones, including the maxilla and the mandible; nevertheless, its effects on dental tissues and the implications for dental care remain unclear. The aim of this study was to characterize the dental features associated with FD and the reaction of affected bones to routine dental therapy. Study design Thirty-two patients with FD underwent dental evaluation and endocrine testing as part of the diagnosis of FD/McCune-Albright syndrome. Any dental anomalies were recorded, and the associations between endocrinopathies and dental anomalies were analyzed statistically by means of the paired t test. RESULTS: Eighty-four percent had FD in the maxilla and/or mandible; endocrine dysfunction; and/or renal phosphate wasting. The caries index scores were 2.9 (ages 4-17 years) and 9.6 (ages 18-50 years). Malocclusion (81%) and other prevalent dental anomalies (41%) included tooth rotation, oligodontia, and taurodontism. The expansion of the maxilla or mandible by FD did not distort the dental arch curvature, and routine dental therapies such as extractions, restorations, and orthodontic treatment did not exacerbate FD lesions. CONCLUSION: Maxillomandibular FD was associated with higher rates of caries and malocclusion than were present in healthy patients. Furthermore, patients with FD did not require special dental management and were able to undergo routine dental care without an exacerbation of FD lesions.

The role of partial recording protocols in reporting prevalence and severity of dental fluorosis.

OBJECTIVES: To evaluate the role of partial recording protocols (PRPs) in reporting prevalence and severity of dental fluorosis and assess whether prevalence/severity estimates derived from PRPs differ by race/ethnicity. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) for the years 1999-2004 were analyzed with Stata(®) v.11. Prevalence of dental fluorosis obtained from a full-mouth examination (28 teeth gold standard) was compared with estimates derived from four subsets of teeth (maxillary canine-to-canine; maxillary first-premolar-to-first-premolar; all-premolars; all-molars). Sensitivity, negative predictive value (NPV), absolute bias, and correction factors were calculated against gold standard estimate. Analysis was stratified according to race/ethnicity to assess differences in estimates derived from PRPs. RESULTS: All subsets underestimated prevalence albeit to varying degrees. Two subsets (all-premolars and all-molars) had prevalence and severity estimates closest to gold standard estimates. The all-molars subset (eight teeth) recorded the highest sensitivity (84.5%) and the lowest absolute bias (3.5%) of all subsets relative to gold standard. Subsets derived from esthetically relevant teeth produced the lowest fluorosis prevalence. For instance, the maxillary canine-to-canine subset underestimated prevalence by 9.5%; incorporating the maxillary first premolars in the span improved prevalence estimate by 31%. Among non-Hispanic Whites, the all-premolars subset produced estimates closest to gold standard while the all-molars subset produced estimates closest to the gold standard among non-Hispanic Blacks and Hispanics. CONCLUSION: While the majority of dental fluorosis in the United States is very mild, concerns regarding its growing prevalence underscore the need for careful monitoring. The use of PRPs offers an alternative method of assessment, with validity of reported prevalence and severity dependent on choice of subset.

A new approach to reliability assessment of dental caries examinations.

OBJECTIVES: The objective of this study is to evaluate reliability of the International Caries Detection and Assessment System (ICDAS) and identify sources of disagreement among eight Kuwaiti dentists with no prior knowledge of the system. METHODS: A 90-min introductory e-course was introduced followed by an examination of extracted teeth using the ICDAS coding system on the first day. Then three sessions of clinical examinations were performed. This study only used the data from the last session where 705 tooth surfaces of 10 patients were examined to assess bias in caries examination and on which codes the examiners had the highest disagreement. Compared with the gold standard, we evaluated bias of the ICDAS coding using three approaches (Bland-Altman plot, maximum kappa statistic, and Bhapkar's chi-square test). Linear weighted kappa statistics were computed to assess interexaminer reliability. RESULTS: Marginal ICDAS distributions for most examiners were significantly different from that of the gold standard (bias present). The primary source of these marginal differences was misclassifying sound surfaces as noncavitated lesions. Interexaminer reliability of the 3-level ICDAS (codes 0, 1-2, and 3-6) classification ranged between 0.43 and 0.73, indicating evidence of substantial inconsistency between examiners. The primary source of examiner differences was agreeing on diagnosing noncavitated lesions. CONCLUSION: This study highlights the importance of assessing both systematic and random sources of examiner agreement to correctly interpret kappa measures of reliability.

Bisphenol A and other compounds in human saliva and urine associated with the placement of composite restorations.

BACKGROUND: Bisphenol A (BPA) and other related chemical compounds may be components used in the manufacturing process of resin-based composite dental restorative material. The purpose of the authors' study was to assess salivary and urinary concentrations of BPA and other compounds before and after placement of resin-based composite dental restorations. METHODS: The authors collected saliva and urine from 172 participants receiving composite restorations before and as long as 30 hours after placement of composite restorations. The authors analyzed saliva specimens from 151 participants and urine specimens from 171 participants for concentrations of BPA and five related compounds by using liquid chromatography/mass spectrometry (LC/MS). RESULTS: Salivary concentrations of BPA and some related compounds increased immediately (within one hour) after composite placement. Salivary concentrations of BPA and most study compounds returned to prerestoration levels within eight hours after composite placement. With the exception of a 43 percent increase in BPA, concentrations of the study compounds in urine returned to prerestoration levels nine to 30 hours after restoration placement. Concentrations in saliva were lower when a rubber dam was used; however, rubber dam use appeared to have no effect on urinary concentrations of the measured compounds during the study period. The authors observed similar changes in study compound levels in both saliva and urine between participants who received anterior restorations and those who received posterior restorations. CONCLUSIONS: Placement of resin-based composite restorations was associated with detectable increases in saliva of BPA and other study compounds within one hour after restoration placement and an increased concentration of BPA in urine nine to 30 hours after restoration placement. Rubber dam use did not reduce the absorption of BPA (measured as BPA level in urine) during the study. CLINICAL IMPLICATIONS: Additional studies are needed to address how long BPA levels in urine associated with composite placement remain elevated to aid in better understanding of the clearance rates of BPA and other study compounds.

Evidence-based clinical recommendations on the prescription of dietary fluoride supplements for caries prevention: a report of the American Dental Association Council on Scientific Affairs.

BACKGROUND: This article presents evidence-based clinical recommendations for the prescription of dietary fluoride supplements. The recommendations were developed by an expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs (CSA). The panel addressed the following questions: when and for whom should fluoride supplements be prescribed, and what should be the recommended dosage schedule for dietary fluoride supplements? TYPES OF STUDIES REVIEWED: A panel of experts convened by the ADA CSA, in collaboration with staff of the ADA Center for Evidence-based Dentistry, conducted a MEDLINE search to identify publications that addressed the research questions: systematic reviews as well as clinical studies published since the systematic reviews were conducted (June 1, 2006). RESULTS: The panel concluded that dietary fluoride supplements should be prescribed only for children who are at high risk of developing caries and whose primary source of drinking water is deficient in fluoride. CLINICAL IMPLICATIONS: These recommendations are a resource for practitioners to consider in the clinical decision-making process. As part of the evidence-based approach to care, these clinical recommendations should be integrated with the practitioner's professional judgment and the patient's needs and preferences. Providers should carefully monitor the patient's adherence to the fluoride dosing schedule to maximize the potential therapeutic benefit.

Surveillance for dental caries, dental sealants, tooth retention, edentulism, and enamel fluorosis--United States, 1988-1994 and 1999-2002.

PROBLEM/CONDITION: Dental caries is a common chronic disease that causes pain and disability across all age groups. If left untreated, dental caries can lead to pain and infection, tooth loss, and edentulism (total tooth loss). Dental sealants are effective in preventing dental caries in the occlusal (chewing) and other pitted and fissured surfaces of the teeth. Enamel fluorosis is a hypomineralization of enamel related to fluoride exposure during tooth formation (first 6 years for most permanent teeth). Exposure to fluoride throughout life is effective in preventing dental caries. This is the first CDC Surveillance Summary that addresses these conditions and practices. REPORTING PERIOD: 1988-1994 and 1999-2002. SYSTEM DESCRIPTION: The National Health and Nutrition Examination Survey (NHANES) is an ongoing survey of representative samples of the civilian, noninstitutionalized U.S. population aged >/=2 months in NHANES 1988-1994 and all ages during 1999-2002. The dental component gathered information on persons aged >/=2 years. RESULTS: During 1999-2002, among children aged 2-11 years, 41% had dental caries in their primary teeth. Forty-two percent of children and adolescents aged 6-19 years and approximately 90% of adults had dental caries in their permanent teeth. Among children aged 6-19 years, 32% had received dental sealants. Adults aged >/=20 years retained a mean of 24 of 28 natural teeth and 8% were edentulous. Among persons aged 6-39 years, 23% had very mild or greater enamel fluorosis. Disparities were noticed across all age groups, among racial/ethnic groups, persons with lower education and income, and by smoking status. From 1988-1994 to 1999-2002, four trends were observed: 1) no change in the prevalence of dental caries in primary teeth among children aged 2-11 years, 2) a reduction in prevalence of caries in permanent teeth of up to 10 percentage points among persons aged 6-19 years and up to six percentage points among dentate adults aged >/=20 years, 3) an increase of 13 percentage points in dental sealants among persons aged 6-19 years, and 4) a six percentage point reduction in total tooth loss (edentulism) among persons aged >/=60 years. INTERPRETATION: The findings of this report indicate that the dental caries status of permanent teeth has improved since the 1988-1994 survey. Despite the decrease in caries prevalence and severity in the permanent dentition and the increase in the proportion of children and adolescents who benefit from dental sealants, disparities remain. PUBLIC HEALTH ACTION: These data provide information for public health professionals in designing interventions to improve oral health and to reduce disparities in oral health, for researchers in assessing factors associated with disparities and dental caries in primary teeth, and in designing timely surveillance tools to monitor total fluoride exposure.

Clinical evaluation of patients with temporomandibular joint implants.

PURPOSE: An undetermined number of patients with temporomandibular joint (TMJ) symptoms have been treated with intra-articular disc implants composed of Teflon ethylene/propylene or Teflon polytetrafluoroethylene and aluminum oxide (Proplast-Teflon; Vitek, Houston, TX). These implants have shown the potential to fragment in situ resulting in nonbiodegradable particles that stimulate a giant cell reaction and lead to degeneration of local structures, pain, and limitation of mandibular opening. We examined the possible relationship between TMJ implants and persistent pain, responses to sensory stimuli, quality of life, and systemic immune dysfunction. PATIENTS AND METHODS: This case series (32 patients) were referred from university-based orofacial pain centers and private practices from across the United States. Laboratory and clinical assessments evaluated orofacial pain symptoms, neurologic function, clinical signs and symptoms of rheumatologic disease, physical function, systemic measures of immune function, and behavioral measures. RESULTS: We found that TMJ implant patients appeared to have altered sensitivity to sensory stimuli, a higher number of tender points with a diagnosis of fibromyalgia, increased self-report of chemical sensitivity, higher psychologic distress and significantly lower functional ability. Systemic illness or autoimmune disease was not evident in this series of TMJ implant patients. CONCLUSIONS: Significant problems were noted on clinical assessment of TMJ implant patients. This is a US government work. There are no restrictions on its use.

Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren's syndrome.

OBJECTIVE: To screen for potential efficacy and assess feasibility and safety of dehydroepiandrosterone (DHEA) as a treatment for Sjögren's syndrome (SS). METHODS: A 24-week randomized, double-blinded, pilot trial of oral DHEA (200 mg/day) versus placebo was conducted. The primary comparison was to a hypothesized 20% placebo response rate. If 14 consecutive subjects on DHEA did not respond, a Phase III trial would be considered futile. A placebo group of 14 subjects was planned to verify placebo response rate and estimate sample size required for a definitive trial. Response criteria required 20% improvement in at least 2 of 3 domains. Analysis of covariance was used to adjust for baseline differences and for stratified randomization. Outcome measures included visual analog scale questionnaires for dry eye and dry mouth symptoms, lissamine green ocular dye staining and Schirmer I tests, stimulated salivary flow, IgG, and erythrocyte sedimentation rate (ESR). RESULTS: Randomization resulted in 14 DHEA and 14 placebo group subjects. At baseline, mean +/- SD for DHEA versus placebo groups were Schirmer I tests 4.5 +/- 4.5 versus 5.4 +/- 6.1 mm/5 minutes; Van Bijsterveld score 5.3 +/- 2.1 versus 5.5 +/- 2.2; unstimulated saliva 0.03 +/- 0.05 versus 0.04 +/- 0.10 ml/minute; IgG 1,699 +/- 749 versus 1,712 +/- 621 g/dl; and ESR 40 +/- 31 versus 44 +/- 28 mm/hour. Apart from changes over the trial in dry mouth symptoms, no significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow; IgG, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. Although 7 subjects met response criteria in the DHEA group, 5 met the criteria in the placebo group, and there was no significant difference between groups. CONCLUSION: DHEA showed no evidence of efficacy in SS. Without evidence for efficacy, patients with SS should avoid using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown.