Ansgar Gerhardus

Diagnostic accuracy of methods for the detection of BRCA1 and BRCA2 mutations: a systematic review.

As sequence analysis for BRCA1 and BRCA2 mutations is both time- and cost-intensive, current strategies often include scanning techniques to identify fragments containing genetic sequence alterations. However, a systematic assessment of the diagnostic accuracy has been lacking so far. Here, we report on a systematic review to assess the internal and external validity of current scanning techniques. Inclusion criteria were: controlled design, investigators blinded, and tests suitable as a scanning tool for the whole genes BRCA1 and BRCA2. Outcome parameters were sensitivity, specificity, and positive and negative predictive values compared to direct sequencing. Out of 3816 publications, 10 studies reporting on 12 methods met our inclusion criteria. The internal and external validity of most of these studies was limited. Sensitivities were reported to be 100% for enzymatic mutation detection (EMD), multiple-dye cleavase fragment length polymorphism (MD-CFLP), fluorescence-based conformation-sensitive gel electrophoresis (F-CSGE), RNA-based sequencing, restriction endonuclease fingerprinting-single strand conformation polymorphism (REF-SSCP), stop codon (SC) assay, and denaturing high-performance liquid chromatography (DHPLC). Sensitivity was 50–96% for SSCP, 88–91% for two-dimensional gene scanning (TDGS), 76% for conformation-sensitive gel electrophoresis (CSGE), 75% for protein truncation test (PTT), and 58% for micronucleus test (MNT). Specificities close to 100% were reported, except for MNT. PTT and SC assay are only able to detect truncating mutations. Most studies were designed to introduce new experimental approaches or modifications of established methods and require further evaluation. F-CSGE, REF-SSCP, RNA-based sequencing, EMD, and MD-CFLP will need further evaluation before their use in a routine setting can be considered. SSCP, MNT, PTT, CSGE, and TDGS cannot be recommended because of their low sensitivity. DHPLC outperforms all other methods studied. However, none of the four studies evaluating DHPLC was performed on BRCA2.

Making sense of complexity in context and implementation: the Context and Implementation of Complex Interventions (CICI) framework

BackgroundThe effectiveness of complex interventions, as well as their success in reaching relevant populations, is critically influenced by their implementation in a given context. Current conceptual frameworks often fail to address context and implementation in an integrated way and, where addressed, they tend to focus on organisational context and are mostly concerned with specific health fields. Our objective was to develop a framework to facilitate the structured and comprehensive conceptualisation and assessment of context and implementation of complex interventions.MethodsThe Context and Implementation of Complex Interventions (CICI) framework was developed in an iterative manner and underwent extensive application. An initial framework based on a scoping review was tested in rapid assessments, revealing inconsistencies with respect to the underlying concepts. Thus, pragmatic utility concept analysis was undertaken to advance the concepts of context and implementation. Based on these findings, the framework was revised and applied in several systematic reviews, one health technology assessment (HTA) and one applicability assessment of very different complex interventions. Lessons learnt from these applications and from peer review were incorporated, resulting in the CICI framework.ResultsThe CICI framework comprises three dimensions—context, implementation and setting—which interact with one another and with the intervention dimension. Context comprises seven domains (i.e., geographical, epidemiological, socio-cultural, socio-economic, ethical, legal, political); implementation consists of five domains (i.e., implementation theory, process, strategies, agents and outcomes); setting refers to the specific physical location, in which the intervention is put into practise. The intervention and the way it is implemented in a given setting and context can occur on a micro, meso and macro level. Tools to operationalise the framework comprise a checklist, data extraction tools for qualitative and quantitative reviews and a consultation guide for applicability assessments.ConclusionsThe CICI framework addresses and graphically presents context, implementation and setting in an integrated way. It aims at simplifying and structuring complexity in order to advance our understanding of whether and how interventions work. The framework can be applied in systematic reviews and HTA as well as primary research and facilitate communication among teams of researchers and with various stakeholders.

A long story made too short: surrogate variables and the communication of HPV vaccine trial results

The story of epidemiologists and surrogate variables is one of a classic love–hate relationship. Epidemiologists love surrogates because many studies would not be possible without them. When events are rare or the time between an intervention and the outcome is long, surrogate variables are used to fill the gap. Epidemiologists hate surrogate variables because they introduce an additional step in the chain between intervention (or exposure) and outcome, and thus an additional source of error. To introduce surrogates means to increase uncertainty — and, perhaps, an error. A recent “collection of misleading surrogate end points” reminds us that caution is warranted: examples from this collection include the Cardiac Arrhythmia Suppression Trial in which a group of patients with asymptomatic or mildly symptomatic ventricular arrhythmia after myocardial infarction were treated with encainide or flecainide. Both drugs are used to suppress ventricular arrhythmia (the surrogate end point), but they were actually associated with excess mortality (the relevant outcome). In another case, patients treated with fluoride developed the desired increase in bone mineral density at the lumbar spine (the surrogate end point) but suffered from a higher rate of vertebral fractures than the control group.1 Assessing whether surrogate variables actually measure what they purport to measure (ie, for their validity) is therefore required. Available instruments, however, can only test if a surrogate correctly indicates the direction of an effect — that …

Logic models help make sense of complexity in systematic reviews and health technology assessments

OBJECTIVE To describe the development and application of logic model templates for systematic reviews and health technology assessments (HTAs) of complex interventions. STUDY DESIGN AND SETTING This study demonstrates the development of a method to conceptualize complexity and make underlying assumptions transparent. Examples from systematic reviews with specific relevance to Sub-Saharan Africa (SSA) and other low- and middle-income countries (LMICs) illustrate its usefulness. RESULTS Two distinct templates are presented: the system-based logic model, describing the system in which the interaction between participants, intervention, and context takes place; and the process-orientated logic model, which displays the processes and causal pathways that lead from the intervention to multiple outcomes. CONCLUSION Logic models can help authors of systematic reviews and HTAs to explicitly address and make sense of complexity, adding value by achieving a better understanding of the interactions between the intervention, its implementation, and its multiple outcomes among a given population and context. They thus have the potential to help build systematic review capacity-in SSA and other LMICs-at an individual level, by equipping authors with a tool that facilitates the review process; and at a system-level, by improving communication between producers and potential users of research evidence.

Human papillomavirus vaccination in Africa

www.thelancet.com Vol 378 July 23, 2011 315 Additionally, observational studies and one randomised trial showed that male circumcision reduces high-risk HPV prevalence in female partners. In both men and their female partners, male circumcision reduces high-risk HPV prevalence by reducing acquisition and increasing clearance of the virus. Giuliano and colleagues have previously shown that male circumcision reduces penile high-risk HPV prevalence. Unfortunately, few data are presented in their more recent study on the eff ect of male circumcision on high-risk HPV acquisi tion or clearance. Currently there are no fully protective measures for high-risk HPV prevention in men. The quadrivalent HPV vaccine only reduces external genital lesions in men by 60·2% and persistent infection with any HPV genotype by 27·1%. Therefore, several interventions might be required to signifi cantly reduce high-risk HPV infection in men and women, and the potential, albeit incomplete, protection aff orded by male circumcision cannot be ignored.

Preferences of patients undergoing hemodialysis – results from a questionnaire-based study with 4,518 patients

Background Chronic kidney disease is an increasing health problem worldwide and in its final stage (stage V) can only be treated by renal replacement therapy, mostly hemodialysis. Hemodialysis has a major influence on the everyday life of patients and many patients report dissatisfaction with treatment. Little is known about which aspects of treatment are considered important by hemodialysis patients. The objective of this study was to rate the relative importance of different outcomes for hemodialysis patients and to analyze whether the relative importance differed among subgroups of patients. Patients and methods Within the framework of a yearly questionnaire which is distributed among patients receiving hemodialysis by the largest hemodialysis provider in Germany, we assessed the relative importance of 23 outcomes as rated on a discrete visual analog scale. Descriptive statistics were used to rank the outcomes. Subgroup analyses were performed using Mann–Whitney U or Kruskal–Wallis tests. Results Questionnaires of 4,518 hemodialysis patients were included in the analysis. The three most important outcomes were safety of treatment, health-related quality of life, and satisfaction with care. Further important outcomes were hospital stays, accompanying symptoms, hemodialysis duration, and the improvement or preservation of a good emotional state. Age, profession, and education had the strongest influence on relevant differences of preferences for outcomes; no relevant influence of sex or comorbidity was observed. Conclusion Outcomes concerning the delivery or provision of care and aspects influencing quality of life are rated by patients to be at least as important as clinical outcomes. Many of the outcomes judged to be important by the patients are not regularly considered in research, evaluation studies, or quality programs.

Applying for, reviewing and funding public health research in Germany and beyond

Public health research is complex, involves various disciplines, epistemological perspectives and methods, and is rarely conducted in a controlled setting. Often, the added value of a research project lies in its inter- or trans-disciplinary interaction, reflecting the complexity of the research questions at hand. This creates specific challenges when writing and reviewing public health research grant applications. Therefore, the German Research Foundation (DFG), the largest independent research funding organization in Germany, organized a round table to discuss the process of writing, reviewing and funding public health research. The aim was to analyse the challenges of writing, reviewing and granting scientific public health projects and to improve the situation by offering guidance to applicants, reviewers and funding organizations. The DFG round table discussion brought together national and international public health researchers and representatives of funding organizations. Based on their presentations and discussions, a core group of the participants (the authors) wrote a first draft on the challenges of writing and reviewing public health research proposals and on possible solutions. Comments were discussed in the group of authors until consensus was reached. Public health research demands an epistemological openness and the integration of a broad range of specific skills and expertise. Applicants need to explicitly refer to theories as well as to methodological and ethical standards and elaborate on why certain combinations of theories and methods are required. Simultaneously, they must acknowledge and meet the practical and ethical challenges of conducting research in complex real life settings. Reviewers need to make the rationale for their judgments transparent, refer to the corresponding standards and be explicit about any limitations in their expertise towards the review boards. Grant review boards, funding organizations and research ethics committees need to be aware of the specific conditions of public health research, provide adequate guidance to applicants and reviewers, and ensure that processes and the expertise involved adequately reflect the topic under review.

Evidenzbasierte Verhältnisprävention und Gesundheitsförderung: Welche Studiendesigns brauchen wir?

Health promotion and health prevention are cornerstones of public health. In Germany, a draft health prevention law was rejected in 2013, partly because it almost exclusively focused on measures at the individual level. Many health promotion and prevention measures, by contrast, (also) address the societal level and the environment, but there are few robust studies on their effectiveness, not least because of a lack of resources, the complexity of the measures, or randomisation problems. For example, regulations that protect non-smokers from smoke are subject to political processes where the majority of decision-makers would decline consent for randomisation. In a workshop at the 15(th) Annual Meeting of the German Network for Evidence-based Medicine (DNEbM) two case studies on controlled before-and-after studies (CBA) and interrupted time series (ITS) were developed by the audience as possible alternatives to randomised controlled trials for the evaluation of health promotion and health prevention programmes. The suggestions made by the audience were compared to the study designs chosen in published studies, and the strengths and weaknesses of the different study designs were discussed. The wide array of suggestions for effectiveness studies illustrated the potential of evidence-based health promotion and prevention, but also the specific challenges to be faced.

INTEGRATING ETHICS IN HEALTH TECHNOLOGY ASSESSMENT: MANY WAYS TO ROME

OBJECTIVES The aim of this study was to identify and discuss appropriate approaches to integrate ethical inquiry in health technology assessment (HTA). METHODS The key question is how ethics can be integrated in HTA. This is addressed in two steps: by investigating what it means to integrate ethics in HTA, and by assessing how suitable the various methods in ethics are to be integrated in HTA according to these meanings of integration. RESULTS In the first step, we found that integrating ethics can mean that ethics is (a) subsumed under or (b) combined with other parts of the HTA process; that it can be (c) coordinated with other parts; or that (d) ethics actively interacts and changes other parts of the HTA process. For the second step, we found that the various methods in ethics have different merits with respect to the four conceptions of integration in HTA. CONCLUSIONS Traditional approaches in moral philosophy tend to be most suited to be subsumed or combined, while processual approaches being close to the HTA or implementation process appear to be most suited to coordinated and interactive types of integration. The article provides a guide for choosing the ethics approach that appears most appropriate for the goals and process of a particular HTA.

SchwerpunktEvidenzbasierte Verhältnisprävention und Gesundheitsförderung: Welche Studiendesigns brauchen wir?Evidence-based health promotion and prevention in settings: Which types of study designs are needed?

Health promotion and health prevention are cornerstones of public health. In Germany, a draft health prevention law was rejected in 2013, partly because it almost exclusively focused on measures at the individual level. Many health promotion and prevention measures, by contrast, (also) address the societal level and the environment, but there are few robust studies on their effectiveness, not least because of a lack of resources, the complexity of the measures, or randomisation problems. For example, regulations that protect non-smokers from smoke are subject to political processes where the majority of decision-makers would decline consent for randomisation. In a workshop at the 15(th) Annual Meeting of the German Network for Evidence-based Medicine (DNEbM) two case studies on controlled before-and-after studies (CBA) and interrupted time series (ITS) were developed by the audience as possible alternatives to randomised controlled trials for the evaluation of health promotion and health prevention programmes. The suggestions made by the audience were compared to the study designs chosen in published studies, and the strengths and weaknesses of the different study designs were discussed. The wide array of suggestions for effectiveness studies illustrated the potential of evidence-based health promotion and prevention, but also the specific challenges to be faced.