Understanding the Continual Reassessment Method for Dose Finding Studies: An Overview for Non-Statisticians

The Continual Reassessment Method (CRM) has gained popularity since its proposal by O’Quigley et al. [1]. Many variations have been published and discussed in the statistical literature, but there has been little attention to making the design considerations accessible to non-statisticians. As a result, some clinicians or reviewers of clinical trials tend to be wary of the CRM due to safety concerns. This paper presents the CRM in a non-technical way, describing the original CRM with some of its modified versions. It also describes the specifications that define a CRM design, along with two simulated examples of CRMs for illustration.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration

Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalizability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies.The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers.This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated web site (http://www.strobe-statement.org) should be helpful resources to improve reporting of observational research.

Grey literature in meta-analyses of randomized trials of health care interventions

BACKGROUND: The inclusion of grey literature (i.e. literature that has not been formally published) in systematic reviews may help to overcome some of the problems of publication bias, which can arise due to the selective availability of data. OBJECTIVES: To review systematically research studies, which have investigated the impact of grey literature in meta-analyses of randomized trials of health care interventions. SEARCH STRATEGY: We searched the Cochrane Methodology Register (The Cochrane Library Issue 3, 2005), MEDLINE (1966 to 20 May 2005), the Science Citation Index (June 2005) and contacted researchers who may have carried out relevant studies. SELECTION CRITERIA: A study was considered eligible for this review if it compared the effect of the inclusion and exclusion of grey literature on the results of a cohort of meta-analyses of randomized trials. DATA COLLECTION AND ANALYSIS: Data were extracted from each report independently by two reviewers. The main outcome measure was an estimate of the impact of trials from the grey literature on the pooled effect estimates of the meta-analyses. Information was also collected on the area of health care, the number of meta-analyses, the number of trials, the number of trial participants, the year of publication of the trials, the language and country of publication of the trials, the number and type of grey and published literature, and methodological quality. MAIN RESULTS: Five studies met the inclusion criteria. All five studies showed that published trials showed an overall greater treatment effect than grey trials. This difference was statistically significant in one of the five studies. Data could be combined for three of the five studies. This showed that, on average, published trials showed a 9% greater treatment effect than grey trials (ratio of odds ratios for grey versus published trials 1.09; 95% CI 1.03-1.16). Overall there were more published trials included in the meta-analyses than grey trials (median 224 (IQR 108-365) versus 45(IQR 40-102)). Published trials had more participants on average. The most common types of grey literature were abstracts (55%) and unpublished data (30%). There is limited evidence to show whether grey trials are of poorer methodological quality than published trials. AUTHORS' CONCLUSIONS: This review shows that published trials tend to be larger and show an overall greater treatment effect than grey trials. This has important implications for reviewers who need to ensure they identify grey trials, in order to minimise the risk of introducing bias into their review.

Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration

Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site (http://www.strobe-statement.org/) should be helpful resources to improve reporting of observational research.

A pain assessment scale for population-based studies: Development and validation of the Pain Module of the Standard Evaluation Questionnaire

The objectives of this study were to develop and validate a tool for assessing pain in population-based observational studies and to develop three subscales for back/neck, upper extremity and lower extremity pain. Based on a literature review, items were extracted from validated questionnaires and reviewed by an expert panel. The initial questionnaire consisted of a pain manikin and 34 items relating to (i) intensity of pain in different body regions (7 items), (ii) pain during activities of daily living (18 items) and (iii) various pain modalities (9 items). Psychometric validation of the initial questionnaire was performed in a random sample of the German-speaking Swiss population. Analyses included tests for reliability, correlation analysis, principal components factor analysis, tests for internal consistency and validity. Overall, 16,634 of 23,763 eligible individuals participated (70%). Test-retest reliability coefficients ranged from 0.32 to 0.97, but only three coefficients were below 0.60. Subscales were constructed combining four items for each of the subscales. Item-total coefficients ranged from 0.76 to 0.86 and Cronbach's alpha were 0.75 or higher for all subscales. Correlation coefficients between subscales and three validated instruments (WOMAC, SPADI and Oswestry) ranged from 0.62 to 0.79. The final Pain Standard Evaluation Questionnaire (SEQ Pain) included 28 items and the pain manikin and accounted for the multidimensionality of pain by assessing pain location and intensity, pain during activity, triggers and time of onset of pain and frequency of pain medication. It was found to be reliable and valid for the assessment of pain in population-based observational studies.

[Pyelonephritis treatment in children in 2007: current literature review]

Four studies, including two being published as an abstract, have recently demonstrated the feasibility of oral treatment of pyelonephritis in children, with no increased risk of treatment failure, early urinary tract re-infection, or renal scars. To do so, the pediatrician must ensure that: (1) the patient does not appear toxic, has no vomiting; (2) there is no known severe obstructive or refluxing uropathy and (3) parents are deemed to be adherent to the treatment. If these criteria are fulfilled, the pediatrician can start an oral treatment with a 3rd generation cephalosporine for 10 to 14 days. Ambulatory follow-up is crucial, and persistance of fever after 3 days is a reason for a new outpatient visit, additional or supplementary imaging studies (renal ultrasonography) and eventually a switch to intravenous treatment.

A call for uniform reporting standards in studies assessing endovascular treatment for chronic ischaemia of lower limb arteries

Endovascular therapy is a rapidly evolving field for the treatment of patients with peripheral arterial disease, and a magnitude of studies reporting on various modern revascularization concepts have been recently published. Thus, studies assessing the efficacy of endovascular therapy of peripheral arteries do not operate with uniformly defined endpoints, rendering a direct comparison of studies difficult. The purpose of this consensus statement is to highlight differences in the terminology used in the current literature and to propose some standardized criteria that must be considered when reporting results of endovascular revascularization for chronic ischaemia of lower limb arteries.

Solid organ transplantation: are there predictors for posttransplant noncompliance? A literature overview

BACKGROUND: Many studies confirm that noncompliance or poor compliance is one of the great problems in health care as it results in waste of resources and funds. METHODS: This overview includes literature on heart, liver, and kidney transplants with emphasis on heart transplantation in adult and pediatric transplant patients and addresses the following variables as potential predictors of postoperative compliance problems: demographic variables (age, marital status, gender) psychological variables (anxiety, denial) psychiatric disorders (major depression, anxiety, and personality disorders), poor social support, pretransplant noncompliance, obesity, substance abuse, and health-related variables (distance from transplant center, indication for transplantation, required pretransplant assist device). Relevant studies on these topics that were conducted up to 1999 are included and discussed in this overview. The most important results are presented in tables. RESULTS: Unfortunately, there has not been any systematic and comprehensive review of the literature on predictors of noncompliance in organ transplant patients so far. With organ transplantation noncompliance impairs both life quality and life span as it is a major risk factor for graft rejection episodes and is responsible for up to 25% of deaths after the initial recovery period. Therefore, it might be assumed that well-informed transplant patients are a highly motivated group whose compliance is just as high. This is not the case. However, even when graft loss means loss of life as in heart or liver transplantation, noncompliance occurs. To best select potential organ recipients, it would be ideal if patients who are very likely to show noncompliant behavior could be identified already before being transplanted. CONCLUSION: The literature overview shows the necessity of preoperative psychosocial screening regarding predictors for posttransplant noncompliance.

Thrombolysis in childhood stroke: report of 2 cases and review of the literature

BACKGROUND AND PURPOSE: No controlled, randomized trial has investigated whether intravenous, intra-arterial (IAT), or mechanical thrombolysis is beneficial in children with ischemic stroke. We report 2 children who underwent IAT for acute ischemic stroke and include them in a review about intravenous thrombolysis, IAT, and mechanical thrombolysis for childhood stroke. METHODS: We searched in MEDLINE and EMBASE for studies that reported on treatment of childhood stroke with intravenous thrombolysis, IAT, or mechanical thrombolysis in the presence of occlusion of the basilar artery, sphenoidal, or insular middle cerebral artery. To be included in this review, the following findings had to be reported: (1) stroke severity at presentation; (2) cerebral imaging findings before thrombolysis; (3) time to treatment; (4) dose of the thrombolytic agent; (5) pre- and postinterventional angiographic findings in IAT; and (6) outcome assessed at hospital discharge or within 12 months after thrombolysis. RESULTS: Adequate data were available in 17 children (including our 2 own cases) who underwent intravenous thrombolysis (n=6), IAT (n=10), or mechanical thrombolysis (n=1). No symptomatic intracranial hemorrhage occurred, but 2 asymptomatic intracranial hemorrhages were present. Sixteen children (94%) survived, and 12 (71%) had a good outcome (modified Rankin Scale score 0 or 1). CONCLUSIONS: The available data about thrombolysis in pediatric stroke are limited. They suggest that this treatment may be beneficial in children with ischemic stroke. Controlled, randomized trials are needed to determine whether thrombolysis is useful in childhood stroke.

Late-onset posttraumatic septal hematoma and abscess formation in a six-year-old Tamil girl--case report and literature review

Nasal septal hematoma with abscess (NSHA) is an uncommon complication of trauma and studies on children are especially rare. We discuss the case of a 6-year-old girl, who was initially evaluated independently by three doctors for minor nasal trauma but had to be re-hospitalized 6 days later with NSHA. Although septal hematoma had initially been excluded (5, 7 and 24 hours after trauma), a secondary accumulation of blood seems to have occured. Delayed hematoma formation has been described in the orbit as a result of possible venous injuries after endoscopic sinus surgery. However, such an observation is new for septal hematoma in children. Thus, we recommend re-evaluation for septal hematoma 48h to 72h after paediatric nasal trauma. Such a scheduled re-examination offers a chance to treat delayed subperichondral hematoma on time before almost inevitable superinfection leads to abscess formation and destruction of the nasal infrastructure. We suggest that parents should be vigilant for delayed nasal obstruction as possible herald of hematoma accumulation within the first week.

High-dose intravenous corticosteroid pulse therapy in alopecia areata: own experience compared with the literature

BACKGROUND: Seven prospective studies including 193 patients have been published on high-dose intravenous corticosteroid pulse therapy in alopecia areata (AA).We compare these data with a retrospective analysis of our own consecutive patients. PATIENTS AND METHODS: Between 1998 and 2002,25 patients with severe AA were treated at the Department of Dermatology, University of Bern, with infusions of 500 mg methylprednisolone on 3 consecutive days.In addition to the inpatient records, in 2004 all patients were followed up by a questionnaire. RESULTS: Four of 10 patients with multifocal AA and 3 of 9 patients with ophiasis-type AA had full re-growth of hair, whereas all 6 patients with AA totalis/universalis failed to respond. CONCLUSION: Intravenous corticosteroid pulse therapy may be helpful in the treatment of multifocal and ophiasis-type AA. Patients with an initial episode of short duration have better chances for success.

Genetic association studies under the population stratification, family pedigree and application to genome-wide association studies

This dissertation has three separate parts: the first part deals with the general pedigree association testing incorporating continuous covariates; the second part deals with the association tests under population stratification using the conditional likelihood tests; the third part deals with the genome-wide association studies based on the real rheumatoid arthritis (RA) disease data sets from Genetic Analysis Workshop 16 (GAW16) problem 1. Many statistical tests are developed to test the linkage and association using either case-control status or phenotype covariates for family data structure, separately. Those univariate analyses might not use all the information coming from the family members in practical studies. On the other hand, the human complex disease do not have a clear inheritance pattern, there might exist the gene interactions or act independently. In part I, the new proposed approach MPDT is focused on how to use both the case control information as well as the phenotype covariates. This approach can be applied to detect multiple marker effects. Based on the two existing popular statistics in family studies for case-control and quantitative traits respectively, the new approach could be used in the simple family structure data set as well as general pedigree structure. The combined statistics are calculated using the two statistics; A permutation procedure is applied for assessing the p-value with adjustment from the Bonferroni for the multiple markers. We use simulation studies to evaluate the type I error rates and the powers of the proposed approach. Our results show that the combined test using both case-control information and phenotype covariates not only has the correct type I error rates but also is more powerful than the other existing methods. For multiple marker interactions, our proposed method is also very powerful. Selective genotyping is an economical strategy in detecting and mapping quantitative trait loci in the genetic dissection of complex disease. When the samples arise from different ethnic groups or an admixture population, all the existing selective genotyping methods may result in spurious association due to different ancestry distributions. The problem can be more serious when the sample size is large, a general requirement to obtain sufficient power to detect modest genetic effects for most complex traits. In part II, I describe a useful strategy in selective genotyping while population stratification is present. Our procedure used a principal component based approach to eliminate any effect of population stratification. The paper evaluates the performance of our procedure using both simulated data from an early study data sets and also the HapMap data sets in a variety of population admixture models generated from empirical data. There are one binary trait and two continuous traits in the rheumatoid arthritis dataset of Problem 1 in the Genetic Analysis Workshop 16 (GAW16): RA status, AntiCCP and IgM. To allow multiple traits, we suggest a set of SNP-level F statistics by the concept of multiple-correlation to measure the genetic association between multiple trait values and SNP-specific genotypic scores and obtain their null distributions. Hereby, we perform 6 genome-wide association analyses using the novel one- and two-stage approaches which are based on single, double and triple traits. Incorporating all these 6 analyses, we successfully validate the SNPs which have been identified to be responsible for rheumatoid arthritis in the literature and detect more disease susceptibility SNPs for follow-up studies in the future. Except for chromosome 13 and 18, each of the others is found to harbour susceptible genetic regions for rheumatoid arthritis or related diseases, i.e., lupus erythematosus. This topic is discussed in part III.

Thrombolysis in patients with acute stroke caused by cervical artery dissection: analysis of 9 patients and review of the literature

BACKGROUND: Results of recently published studies suggest that intravenous thrombolysis (IVT) and local intra-arterial thrombolysis (LIT) are feasible procedures in acute stroke after cervical artery dissection (CAD). OBJECTIVES: To describe 9 patients with acute stroke caused by CAD who were treated by LIT (n = 7) or IVT (n = 2) and to review the literature. METHODS: Retrospective analysis of clinical and neuroradiological findings; literature review from 1980 to present. MAIN OUTCOME MEASURE: Modified Rankin Scale (mRS) score. RESULTS: Of 7 patients treated with LIT, 3 had good outcomes (mRS score of 0-2) and 4 had bad outcomes (mRS score of 3-6) at 3 months. The 2 patients who had received IVT recovered to mRS scores of 0 and 3. Twenty-one patients were identified in the literature. Overall (N = 30), in the IVT group (n = 19), the outcome was good in 8 patients (42%) and bad in 11 (58%); in the LIT group (n = 11), 6 patients (55%) had a good outcome and 5 (45%) had a bad outcome. Overall, 47% (14/30) of the patients (IVT and LIT groups) had a good outcome. Total mortality was 13% (4/30). There were no secondary complications due to extension of wall hematoma or angiography. One symptomatic hemorrhage occurred. CONCLUSIONS: Thrombolysis is feasible in acute stroke caused by CAD. Local complications from extension of wall hematoma did not occur. Further prospective studies are needed to determine the safety and efficacy of thrombolysis in the special circumstance of acute stroke caused by CAD.

[Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration]

Much medical research is observational. The reporting of observational studies is often of insufficient quality. Poor reporting hampers the assessment of the strengths and weaknesses of a study and the generalisability of its results. Taking into account empirical evidence and theoretical considerations, a group of methodologists, researchers, and editors developed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations to improve the quality of reporting of observational studies. The STROBE Statement consists of a checklist of 22 items, which relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to cohort studies, case-control studies and cross-sectional studies and four are specific to each of the three study designs. The STROBE Statement provides guidance to authors about how to improve the reporting of observational studies and facilitates critical appraisal and interpretation of studies by reviewers, journal editors and readers. This explanatory and elaboration document is intended to enhance the use, understanding, and dissemination of the STROBE Statement. The meaning and rationale for each checklist item are presented. For each item, one or several published examples and, where possible, references to relevant empirical studies and methodological literature are provided. Examples of useful flow diagrams are also included. The STROBE Statement, this document, and the associated Web site (http://www.strobe-statement.org/) should be helpful resources to improve reporting of observational research.

Nervous system dysfunction in Henoch-Schonlein syndrome: systematic review of the literature

OBJECTIVE: CNS or peripheral nervous system dysfunction sometimes occurs in Henoch-Schönlein patients. METHODS: We review all Henoch-Schönlein cases published after 1969 with CNS dysfunction without severe hypertension and neuroimaging studies (n = 35), cranial or peripheral neuropathy (n = 15), both CNS and peripheral nervous system dysfunction without severe hypertension (n = 2) or nervous system dysfunction with severe hypertension (n = 2). Forty-four of the 54 patients were <20 years of age. RESULTS: In patients with CNS dysfunction without or with severe hypertension the following presentations were observed in decreasing order of frequency: altered level of consciousness, convulsions, focal neurological deficits, visual abnormalities and verbal disability. Imaging studies disclosed the following lesions: vascular lesions almost always involving two or more vessels, intracerebral haemorrhage, posterior subcortical oedema, diffuse brain oedema and thrombosis of the superior sagittal sinus. Following lesions were noted in the subjects with cranial or peripheral neuropathy without severe hypertension: peroneal neuropathy, peripheral facial palsy, Guillain-Barré syndrome, brachial plexopathy, posterior tibial nerve neuropathy, femoral neuropathy, ulnar neuropathy and mononeuritis multiplex. Persisting signs of either CNS (n = 9) or peripheral (n = 1) nervous system dysfunction were sometimes reported. CONCLUSIONS: In Henoch-Schönlein syndrome, signs of nervous system dysfunction are uncommon but clinically relevant. This review helps clinicians managing Henoch-Schönlein syndrome with nervous system dysfunction.