INTERVAL (investigation of NICE technologies for enabling risk-variable-adjusted-length) dental recalls trial: a multicentre randomised controlled trial investigating the best dental recall interval for optimum, cost-effective maintenance of oral health in dentate adults attending dental primary care.

BACKGROUND: Traditionally, patients at low risk and high risk of developing dental disease have been encouraged to attend dental recall appointments at regular intervals of six months between appointments. The lack of evidence for the effect that different recall intervals between dental check-ups have on patient outcomes, provider workload and healthcare costs is causing considerable uncertainty for the profession and patients, despite the publication of the NICE Guideline on dental recall. The need for primary research has been highlighted in the Health Technology Assessment Group's systematic review of routine dental check-ups, which found little evidence to support or refute the practice of encouraging 6-monthly dental check-ups in adults. The more recent Cochrane review on recall interval concluded there was insufficient evidence to draw any conclusions regarding the potential beneficial or harmful effects of altering the recall interval between dental check-ups. There is therefore an urgent need to assess the relative effectiveness and cost-benefit of different dental recall intervals in a robust, sufficiently powered randomised control trial (RCT) in primary dental care. METHODS: This is a four year multi-centre, parallel-group, randomised controlled trial with blinded outcome assessment based in dental primary care in the UK. Practitioners will recruit 2372 dentate adult patients. Patient participants will be randomised to one of three groups: fixed-period six month recall, risk-based recall, or fixed-period twenty-four month recall. Outcome data will be assessed through clinical examination, patient questionnaires and NHS databases. The primary outcomes measure gingival inflammation/bleeding on probing and oral health-related quality of life. DISCUSSION: INTERVAL will provide evidence for the most clinically-effective and cost-beneficial recall interval for maintaining optimum oral health in dentate adults attending general dental practice. TRIAL REGISTRATION: ISRCTN95933794 (Date assigned 20/08/2008).

Methods for specifying the target difference in a randomised controlled trial: the Difference ELicitation in TriAls (DELTA) systematic review.

BACKGROUND: Randomised controlled trials (RCTs) are widely accepted as the preferred study design for evaluating healthcare interventions. When the sample size is determined, a (target) difference is typically specified that the RCT is designed to detect. This provides reassurance that the study will be informative, i.e., should such a difference exist, it is likely to be detected with the required statistical precision. The aim of this review was to identify potential methods for specifying the target difference in an RCT sample size calculation. METHODS AND FINDINGS: A comprehensive systematic review of medical and non-medical literature was carried out for methods that could be used to specify the target difference for an RCT sample size calculation. The databases searched were MEDLINE, MEDLINE In-Process, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, the Education Resources Information Center (ERIC), and Scopus (for in-press publications); the search period was from 1966 or the earliest date covered, to between November 2010 and January 2011. Additionally, textbooks addressing the methodology of clinical trials and International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) tripartite guidelines for clinical trials were also consulted. A narrative synthesis of methods was produced. Studies that described a method that could be used for specifying an important and/or realistic difference were included. The search identified 11,485 potentially relevant articles from the databases searched. Of these, 1,434 were selected for full-text assessment, and a further nine were identified from other sources. Fifteen clinical trial textbooks and the ICH tripartite guidelines were also reviewed. In total, 777 studies were included, and within them, seven methods were identified-anchor, distribution, health economic, opinion-seeking, pilot study, review of the evidence base, and standardised effect size. CONCLUSIONS: A variety of methods are available that researchers can use for specifying the target difference in an RCT sample size calculation. Appropriate methods may vary depending on the aim (e.g., specifying an important difference versus a realistic difference), context (e.g., research question and availability of data), and underlying framework adopted (e.g., Bayesian versus conventional statistical approach). Guidance on the use of each method is given. No single method provides a perfect solution for all contexts.

Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia.

Schizophrenia is a debilitating psychiatric disease with a strong genetic contribution, potentially linked to altered glutamatergic function in brain regions such as the prefrontal cortex (PFC). Here, we report converging evidence to support a functional candidate gene for schizophrenia. In post-mortem PFC from patients with schizophrenia, we detected decreased expression of MKK7/MAP2K7-a kinase activated by glutamatergic activity. While mice lacking one copy of the Map2k7 gene were overtly normal in a variety of behavioural tests, these mice showed a schizophrenia-like cognitive phenotype of impaired working memory. Additional support for MAP2K7 as a candidate gene came from a genetic association study. A substantial effect size (odds ratios: ~1.9) was observed for a common variant in a cohort of case and control samples collected in the Glasgow area and also in a replication cohort of samples of Northern European descent (most significant P-value: 3 × 10(-4)). While some caution is warranted until these association data are further replicated, these results are the first to implicate the candidate gene MAP2K7 in genetic risk for schizophrenia. Complete sequencing of all MAP2K7 exons did not reveal any non-synonymous mutations. However, the MAP2K7 haplotype appeared to have functional effects, in that it influenced the level of expression of MAP2K7 mRNA in human PFC. Taken together, the results imply that reduced function of the MAP2K7-c-Jun N-terminal kinase (JNK) signalling cascade may underlie some of the neurochemical changes and core symptoms in schizophrenia.

Use of methods for specifying the target difference in randomised controlled trial sample size calculations: Two surveys of trialists' practice.

BACKGROUND: Central to the design of a randomised controlled trial (RCT) is a calculation of the number of participants needed. This is typically achieved by specifying a target difference, which enables the trial to identify a difference of a particular magnitude should one exist. Seven methods have been proposed for formally determining what the target difference should be. However, in practice, it may be driven by convenience or some other informal basis. It is unclear how aware the trialist community is of these formal methods or whether they are used. PURPOSE: To determine current practice regarding the specification of the target difference by surveying trialists. METHODS: Two surveys were conducted: (1) Members of the Society for Clinical Trials (SCT): participants were invited to complete an online survey through the society's email distribution list. Respondents were asked about their awareness, use of, and willingness to recommend methods; (2) Leading UK- and Ireland-based trialists: the survey was sent to UK Clinical Research Collaboration registered Clinical Trials Units, Medical Research Council UK Hubs for Trial Methodology Research, and the Research Design Services of the National Institute for Health Research. This survey also included questions about the most recent trial developed by the respondent's group. RESULTS: Survey 1: Of the 1182 members on the SCT membership email distribution list, 180 responses were received (15%). Awareness of methods ranged from 69 (38%) for health economic methods to 162 (90%) for pilot study. Willingness to recommend among those who had used a particular method ranged from 56% for the opinion-seeking method to 89% for the review of evidence-base method. Survey 2: Of the 61 surveys sent out, 34 (56%) responses were received. Awareness of methods ranged from 33 (97%) for the review of evidence-base and pilot methods to 14 (41%) for the distribution method. The highest level of willingness to recommend among users was for the anchor method (87%). Based upon the most recent trial, the target difference was usually one viewed as important by a stakeholder group, mostly also viewed as a realistic difference given the interventions under evaluation, and sometimes one that led to an achievable sample size. LIMITATIONS: The response rates achieved were relatively low despite the surveys being short, well presented, and having utilised reminders. CONCLUSION: Substantial variations in practice exist with awareness, use, and willingness to recommend methods varying substantially. The findings support the view that sample size calculation is a more complex process than would appear to be the case from trial reports and protocols. Guidance on approaches for sample size estimation may increase both awareness and use of appropriate formal methods.

Examining the effectiveness of different dental recall strategies on maintenance of optimum oral health: the INTERVAL dental recalls randomised controlled trial.

Objective To compare the clinical effectiveness of different frequencies of dental recall over a four-year period.Design A multi-centre, parallel-group, randomised controlled trial with blinded clinical outcome assessment. Participants were randomised to receive a dental check-up at six-monthly, 24-monthly or risk-based recall intervals. A two-strata trial design was used, with participants randomised within the 24-month stratum if the recruiting dentist considered them clinically suitable. Participants ineligible for 24-month recall were randomised to a risk-based or six-month recall interval.Setting UK primary dental care.Participants Practices providing NHS care and adults who had received regular dental check-ups.Main outcome measures The percentage of sites with gingival bleeding on probing, oral health-related quality of life (OHRQoL), cost-effectiveness.Results In total, 2,372 participants were recruited from 51 dental practices. Of those, 648 were eligible for the 24-month recall stratum and 1,724 participants were ineligible. There was no evidence of a significant difference in the mean percentage of sites with gingival bleeding on probing between intervention arms in any comparison. For those eligible for 24-month recall stratum: the 24-month versus six-month group had an adjusted mean difference of -0.91%, 95% CI (-5.02%, 3.20%); the 24-month group versus risk-based group had an adjusted mean difference of 0.07%, 95% CI (-3.99%, 4.12%). For the overall sample, the risk-based versus six-month adjusted mean difference was 0.78%, 95% CI (-1.17%, 2.72%). There was no evidence of a difference in OHRQoL (0-56 scale, higher score for poorer OHRQoL) between intervention arms in any comparison. For the overall sample, the risk-based versus six-month effect size was -0.35, 95% CI (-1.02, 0.32). There was no evidence of a clinically meaningful difference between the groups in any comparison in either eligibility stratum for any of the secondary clinical or patient-reported outcomes.Conclusion Over a four-year period, we found no evidence of a difference in oral health for participants allocated to a six-month or a risk-based recall interval, nor between a 24-month, six-month or risk-based recall interval for participants eligible for a 24-month recall. However, patients greatly value and are willing to pay for frequent dental check-ups.

Specifying the target difference in the primary outcome for a randomised controlled trial: guidance for researchers.

BACKGROUND: Central to the design of a randomised controlled trial is the calculation of the number of participants needed. This is typically achieved by specifying a target difference and calculating the corresponding sample size, which provides reassurance that the trial will have the required statistical power (at the planned statistical significance level) to identify whether a difference of a particular magnitude exists. Beyond pure statistical or scientific concerns, it is ethically imperative that an appropriate number of participants should be recruited. Despite the critical role of the target difference for the primary outcome in the design of randomised controlled trials, its determination has received surprisingly little attention. This article provides guidance on the specification of the target difference for the primary outcome in a sample size calculation for a two parallel group randomised controlled trial with a superiority question. METHODS: This work was part of the DELTA (Difference ELicitation in TriAls) project. Draft guidance was developed by the project steering and advisory groups utilising the results of the systematic review and surveys. Findings were circulated and presented to members of the combined group at a face-to-face meeting, along with a proposed outline of the guidance document structure, containing recommendations and reporting items for a trial protocol and report. The guidance and was subsequently drafted and circulated for further comment before finalisation. RESULTS: Guidance on specification of a target difference in the primary outcome for a two group parallel randomised controlled trial was produced. Additionally, a list of reporting items for protocols and trial reports was generated. CONCLUSIONS: Specification of the target difference for the primary outcome is a key component of a randomized controlled trial sample size calculation. There is a need for better justification of the target difference and reporting of its specification.

Effect of apolipoprotein E genotype on hematoma volume after trauma.

OBJECT: The apolipoprotein E-epsilon4 (APOE-epsilon4) allele is associated with poor outcome after head injury and spontaneous intracerebral hemorrhage (SICH). The aims of this study were to determine if patients in whom one or more APOE-epsilon4 alleles are present are more likely to sustain intracranial mass lesions after head injury and to determine whether there is an isoform-specific effect on the size of the intracranial hematoma. METHODS: The authors performed a computerized volumetric analysis of 142 hematomas visible on computerized tomography (CT) scans obtained in 129 patients. The APOE genotype was determined by subjecting buccal smear samples to polymerase chain reaction and restriction enzyme digestion. Allele frequencies were similar in head-injured patients with and without intracranial hematomas (p = 0.36). Univariate analysis revealed that in those patients with one or more APOE-epsilon4 alleles hematoma volume was greater (cube root-transformed values) than that found in patients without the APOE-epsilon4 allele (3.1 cm compared with 2.5 cm, p = 0.0039). The results of univariate analysis also suggested significant effects of patient age, injury severity (mild, moderate, or severe according to admission Glasgow Coma Scale scores) and hematoma location (extraaxial, intraaxial, or both) on hematoma volume. The mechanism of injury (assault, fall, or other) was marginally associated with hematoma volume (p = 0.052). Time from injury to CT scan, hypoxia, and hypotension had no significant effect on hematoma volume. The results of multiple linear regression analysis showed that the presence of an APOE-epsilon4 allele and an extraaxial hematoma location were independent predictors of hematoma volume, after adjusting for patient age, hours between injury and CT scan, injury severity, and injury mechanism. CONCLUSIONS: Larger hematomas were found in head-injured patients with one or more APOE-epsilon4 alleles than in patients without the allele. This may contribute to the poorer outcomes observed in these patients.

Assessing methods to specify the target difference for a randomised controlled trial: DELTA (Difference ELicitation in TriAls) review.

BACKGROUND: The randomised controlled trial (RCT) is widely considered to be the gold standard study for comparing the effectiveness of health interventions. Central to the design and validity of a RCT is a calculation of the number of participants needed (the sample size). The value used to determine the sample size can be considered the 'target difference'. From both a scientific and an ethical standpoint, selecting an appropriate target difference is of crucial importance. Determination of the target difference, as opposed to statistical approaches to calculating the sample size, has been greatly neglected though a variety of approaches have been proposed the current state of the evidence is unclear. OBJECTIVES: The aim was to provide an overview of the current evidence regarding specifying the target difference in a RCT sample size calculation. The specific objectives were to conduct a systematic review of methods for specifying a target difference; to evaluate current practice by surveying triallists; to develop guidance on specifying the target difference in a RCT; and to identify future research needs. DESIGN: The biomedical and social science databases searched were MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register, PsycINFO, Science Citation Index, EconLit, Education Resources Information Center (ERIC) and Scopus for in-press publications. All were searched from 1966 or the earliest date of the database coverage and searches were undertaken between November 2010 and January 2011. There were three interlinked components: (1) systematic review of methods for specifying a target difference for RCTs - a comprehensive search strategy involving an electronic literature search of biomedical and some non-biomedical databases and clinical trials textbooks was carried out; (2) identification of current trial practice using two surveys of triallists - members of the Society for Clinical Trials (SCT) were invited to complete an online survey and respondents were asked about their awareness and use of, and willingness to recommend, methods; one individual per triallist group [UK Clinical Research Collaboration (UKCRC)-registered Clinical Trials Units (CTUs), Medical Research Council (MRC) UK Hubs for Trials Methodology Research and National Institute for Health Research (NIHR) UK Research Design Services (RDS)] was invited to complete a survey; (3) production of a structured guidance document to aid the design of future trials - the draft guidance was developed utilising the results of the systematic review and surveys by the project steering and advisory groups. SETTING: Methodological review incorporating electronic searches, review of books and guidelines, two surveys of experts (membership of an international society and UK- and Ireland-based triallists) and development of guidance. PARTICIPANTS: The two surveys were sent out to membership of the SCT and UK- and Ireland-based triallists. INTERVENTIONS: The review focused on methods for specifying the target difference in a RCT. It was not restricted to any type of intervention or condition. MAIN OUTCOME MEASURES: Methods for specifying the target difference for a RCT were considered. RESULTS: The search identified 11,485 potentially relevant studies. In total, 1434 were selected for full-text assessment and 777 were included in the review. Seven methods to specify the target difference for a RCT were identified - anchor, distribution, health economic, opinion-seeking, pilot study, review of evidence base (RoEB) and standardised effect size (SES) - each having important variations in implementation. A total of 216 of the included studies used more than one method. A total of 180 (15%) responses to the SCT survey were received, representing 13 countries. Awareness of methods ranged from 38% (n =69) for the health economic method to 90% (n =162) for the pilot study. Of the 61 surveys sent out to UK triallist groups, 34 (56%) responses were received. Awareness ranged from 97% (n =33) for the RoEB and pilot study methods to only 41% (n =14) for the distribution method. Based on the most recent trial, all bar three groups (91%, n =30) used a formal method. Guidance was developed on the use of each method and the reporting of the sample size calculation in a trial protocol and results paper. CONCLUSIONS: There is a clear need for greater use of formal methods to determine the target difference and better reporting of its specification. Raising the standard of RCT sample size calculations and the corresponding reporting of them would aid health professionals, patients, researchers and funders in judging the strength of the evidence and ensuring better use of scarce resources. FUNDING: The Medical Research Council UK and the National Institute for Health Research Joint Methodology Research programme.