A NOVEL AND SIMPLE RULE OF THUMB FOR MULTIPLICITY CONTROL IN EQUIVALENCE TESTING USING TWO ONE-SIDED TESTS

Equivalence testing is growing in use in scientific research outside of its traditional role in the drug approval process. Largely due to its ease of use and recommendation from the United States Food and Drug Administration guidance, the most common statistical method for testing (bio)equivalence is the two one-sided tests procedure (TOST). Like classical point-null hypothesis testing, TOST is subject to multiplicity concerns as more comparisons are made. In this manuscript, a condition that bounds the family-wise error rate (FWER) using TOST is given. This condition then leads to a simple solution for controlling the FWER. Specifically, we demonstrate that if all pairwise comparisons of k independent groups are being evaluated for equivalence, then simply scaling the nominal Type I error rate down by (k - 1) is sufficient to maintain the family-wise error rate at the desired value or less. The resulting rule is much less conservative than the equally simple Bonferroni correction. An example of equivalence testing in a non drug-development setting is given.

RANDOM EFFECTS MODELS IN A META-ANALYSIS OF THE ACCURACY OF DIAGNOSTIC TESTS WITHIN A GOLD STANDARD IN THE PRESENCE OF MISSING DATA

In evaluating the accuracy of diagnosis tests, it is common to apply two imperfect tests jointly or sequentially to a study population. In a recent meta-analysis of the accuracy of microsatellite instability testing (MSI) and traditional mutation analysis (MUT) in predicting germline mutations of the mismatch repair (MMR) genes, a Bayesian approach (Chen, Watson, and Parmigiani 2005) was proposed to handle missing data resulting from partial testing and the lack of a gold standard. In this paper, we demonstrate an improved estimation of the sensitivities and specificities of MSI and MUT by using a nonlinear mixed model and a Bayesian hierarchical model, both of which account for the heterogeneity across studies through study-specific random effects. The methods can be used to estimate the accuracy of two imperfect diagnostic tests in other meta-analyses when the prevalence of disease, the sensitivities and/or the specificities of diagnostic tests are heterogeneous among studies. Furthermore, simulation studies have demonstrated the importance of carefully selecting appropriate random effects on the estimation of diagnostic accuracy measurements in this scenario.

A review identifies and classifies reasons for ordering diagnostic tests

OBJECTIVE: To consider the reasons and context for test ordering by doctors when faced with an undiagnosed complaint in primary or secondary care. STUDY DESIGN AND SETTING: We reviewed any study of any design that discussed factors that may affect a doctor's decision to order a test. Articles were located through searches of electronic databases, authors' files on diagnostic methodology, and reference lists of relevant studies. We extracted data on: study design, type of analysis, setting, topic area, and any factors reported to influence test ordering. RESULTS: We included 37 studies. We carried out a thematic analysis to synthesize data. Five key groupings arose from this process: diagnostic factors, therapeutic and prognostic factors, patient-related factors, doctor-related factors, and policy and organization-related factors. To illustrate how the various factors identified may influence test ordering we considered the symptom low back pain and the diagnosis multiple sclerosis as examples. CONCLUSIONS: A wide variety of factors influence a doctor's decision to order a test. These are integral to understanding diagnosis in clinical practice. Traditional diagnostic accuracy studies should be supplemented with research into the broader context in which doctors perform their work.

Confidence Bands for Convex Median Curves using Sign-Tests

Suppose that one observes pairs (x1,Y1), (x2,Y2), ..., (xn,Yn), where x1 < x2 < ... < xn are fixed numbers while Y1, Y2, ..., Yn are independent random variables with unknown distributions. The only assumption is that Median(Yi) = f(xi) for some unknown convex or concave function f. We present a confidence band for this regression function f using suitable multiscale sign tests. While the exact computation of this band seems to require O(n4) steps, good approximations can be obtained in O(n2) steps. In addition the confidence band is shown to have desirable asymptotic properties as the sample size n tends to infinity.

Regional structural characteristics of bovine periodontal ligament samples and their suitability for biomechanical tests

Mechanical testing of the periodontal ligament requires a practical experimental model. Bovine teeth are advantageous in terms of size and availability, but information is lacking as to the anatomy and histology of their periodontium. The aim of this study, therefore, was to characterize the anatomy and histology of the attachment apparatus in fully erupted bovine mandibular first molars. A total of 13 teeth were processed for the production of undecalcified ground sections and decalcified semi-thin sections, for NaOH maceration, and for polarized light microscopy. Histomorphometric measurements relevant to the mechanical behavior of the periodontal ligament included width, number, size and area fraction of blood vessels and fractal analysis of the two hard-soft tissue interfaces. The histological and histomorphometric analyses were performed at four different root depths and at six circumferential locations around the distal and mesial roots. The variety of techniques applied provided a comprehensive view of the tissue architecture of the bovine periodontal ligament. Marked regional variations were observed in width, surface geometry of the two bordering hard tissues (cementum and alveolar bone), structural organization of the principal periodontal ligament connective tissue fibers, size, number and numerical density of blood vessels in the periodontal ligament. No predictable pattern was observed, except for a statistically significant increase in the area fraction of blood vessels from apical to coronal. The periodontal ligament width was up to three times wider in bovine teeth than in human teeth. The fractal analyses were in agreement with the histological observations showing frequent signs of remodeling activity in the alveolar bone - a finding which may be related to the magnitude and direction of occlusal forces in ruminants. Although samples from the apical root portion are not suitable for biomechanical testing, all other levels in the buccal and lingual aspects of the mesial and distal roots may be considered. The bucco-mesial aspect of the distal root appears to be the most suitable location.

Development of specifications for the superpave simple performance tests

This study describes the development and establishment of a proposed Simple Performance Test (SPT) specification in order to contribute to the asphalt materials technology in the state of Michigan. The properties and characteristic of materials, performance testing of specimens, and field analyses are used in developing draft SPT specifications. These advanced and more effective specifications should significantly improve the qualities of designed and constructed hot mix asphalt (HMA) leading to improvement in pavement life in Michigan. The objectives of this study include the following: 1) using the SPT, conduct a laboratory study to measure the parameters including the dynamic modulus terms (E*/sinϕ and E*) and the flow number (Fn) for typical Michigan HMA mixtures, 2) correlate the results of the laboratory study to field performance as they relate to flexible pavement performance (rutting, fatigue, and low temperature cracking), and 3) make recommendations for the SPT criteria at specific traffic levels (e.g. E3, E10, E30), including recommendations for a draft test specification for use in Michigan. The specification criteria of dynamic modulus were developed based upon field rutting performance and contractor warranty criteria.

Preliminary Floatation Tests on the Beneficiation of a Low-Grade Montana Bituminous Coal.

Coal is an aggregation of vegetal matter with varying small amounts of mineral and animal matter which have been so changed by the processes of sedimentation, decay and metamorphism that it has become a dense, dark, combustible substance. It occurs in beds varying in thickness from one foot or less to over 300 feet. The horizontal extent of a bed is sometimes continuous over an area as large as the State of Montana.

Rapid diagnostic tests for the home-based management of malaria, in a high-transmission area

Rapid diagnostic tests (RDT) are sometimes recommended to improve the home-based management of malaria. The accuracy of an RDT for the detection of clinical malaria and the presence of malarial parasites has recently been evaluated in a high-transmission area of southern Mali. During the same study, the cost-effectiveness of a 'test-and-treat' strategy for the home-based management of malaria (based on an artemisinin-combination therapy) was compared with that of a 'treat-all' strategy. Overall, 301 patients, of all ages, each of whom had been considered a presumptive case of uncomplicated malaria by a village healthworker, were checked with a commercial RDT (Paracheck-Pf). The sensitivity, specificity, and positive and negative predictive values of this test, compared with the results of microscopy and two different definitions of clinical malaria, were then determined. The RDT was found to be 82.9% sensitive (with a 95% confidence interval of 78.0%-87.1%) and 78.9% (63.9%-89.7%) specific compared with the detection of parasites by microscopy. In the detection of clinical malaria, it was 95.2% (91.3%-97.6%) sensitive and 57.4% (48.2%-66.2%) specific compared with a general practitioner's diagnosis of the disease, and 100.0% (94.5%-100.0%) sensitive but only 30.2% (24.8%-36.2%) specific when compared against the fulfillment of the World Health Organization's (2003) research criteria for uncomplicated malaria. Among children aged 0-5 years, the cost of the 'test-and-treat' strategy, per episode, was about twice that of the 'treat-all' (U.S.$1.0. v. U.S.$0.5). In older subjects, however, the two strategies were equally costly (approximately U.S.$2/episode). In conclusion, for children aged 0-5 years in a high-transmission area of sub-Saharan Africa, use of the RDT was not cost-effective compared with the presumptive treatment of malaria with an ACT. In older patients, use of the RDT did not reduce costs. The question remains whether either of the strategies investigated can be made affordable for the affected population.

S-Adenosylmethionine for osteoarthritis of the knee or hip

BACKGROUND: Osteoarthritis is the most common form of joint disease and the leading cause of pain and disability in the elderly. S-Adenosylmethionine may be a viable treatment option but the evidence about its effectiveness and safety is equivocal. OBJECTIVES: We set out to compare S-Adenosylmethionine (SAMe) with placebo or no specific intervention in terms of effects on pain and function and safety outcomes in patients with knee or hip osteoarthritis. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, CINAHL and PEDro up to 5 August 2008, checked conference proceedings and reference lists, and contacted authors. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials that compared SAMe at any dosage and in any formulation with placebo or no intervention in patients with osteoarthritis of the knee or hip. DATA COLLECTION AND ANALYSIS: Two independent authors extracted data using standardised forms. We contacted investigators to obtain missing outcome information. We calculated standardised mean differences (SMDs) for pain and function, and relative risks for safety outcomes. We combined trials using inverse-variance random-effects meta-analysis. MAIN RESULTS: Four trials including 656 patients were included in the systematic review, all compared SAMe with placebo. The methodological quality and the quality of reporting were poor. For pain, the analysis indicated a small SMD of -0.17 (95% CI -0.34 to 0.01), corresponding to a difference in pain scores between SAMe and placebo of 0.4 cm on a 10 cm VAS, with no between trial heterogeneity (I(2) = 0). For function, the analysis suggested a SMD of 0.02 (95% CI -0.68 to 0.71) with a moderate degree of between-trial heterogeneity (I2 = 54%). The meta-analyses of the number of patients experiencing any adverse event, and withdrawals or drop-outs due to adverse events, resulted in relative risks of 1.27 (95% CI 0.94 to 1.71) and 0.94 (95% CI 0.48 to 1.86), respectively, but confidence intervals were wide and tests for overall effect were not significant. No trial provided information concerning the occurrence of serious adverse events. AUTHORS' CONCLUSIONS: The current systematic review is inconclusive, hampered by the inclusion of mainly small trials of questionable quality. The effects of SAMe on both pain and function may be potentially clinically relevant and, although effects are expected to be small, deserve further clinical evaluation in adequately sized randomised, parallel-group trials in patients with knee or hip osteoarthritis. Meanwhile, routine use of SAMe should not be advised.

Predicting the population impact of chlamydia screening programmes: comparative mathematical modelling study

BACKGROUND: Published individual-based, dynamic sexual network modelling studies reach different conclusions about the population impact of screening for Chlamydia trachomatis. The objective of this study was to conduct a direct comparison of the effect of organised chlamydia screening in different models. METHODS: Three models simulating population-level sexual behaviour, chlamydia transmission, screening and partner notification were used. Parameters describing a hypothetical annual opportunistic screening program in 16-24 year olds were standardised, whereas other parameters from the three original studies were retained. Model predictions of the change in chlamydia prevalence were compared under a range of scenarios. RESULTS: Initial overall chlamydia prevalence rates were similar in women but not men and there were age and sex-specific differences between models. The number of screening tests carried out was comparable in all models but there were large differences in the predicted impact of screening. After 10 years of screening, the predicted reduction in chlamydia prevalence in women aged 16-44 years ranged from 4% to 85%. Screening men and women had a greater impact than screening women alone in all models. There were marked differences between models in assumptions about treatment seeking and sexual behaviour before the start of the screening intervention. CONCLUSIONS: Future models of chlamydia transmission should be fitted to both incidence and prevalence data. This meta-modelling study provides essential information for explaining differences between published studies and increasing the utility of individual-based chlamydia transmission models for policy making.