Outcomes research in the development and evaluation of practice guidelines

BACKGROUND: Practice guidelines have been developed in response to the observation that variations exist in clinical medicine that are not related to variations in the clinical presentation and severity of the disease. Despite their widespread use, however, practice guideline evaluation lacks a rigorous scientific methodology to support its development and application. DISCUSSION: Firstly, we review the major epidemiological foundations of practice guideline development. Secondly, we propose a chronic disease epidemiological model in which practice patterns are viewed as the exposure and outcomes of interest such as quality or cost are viewed as the disease. Sources of selection, information, confounding and temporal trend bias are identified and discussed. SUMMARY: The proposed methodological framework for outcomes research to evaluate practice guidelines reflects the selection, information and confounding biases inherent in its observational nature which must be accounted for in both the design and the analysis phases of any outcomes research study

Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity

International audienc

Safety and efficacy of incobotulinumtoxinA doses up to 800 U in limb spasticity: The TOWER study

OBJECTIVE: To evaluate safety (primary objective) and efficacy of increasing doses (400 U up to 800 U) of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH) for patients with limb spasticity. METHODS: In this prospective, single-arm, dose-titration study (NCT01603459), patients (18-80 years) with spasticity due to cerebral causes, who were clinically deemed to require total doses of 800 U incobotulinumtoxinA, received 3 consecutive injection cycles (ICs) with 400 U, 600 U, and 600-800 U incobotulinumtoxinA, respectively, each followed by 12-16 weeks' observation. Outcomes included adverse events (AEs), antibody testing, Resistance to Passive Movement Scale (REPAS; based on the Ashworth Scale), and Goal Attainment Scale. RESULTS: In total, 155 patients were enrolled. IncobotulinumtoxinA dose escalation did not lead to an increased incidence of treatment-related AEs (IC1: 4.5%; IC2: 5.3%; IC3: 2.9%). No treatment-related serious AEs occurred. The most frequent AEs overall were falls (7.7%), nasopharyngitis, arthralgia, and diarrhea (6.5% each). Five patients (3.2%) discontinued due to AEs. No patient developed secondary nonresponse due to neutralizing antibodies. Mean (SD) REPAS score improvements from each injection to 4 weeks postinjection increased throughout the study (IC1: -4.6 [3.9]; IC2: -5.9 [4.2]; IC3: -7.1 [4.8]; p < 0.0001 for all). The proportion of patients achieving 653 (of 4) treatment goals also increased (IC1: 25.2%; IC2: 50.7%; IC3: 68.6%). CONCLUSION: Escalating incobotulinumtoxinA doses (400 U up to 800 U) did not compromise safety or tolerability, enabled treatment in a greater number of muscles/spasticity patterns, and was associated with increased treatment efficacy, improved muscle tone, and goal attainment. CLINICALTRIALSGOV IDENTIFIER: NCT01603459. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, for patients with limb spasticity, escalating incobotulinumtoxinA doses (400 U up to 800 U) increases treatment efficacy without compromising safety or tolerability

The Childhood Leukemia International Consortium

Background: Acute leukemia is the most common cancer in children under 15 years of age; 80% are acute lymphoblastic leukemia (ALL) and 17% are acute myeloid leukemia (AML). Childhood leukemia shows further diversity based on cytogenetic and molecular characteristics, which may relate to distinct etiologies. Case-control studies conducted worldwide, particularly of ALL, have collected a wealth of data on potential risk factors and in some studies, biospecimens. There is growing evidence for the role of infectious/immunologic factors, fetal growth, and several environmental factors in the etiology of childhood ALL. The risk of childhood leukemia, like other complex diseases, is likely to be influenced both by independent and interactive effects of genes and environmental exposures. While some studies have analyzed the role of genetic variants, few have been sufficiently powered to investigate gene-environment interactions. Objectives: The Childhood Leukemia International Consortium (CLIC) was established in 2007 to promote investigations of rarer exposures, gene-environment interactions and subtype-specific associations through the pooling of data from independent studies. Methods: By September 2012, CLIC included 22 studies (recruitment period: 1962-present) from 12 countries, totaling approximately 31. 000 cases and 50. 000 controls. Of these, 19 case-control studies have collected detailed epidemiologic data, and DNA samples have been collected from children and child-parent trios in 15 and 13 of these studies, respectively. Two registry-based studies and one study comprising hospital records routinely obtained at birth and/or diagnosis have limited interview data or biospecimens. Conclusions: CLIC provides a unique opportunity to fill gaps in knowledge about the role of environmental and genetic risk factors, critical windows of exposure, the effects of gene-environment interactions and associations among specific leukemia subtypes in different ethnic groups. © 2013 Elsevier Ltd