Pixantrone dimaleate in combination with fludarabine, dexamethasone, and rituximab in patients with relapsed or refractory indolent non‐Hodgkin lymphoma Re-orientation of clinical research in traumatic brain injury: report of an international workshop on comparative effectiveness research. Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center. Interventions aimed at increasing research use in nursing: a systematic review Strategies to Promote Physical Activity During Pregnancy Clinical research in implant dentistry: study design, reporting and outcome measurements: consensus report of Working Group 2 of the VIII European Workshop on Periodontology. A protocol for developing, disseminating, and implementing a core outcome set for pre-eclampsia. A systematic review and development of a classification framework for factors associated with missing patient-reported outcome data Self-help interventions for depressive disorders and depressive symptoms: a systematic review Adapting and testing a brief intervention to reduce maternal anxiety during pregnancy (ACORN): study protocol for a randomised controlled trial Prioritization of Research Addressing Management Strategies for Ductal Carcinoma In Situ Design of treatment trials for functional gastrointestinal disorders. Evaluation of the Quality of Prognosis Studies in Systematic Reviews The electronic, personalizable Rosetta system for dementia care: exploring the user-friendliness, usefulness and impact Cognitive rehabilitation for early post-surgery inpatients affected by primary brain tumor: a randomized, controlled trial The challenges of real-world implementation of web-based shared care software: the HopSCOTCH Shared-Care Obesity Trial in Children Adjunctive psychosocial intervention following Hospital discharge for Patients with bipolar disorder and comorbid substance use: A pilot randomized controlled trial Lifting the lid of the "black intervention box" - the systematic development of an action competence programme for people with screen-detected dysglycaemia Measures for assessing practice change in medical practitioners Recommendations for clinical trials of off-label drugs used to treat advanced-stage cancer. Towards systematic reviews that inform health care management and policy-making Improving the reporting of randomised trials: the CONSORT Statement and beyond. PROBAST: A Tool to Assess the Risk of Bias and Applicability of Prediction Model Studies
Pixantrone dimaleate ( pixantrone ) has been shown to have antitumor activity in leukemia and lymphoma in vitro models and to lack delayed cardiotoxicity associated with mitoxantrone in animal models . FND‐R , a combination regimen of fludarabine , mitoxantrone , dexamethasone , and rituximab , has been shown to be an effective regimen for low‐ grade lymphomas During the National Neurotrauma Symposium 2010 , the DG Research of the European Commission and the National Institutes of Health/National Institute of Neurological Disorders and Stroke ( NIH/NINDS ) organized a workshop on  comparative effectiveness research  ( CER ) in traumatic brain injury ( TBI ) . This workshop review ed existing approaches to improve outcomes of TBI patients . It had two main outcomes : First , it initiated a process of re-orientation of clinical research in TBI . Second , it provided ideas for a potential collaboration between the European Commission and the NIH/NINDS to stimulate research in TBI . Advances in provision of care for TBI patients have result ed from observational studies , guideline development , and meta-analyses of individual patient data . In contrast , r and omized controlled trials have not led to any identifiable major advances . Rigorous protocol s and tightly selected population s constrain generalizability . The workshop addressed additional research approaches , summarized the greatest unmet needs , and highlighted priorities for future research . The collection of high- quality clinical data bases , associated with systems biology and CER , offers substantial opportunities . Systems biology aims to identify multiple factors contributing to a disease and addresses complex interactions . Effectiveness research aims to measure benefits and risks of systems of care and interventions in ordinary setting s and broader population s. These approaches have great potential for TBI research . Although not new , they still need to be introduced to and accepted by TBI research ers as instruments for clinical research . As with therapeutic targets in individual patient management , so it is with research tools : one size does not fit all PURPOSE Advanced-stage follicular lymphoma is considered incurable . The pace of improvements in treatment has been slow . This article analyzes five sequential cohorts of patients with stage IV follicular lymphoma treated between 1972 and 2002 . METHODS Five consecutive studies ( two were r and omized trials ) involving 580 patients were analyzed for overall survival ( OS ) , failure-free survival ( FFS ) , and survival after first relapse . A proportional hazards analysis , and subset analyses using the follicular lymphoma international prognostic index ( FLIPI ) score were performed . Treatment regimens included : cyclophosphamide , doxorubicin , vincristine , prednisone , bleomycin ( CHOP-Bleo ) ; CHOP-Bleo followed by interferon alfa ( IFN-alpha ) ; a rotation of three regimens ( alternating triple therapy ) , followed by IFN-alpha ; fludarabine , mitoxantrone , dexamethasone ( FND ) followed by IFN-alpha ; and FND plus delayed versus concurrent rituximab followed by IFN-alpha . RESULTS Improvements in 5-year OS ( from 64 % to 95 % ) and FFS ( from 29 % to 60 % ) indicate steady progress , perhaps partly due to more effective salvage therapies , but the FFS data also indicate improved front-line therapies ; these observations held true after controlling for differences in prognostic factors among the cohorts . The FLIPI model adds rigor to and facilitates comparisons among the different cohorts . An unexpected finding in this study was a trend toward an apparent FFS plateau . CONCLUSION Evolving therapy , including the incorporation of biologic agents , has led to stepwise significant outcome improvements for patients with advanced-stage follicular lymphoma . The apparent plateau in the FFS curve , starting approximately 8 to 10 years from the beginning of treatment , raises the issue of the potential curability of these patients Background There has been considerable interest recently in developing and evaluating interventions to increase research use by clinicians . However , most work has focused on medical practice s ; and nursing is not well represented in existing systematic review s. The purpose of this article is to report findings from a systematic review of interventions aim ed at increasing research use in nursing . Objective To assess the evidence on interventions aim ed at increasing research use in nursing . Methods A systematic review of research use in nursing was conducted using data bases ( Medline , CINAHL , Healthstar , ERIC , Cochrane Central Register of Controlled Trials , and Psychinfo ) , grey literature , ancestry search ing ( Cochrane Data base of Systematic Review s ) , key informants , and manual search ing of journals . R and omized controlled trials and controlled before- and after- studies were included if they included nurses , if the intervention was explicitly aim ed at increasing research use or evidence -based practice , and if there was an explicit outcome to research use . Method ological quality was assessed using pre-existing tools . Data on interventions and outcomes were extracted and categorized using a pre-established taxonomy . Results Over 8,000 titles were screened . Three r and omized controlled trials and one controlled before- and after- study met the inclusion criteria . The method ological quality of included studies was generally low . Three investigators evaluated single interventions . The most common intervention was education . Investigators measured research use using a combination of surveys ( three studies ) and compliance with guidelines ( one study ) . Research er-led educational meetings were ineffective in two studies . Educational meetings led by a local opinion leader ( one study ) and the formation of multidisciplinary committees ( one study ) were both effective at increasing research use . Conclusion Little is known about how to increase research use in nursing , and the evidence to support or refute specific interventions is inconclusive . To advance the field , we recommend that investigators : ( 1 ) use theoretically informed interventions to increase research use , ( 2 ) measure research use longitudinally using theoretically informed and psychometrically sound measures of research use , as well as , measuring patient outcomes relevant to the intervention , and ( 3 ) use more robust and method ologically sound study design s to evaluate interventions . If investigators aim to establish a link between using research and improved patient outcomes they must first identify those interventions that are effective at increasing research use Physical activity during pregnancy has been associated with significant health benefits ; however , most women in the United States do not meet the current guidelines . This systematic review evaluates evidence for interventions to improve physical activity during pregnancy in order to identify best practice s and inform future research . Electronic data bases ( PubMed , CINAHL , SportD ISCUS , Embase , ERIC , Psych Info , and ISI Web of Science ) were search ed in July 2011 for peer- review ed journal articles . Studies were included if they were English- language r and omized control trials that measured the efficacy of an intervention targeted at pregnant women and were design ed to change physical activity as a primary or secondary outcome . Out of 777 studies identified through the systematic search , 9 interventions were selected for inclusion by multiple review ers . Data were abstract ed using an abstract ion form modeled after the “ Guide to Community Preventive Services . ” Of the 9 interventions included in the review , 3 reported statistically significant positive results for physical activity . Although the interventions included a variety of strategies and techniques , none were uniquely associated with positive outcomes . Overall , this review suggests that little is known about the efficacy of interventions for physical activity during pregnancy . This study provides several recommendations for future research and intervention design AIMS The objective of this working group was to assess and make specific recommendations to improve the quality of reporting of clinical research in implant dentistry and discuss ways to reach a consensus on choice of outcomes . MATERIAL AND METHODS Discussion s were informed by three systematic review s on quality of reporting of observational studies ( case series , case-control and cohort ) and experimental research ( r and omized clinical trials ) . An additional systematic review provided information on choice of outcomes and analytical methods . In addition , an open survey among all workshop participants was utilized to capture a consensus view on the limits of currently used survival and success-based outcomes as well as to identify domains that need to be captured by future outcome systems . RESULTS The Workshop attempted to clarify the characteristics and the value in dental implant research of different study design s. In most areas , measurable quality improvements over time were identified . The Workshop recognized important aspects that require continued attention by clinical research ers , funding agencies and peer review ers to decrease potential bias . With regard to choice of outcomes , the limitations of currently used systems were recognized . Three broad outcome domains that need to be captured by future research were identified : ( i ) patient reported outcome measures , ( ii ) peri-implant tissue health and ( iii ) performance of implant supported restorations . Peri-implant tissue health can be measured by marginal bone level changes and soft tissue inflammation and can be incorporated in time to event analyses . CONCLUSIONS The Workshop recommended that collaboration between clinicians and epidemiologists/ clinical trials specialists should be encouraged . Aspects of design aim ed at limitation of potential bias should receive attention by clinical research ers , funding agencies and journal editors . Adherence to appropriate reporting guidelines such as STROBE and CONSORT are necessary st and ards . Research on outcome measure domains is an area of top priority and should urgently inform a proper process leading to a consensus on outcome measures in dental implant research BACKGROUND Pre-eclampsia is a serious complication of pregnancy and contributes to maternal and offspring mortality and morbidity . R and omised controlled trials evaluating therapeutic interventions for pre-eclampsia have reported many different outcomes and outcome measures . Such variation contributes to an inability to compare , contrast , and combine individual studies , limiting the usefulness of research to inform clinical practice . The development and use of a core outcome set would help to address these issues ensuring outcomes important to all stakeholders , including patients , will be collected and reported in a st and ardised fashion . METHODS An international steering group including healthcare professionals , research ers , and patients , has been formed to guide the development of this core outcome set . Potential outcomes will be identified through a comprehensive literature review and semi-structured interviews with patients . Potential core outcomes will be entered into an international , multi-perspective online Delphi survey . All key stakeholders , including healthcare professionals , research ers , and patients will be invited to participate . The modified Delphi method encourages whole and stakeholder group convergence towards consensus ' core ' outcomes . Once core outcomes have been agreed upon it is important to determine how they should be measured . The truth , discrimination , and feasibility assessment framework will assess the quality of potential outcome measures . High quality outcome measures will be associated with core outcomes . Mechanisms exist to disseminate and implement the result ing core outcome set within an international context . DISCUSSION Embedding the core outcome set within future clinical trials , systematic review s , and clinical practice guidelines could make a profound contribution to advancing the usefulness of research to inform clinical practice , enhance patient care , and improve maternal and offspring outcomes . The infrastructure created by developing a core outcome set for pre-eclampsia could be leveraged in other setting s , for example selecting research priorities and clinical practice guideline development . PROSPECT IVE REGISTRATION : [ 1 ] Core Outcome Measures in Effectiveness Trials ( COMET ) registration number : 588 . [ 2 ] International Prospect i ve Register of Systematic Review s ( PROSPERO ) registration number : CRD42015015529 Background / aims : Missing patient-reported outcome data can lead to biased results , to loss of power to detect between-treatment differences , and to research waste . Awareness of factors may help research ers reduce missing patient-reported outcome data through study design and trial processes . The aim was to construct a Classification Framework of factors associated with missing patient-reported outcome data in the context of comparative studies . The first step in this process was informed by a systematic review . Methods : Two data bases ( MEDLINE and CINAHL ) were search ed from inception to March 2015 for English articles . Inclusion criteria were ( a ) relevant to patient-reported outcomes , ( b ) discussed missing data or compliance in prospect i ve medical studies , and ( c ) examined predictors or causes of missing data , including reasons identified in actual trial data sets and reported on cover sheets . Two review ers independently screened titles and abstract s. Discrepancies were discussed with the research team prior to finalizing the list of eligible papers . In completing the systematic review , four particular challenges to synthesizing the extracted information were identified . To address these challenges , operational principles were established by consensus to guide the development of the Classification Framework . Results : A total of 6027 records were screened . In all , 100 papers were eligible and included in the review . Of these , 57 % focused on cancer , 23 % did not specify disease , and 20 % reported for patients with a variety of non-cancer conditions . In total , 40 % of the papers offered a descriptive analysis of possible factors associated with missing data , but some papers used other methods . In total , 663 excerpts of text ( units ) , each describing a factor associated with missing patient-reported outcome data , were extracted verbatim . Redundant units were identified and sequestered . Similar units were grouped , and an iterative process of consensus among the investigators was used to reduce these units to a list of factors that met the guiding principles . The list was organized on a framework , using an iterative consensus-based process . The result ant Classification Framework is a summary of the factors associated with missing patient-reported outcome data described in the literature . It consists of 5 components ( instrument , participant , centre , staff , and study ) and 46 categories , each with one or more sub-categories or examples . Conclusion : A systematic review of the literature revealed 46 unique categories of factors associated with missing patient-reported outcome data , organized into 5 main component groups . The Classification Framework may assist research ers to improve the design of new r and omized clinical trials and to implement procedures to reduce missing patient-reported outcome data . Further research using the Classification Framework to inform quantitative analyses of missing patient-reported outcome data in existing clinical trials and to inform qualitative inquiry of research staff is planned Background Research suggests that depressive disorders exist on a continuum , with subthreshold symptoms causing considerable population burden and increasing individual risk of developing major depressive disorder . An alternative strategy to professional treatment of subthreshold depression is population promotion of effective self-help interventions that can be easily applied by an individual without professional guidance . The evidence for self-help interventions for depressive symptoms is review ed in the present work , with the aim of identifying promising interventions that could inform future health promotion campaigns or stimulate further research . Methods A literature search for r and omised controlled trials investigating self-help interventions for depressive disorders or depressive symptoms was performed using PubMed , PsycINFO and the Cochrane Data base of Systematic Review s. Reference lists and citations of included studies were also checked . Studies were grouped into those involving participants with depressive disorders or a high level of depressive symptoms , or non- clinical ly depressed participants not selected for depression . A number of exclusion criteria were applied , including trials with small sample sizes and where the intervention was adjunctive to antidepressants or psychotherapy . Results The majority of interventions search ed had no relevant evidence to review . Of the 38 interventions review ed , the ones with the best evidence of efficacy in depressive disorders were S-adenosylmethionine , St John 's wort , bibliotherapy , computerised interventions , distraction , relaxation training , exercise , pleasant activities , sleep deprivation , and light therapy . A number of other interventions showed promise but had received less research attention . Research in non- clinical sample s indicated immediate beneficial effects on depressed mood for distraction , exercise , humour , music , negative air ionisation , and singing ; while potential for helpful longer-term effects was found for autogenic training , light therapy , omega 3 fatty acids , pets , and prayer . Many of the trials were poor quality and may not generalise to self-help without professional guidance . Conclusion A number of self-help interventions have promising evidence for reducing subthreshold depressive symptoms . Other forms of evidence such as expert consensus may be more appropriate for interventions that are not feasible to evaluate in r and omised controlled trials . There needs to be evaluation of whether promotion to the public of effective self-help strategies for subthreshold depressive symptoms could delay or prevent onset of depressive illness , reduce functional impairment , and prevent progression to other undesirable outcomes such as harmful use of substances Background National guidelines in the UK , United States of America , Canada , and Australia have recently stressed the importance of identifying and treating antenatal anxiety and depression . However , there is little research into the most effective and acceptable ways of helping women manage their symptoms of anxiety and stress during pregnancy . Research indicates the necessity to consider the unique needs and concerns of perinatal population s to ensure treatment engagement , highlighting the need to develop specialised treatments which could be integrated within routine antenatal healthcare services . This trial aims to develop a brief intervention for antenatal anxiety , with a focus on embedding the delivery of the treatment within routine antenatal care . Methods / Design This study is a two-phase feasibility trial . In phase 1 we will develop and pilot a brief intervention for antenatal anxiety , blended with group support , to be led by midwives . This intervention will draw on cognitive behavioural principles and wider learning from existing interventions that have been used to reduce anxiety in expectant mothers . The intervention will then be tested in a pilot r and omised controlled trial in phase 2 . The following outcomes will be assessed : ( 1 ) number of participants meeting eligibility criteria  , ( 2 ) number of participants consenting to the study , ( 3 )  number of participants r and omised  , ( 4 ) number of sessions completed by those in the intervention arm , and ( 5 ) number of participants completing the post-intervention outcome measures . Secondary outcomes comprise : detailed feedback on acceptability , which will guide further development of the intervention ; and outcome data on symptoms of maternal and paternal anxiety and depression , maternal quality of life , quality of couple relationship , mother-child bonding , infant temperament and infant sleep . Discussion The study will provide important data to inform the design of a future full-scale r and omised controlled trial of a brief intervention for anxiety during pregnancy . This will include information on its acceptability and feasibility regarding implementation within current antenatal services , which will inform whether ultimately this provision could be rolled out widely in healthcare setting s . Trial registration Current Controlled Trials IS RCT N95282830 . Registered on 29 October 2014 Ductal carcinoma in situ ( DCIS ) is a condition in which abnormal cells line the milk ducts of the breast but have not invaded the underlying breast tissue . Approximately 55000 new cases of DCIS were expected to occur among U.S. women in 2013 , which accounted for approximately 24 % of all new breast cancer diagnoses ( 1 ) . Although the annual incidence of DCIS is less than that of invasive breast cancer , exp and ed use of screening mammography has led to a dramatic increase in the diagnosis of DCIS ( 32.5 cases per 100000 women ) ( 2 ) . There is considerable uncertainty about the optimal clinical management of DCIS because of the lack of reliable methods for distinguishing DCIS that would never become symptomatic from DCIS that is likely to progress to life-threatening invasive cancer ( 3 ) . Current treatment options for DCIS include mastectomy , breast-conserving surgery ( BCS ) , and BCS plus radiation therapy ( 2 , 46 ) . There are limited r and omized , controlled trials ( RCTs ) on which to base decisions about the tradeoffs among DCIS treatment options , and the existing trials may not capture all relevant patient-centered outcomes . For example , 4 large RCTs comparing BCS alone with BCS plus radiation therapy all show similar , very high overall survival regardless of treatment ( 710 ) . The addition of radiation therapy significantly reduces the risk for local recurrence ; approximately one half of all recurrences are DCIS rather than invasive cancer ( 5 , 11 ) . The long-term benefit of preventing the recurrence of an asymptomatic condition that may or may not progress to cancer is difficult to quantify . In other conditions where screening may detect early cancer or cancer precursors that may not progress to a life-threatening stage , such as early-stage prostate cancer , active surveillance or watchful waiting ( an observation strategy ) is an acceptable option for some patients . A similar strategy may be acceptable for some women diagnosed with DCIS , although no studies have compared management strategies that involve no immediate treatment ( that is , observation or active surveillance ) versus immediate treatments . The most important potential benefit of treatment of DCIS is the reduction in the number of deaths due to invasive breast cancer . For many women with a DCIS diagnosis , this may be an unrealized benefit . Some proportion of DCIS may never progress to life-threatening invasive cancer , so these women only have the adverse outcomes of diagnosis and treatments . Both active management strategies and surveillance approaches present tradeoffs relevant to patient-centered outcomes , such as symptoms , function , and well-being . Given the clinical importance of DCIS , the diversity of available treatment strategies , variety of patient-centered outcomes of interest , and areas of uncertainty , we sought to create a prioritized research agenda for the Patient-Centered Outcomes Research Institute ( PCORI ) that would incorporate different stakeholders ' perspectives . A central goal of PCORI is to engage stakeholders in its work in a meaningful way . Between September 2012 and January 2013 , PCORI undertook a broad effort tosolicit research topics to consider for targeted funding from patients , caregivers , research ers , and results of previous prioritization processes by groups , such as the Institute of Medicine . In April 2013 , PCORI 's Assessment of Prevention , Diagnosis , and Treatment Options program , together with the program 's external advisory panel , have identified DCIS management as an important topic with unmet research needs . Then , PCORI tasked the Duke University Evidence Synthesis Group ( ESG ) to work with various stakeholders to identify and prioritize the future research that is most needed by patients and other decision makers on this topic . Methods Overview of Prioritization Approach Our approach to prioritizing future research and developing recommendations for targeted future funding by PCORI included several steps ( Figure 1 ) . These included appraisal s of recent systematic review s to preliminarily identify important evidence gaps , transformation of evidence gaps into research questions and organization of the questions within a comprehensive analytic framework , engagement of stakeholders to identify additional gaps and prioritize research needs or questions , scans of recently published and ongoing studies relevant to the stakeholders ' list of prioritized research needs , and identification of potential study design s to address prioritized research questions . Figure 1 . Overview of prioritization process Adapted from reference 12 . ESG = Evidence Synthesis Group ; PCORI = Patient-Centered Outcomes Research Institute . Identification of Evidence Gaps We used an iterative process to identify evidence gaps for DCIS management . First , we identified and appraised recent published systematic review s , clinical practice guidelines , and future research needs documents to develop an initial list of evidence gaps . This list was neither exhaustive nor prioritized . Next , we organized these gaps according to the population s , interventions , comparators , outcomes , timing , and setting of interest and transformed them into research questions informed by the criteria . Selection and Engagement of Stakeholders We convened a group of 9 stakeholders , including clinical experts and research ers in DCIS management strategies , representatives from federal and nongovernmental funding agencies , representatives from relevant professional societies , health care decision makers and policymakers , and representatives from related consumer and patient advocacy groups ( Table 1 of the Supplement ) . Within each of these categories , we sought to identify a person who was either familiar with the clinical area and its current uncertainties or brought a specific method ological expertise to the stakeholder panel . The University of Minnesota Evidence -based Practice Center , which did a comparative effectiveness review on DCIS management in 2009 ( 13 ) , and PCORI 's patient engagement group provided input on potential stakeholders . Each potential stakeholder completed a disclosure statement and was screened for conflicts of interest . We solicited and received stakeholder input at various points in the process through group discussion s via teleconferences detailing the process and outlining existing evidence gaps , Web-based surveys to obtain priority ranking of topics , and e-mail communications to solicit or provide further clarification of research gaps from teleconferences . Supplement . Supplementary Data for Prioritization of Research Addressing the Management of DCIS Development of an Analytic Framework On the basis of the exp and ed list of 30 evidence gaps and informed by an analytic framework in a recent evidence synthesis on DCIS ( 13 ) , we constructed an analytic framework that depicted the identified knowledge gaps within the context of the population s , interventions , comparators , outcomes , timing , and setting criteria ( Figure 2 ) . This framework shows that women diagnosed with DCIS may have pretreatment evaluations . After these evaluations , women may undergo several management strategies . These management strategies affect patient-centered outcomes ( such as development of comorbid conditions , DCIS recurrence , invasive cancer , and sexual functioning ) . Throughout the analytic framework , population factors ( such as socioeconomic , family history , and genetic factors ) and effects of decisional uncertainty about management strategies were highlighted as potential modifiers . Figure 2 . Analytic framework . DCIS = ductal carcinoma in situ ; FRN = future research need ; MRI = magnetic resonance imaging . Prioritization of Future Research After expansion of the identified research priorities , stakeholders were invited to rank the revised future research needs online . The survey used a forced-ranking prioritization method described by the Agency for Healthcare Research and Quality Evidence -based Practice Center 's Future Research Needs projects ( 14 ) , whereby participants were given 10 votes that could be allocated to any identified research priorities , with a maximum of 3 votes per item . The stakeholders were not given specific prioritization criteria to use but rather were told to decide , on the basis of their perspectives , which were the most important unanswered research questions in DCIS management . Only the priorities in the top tier ( n= 10 ) moved on to the final stage of horizon scan and study design determination . Stakeholders were informed of the final ranking of future research priorities . Horizon Scan of Studies Potentially Relevant to Top-Tier Research Questions We performed 2 data base search es to identify recently published and ongoing studies relevant to the top-tier future research questions result ing from the stakeholder forced-ranking prioritization exercise . We search ed PubMed to identify relevant literature published since 2008 and Clinical Trials.gov for ongoing studies . Members of the ESG team review ed the titles and abstract s identified by search ing PubMed for applicability to the top-tier research questions ; full texts were then obtained and screened for all citations passing the title- and - abstract screening . At both the title- and - abstract and full-text screening stages , articles were included if they met all of the following criteria : presented original data or secondary analysis of data from an RCT , prospect i ve or retrospective observational study , or relevant modeling study ; included data for a pretreatment evaluation or management strategy of interest ; included women with DCIS ; and had a stated objective that could be categorized according to our identified list of research priorities . We search ed Clinical Trials.gov using the keywords ductal carcinoma in situ and DCIS . A member of the ESG team review ed all study abstract s result ing from the search and coded them as potentially relevant to 1 or more of the identified research priorities . We then abstract ed study type ( such as Until recently many clinical trials of functional gastrointestinal disorders ( FGIDs ) suffered from important weaknesses in trial design , study execution , and data analysis . This makes it difficult to determine whether truly efficacious therapies exist for these disorders . One of the important method ologic problems is the absence of vali date d outcome measures and lack of consensus among stakeholders on how to measure outcome . Currently much of the effort is being put into the development of vali date d outcome measures for several of the FGIDs . The r and omized , controlled trial with parallel groups is the design of choice . In this report , guidelines are given for the basic architecture of intervention studies of FGIDs . Further studies on design issues are required to ensure the recommendations will become evidence based in the future Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items Abstract Purpose : This research aim ed to integrate three previously developed assistive technology ( AT ) systems into one modular , multifunctional system , which can support people with dementia and carers throughout the course of dementia . . In an explorative evaluation study , the integrated system , called Rosetta , was tested on usefulness , user-friendliness and impact , in people with dementia , their informal carers and professional carers involved . The Rosetta system was installed in participants ‘ homes in three countries : The Netherl and s , Germany and Belgium . Methods : Controlled trial with pre- and post-test measures across three countries ( r and omized controlled trial in Germany ; matched groups in the Netherl and s and Belgium ) . Participants completed question naires for impact measurement and participated in semi-structured interviews regarding usefulness and user-friendliness of Rosetta . Results : All participants agreed that Rosetta is a very useful development . They did not rate the user-friendliness of the system highly . No significant effects were found on impact measurements . Conclusion : All participants found Rosetta a very useful development for future care , and would consider using it . Since Rosetta was still in development during evaluation , a discrepancy between expectations and actual functioning of Rosetta existed , which may explain the lack of findings on the impact of the system and the low appreciation of user-friendliness . Implication s for Rehabilitation People with dementia and carers find assistive technology ( AT ) a useful future development and they are willing to use it in the future . People with dementia and carers have little privacy issues with AT . If they have concerns , they are willing to accept the trade-off of reduced privacy in exchange for the ability to live in their own homes for longer . Given that a system works flawlessly , informal carers indicate that integrated AT can reduce their burden and stress . This can in turn help informal carers to provide better care for a longer period of time Cognitive impairment is one of the most common neurological disorders in neuro-oncological patients and exerts a deep negative impact on quality of life interfering with familiar , social and career-related activities . To test the effectiveness of early cognitive rehabilitation treatment for in patients affected by primary brain tumors . Out of 109 consecutive patients enrolled in the study , 58 patients were r and omly assigned to a rehabilitation group or to a control group . The rehabilitation consisted of 16 one-hour individual sessions of therapist-guided cognitive training , spread over 4 weeks , combining computer exercises and metacognitive training . Patients in the control group received usual care without cognitive training . All patients were evaluated by means of a comprehensive neuropsychological battery at the admission ( T0 ) and after 4 weeks ( T1 ) . Patients in the rehabilitation group showed a significant improvement of cognitive functions . In particular , the domains that benefited most from the training were visual attention and verbal memory . The control group exhibited only a slightly , not statistically relevant , enhancement of cognitive performances .  Cognitive rehabilitation for neuro-oncological in patients result ed in a significant enhancement of cognitive performances after the training , also providing a foundation for early administration . Future research should be aim ed to clarify the patients ’ characteristics that predict neuropsychological improvement , to identify the most effective elements in rehabilitative programs and to study the effects of treatment extension to everyday life Background E-health initiatives hold promise to improve shared-care models of health care . In 2008–2011 we developed and trialled web-based software to facilitate a r and omised trial of a shared-care approach for childhood obesity involving General Practitioners ( GPs ) working with tertiary specialists . We describe the software ’s development , implementation and evaluation , and make recommendations for future e-health initiatives . The web-based software was design ed with the goals of allowing both GPs and specialists to communicate and review patient progress ; integrating with existing GP software ; and supporting GPs to deliver the structured intervention . Specifically , we aim ed to highlight the challenges inherent in this process , and report on the extent to which the software ultimately met its implementation and user aims . Methods The study was conducted at the Royal Children ’s Hospital and 22 general practice s across Melbourne , Australia . Participants comprised 30 GPs delivering the shared-care intervention .  Outcomes included the following . ( 1 ) GPs ’ pre-specified software requirements : transcribed from two focus groups and analysed for themes using content analysis . ( 2 ) Software implementation and performance based on the experience of the research team and GPs . ( 3 )  GP users ’ evaluation collected via question naire . ( 4 ) Software usage collected via GP question naire and qualified through visual inspection of the software meta- data . Results Software implementation posed difficult and at times disabling technological barriers ( e.g. out- date d hardware , poor internet connections ) . The software ’s speed and inability to seamlessly link with day-to-day software was a source of considerable frustration . Overall , GPs rated software usability as poor , although most ( 68 % ) felt that the structure and functionality of the software was useful . Recommendations for future e-health initiatives include thorough scoping of IT systems and server speed , testing across diverse environments , automated pre-requisite checks and up grade s of processors/memory where necessary , and user-created usernames and passwords . Conclusions GPs are willing to embrace novel technologies to support their practice . However , implementation remains challenging mainly for technical reasons , and this precludes further evaluation of potential user-specific barriers . These findings could inform future e-health ventures into shared-care , and highlight the need for an appropriate infrastructure . Trial registration Australian New Zeal and Clinical Trials Registry : ACTRN126080000553 Bipolar disorder and substance use disorders are highly debilitating conditions , and especially when co-occurring , are associated with a variety of negative outcomes . Surprisingly , there is a relative lack of research on feasible and effective psychosocial treatments for individuals with comorbid bipolar and substance use disorder ( BD-SUD ) , and a dearth of literature examining interventions design ed specifically to improve outcomes such as symptoms , functioning , and treatment engagement/adherence following psychiatric hospitalization in this population . In the current paper , we report results of a pilot r and omized controlled trial ( n=30 ) , comparing the recently developed Integrated Treatment Adherence Program , which includes individual and telephone sessions provided to patients and their significant others , versus Enhanced Assessment and Monitoring for those with BD-SUD . Participants who received the Integrated Treatment Adherence Program demonstrated significantly faster and greater improvements in depression , mania , functioning , and values-consistent living than participants r and omized to Enhanced Assessment and Monitoring , and there was a trend for increased treatment adherence over time . Results are discussed in light of existing literature and study limitations , and suggestions for future research are proposed Background The evidence gained from effective self-management interventions is often criticised for the ambiguity of its active components , and consequently the obstruction of their implementation into daily practice .Our aim is to report how an intervention development model aids the careful selection of active components in an intervention for people with dysglycaemia . Methods The first three phases of the UK Medical Research Council 's model for developing complex interventions in primary care were used to develop a self-management intervention targeting people with screen-detected dysglycaemia . In the pre clinical phase , the expected needs of the target group were assessed by review of empirical literature and theories . In phase I , a preliminary intervention was modelled and in phase II , the preliminary intervention was pilot tested . Results In the pre clinical phase the achievement of health-related action competence was defined as the overall intervention goal and four learning objectives were identified : motivation , informed decision-making , action experience and social involvement . In Phase I , the educational activities were defined and the pedagogical tools tested . In phase II , the intervention was tested in two different primary healthcare setting s and adjusted accordingly . The 18-hour intervention " Ready to Act " ran for 3 months and consisted of two motivational one-to-one sessions conducted by nurses and eight group meetings conducted by multidisciplinary teams . Conclusions An intervention aim ed at health-related action competence was successfully developed for people with screen-detected dysglycaemia . The systematic and transparent developmental process is expected to facilitate future clinical research . The MRC model provides the necessary steps to inform intervention development but should be prioritised according to existing evidence in order to save time Background There are increasing numbers of r and omised trials and systematic review s examining the efficacy of interventions design ed to bring about a change in clinical practice . The findings of this research are being used to guide strategies to increase the uptake of evidence into clinical practice . Knowledge of the outcomes measured by these trials is vital not only for the interpretation and application of the work done to date , but also to inform future research in this exp and ing area of endeavour and to assist in collation of results in systematic review s and meta-analyses . Methods The objective of this review was to identify methods used to measure change in the clinical practice s of health professionals following an intervention aim ed at increasing the uptake of evidence into practice . All published trials included in a recent , comprehensive Health Technology Assessment of interventions to implement clinical practice guidelines and change clinical practice ( n = 228 ) formed the sample for this study . Using a st and ardised data extraction form , one review er ( SH ) , extracted the relevant information from the methods and /or results sections of the trials . Results Measures of a change of health practitioner behaviour were the most common , with 88.8 % of trials using these as outcome measures . Measures that assessed change at a patient level , either actual measures of change or surrogate measures of change , were used in 28.8 % and 36.7 % of studies ( respectively ) . Health practitioners ' knowledge and attitudes were assessed in 22.8 % of the studies and changes at an organisational level were assessed in 17.6 % . Conclusion Most trials of interventions aim ed at changing clinical practice measured the effect of the intervention at the level of the practitioner , i.e. did the practitioner change what they do , or has their knowledge of and /or attitude toward that practice changed ? Less than one-third of the trials measured , whether or not any change in practice , result ed in a change in the ultimate end-point of patient health status PURPOSE To provide recommendations to trialists and sponsors that guide the design and implementation of prospect i ve postapproval clinical trials for oncology drugs used outside US Food and Drug Administration-labeled indications for treatment of late-stage cancers . METHODS A meeting was hosted by the Center for Medical Technology Policy in Baltimore , MD , on November 12 , 2009 . Discussion s during the meeting and key informant interviews were conducted before and after this stakeholder meeting . Peer review by multidisciplinary stakeholders was followed by a public comment period . Input was received from patient advocacy groups , medical oncologists , pharmaceutical companies , the US Food and Drug Administration , Centers for Medicare and Medicaid Services , the National Cancer Institute , foreign government agencies involved in health technology assessment , public and private payers , drug compendia , clinical research entities , statisticians , academics , and the American Society of Clinical Oncology . RESULTS To address the needs of patients and their clinical providers , compendia , payers , and policy makers , recommendations are proposed to guide the design of future prospect i ve trials for off-label use of oncology drugs across four areas : trial design and data analysis , patient and site recruitment , comparators , and outcomes . CONCLUSION The US Food and Drug Administration provides guidance to the pharmaceutical industry and others design ing r and omized clinical trials for regulatory approval . However , a gap exists for postregulatory decision makers , including patients , prescribers , and payers , because regulatory trials do not answer the questions most relevant to them . Therefore , guidance is needed for trials performed in the postapproval environment for these postapproval decision makers Objectives To identify ways to improve the usefulness of systematic review s for health care managers and policy-makers that could then be evaluated prospect ively . Methods We systematic ally review ed studies of decision-making by health care managers and policy-makers , conducted interviews with a purposive sample of them in Canada and the United Kingdom ( n=29 ) , and review ed the websites of research funders , producers/purveyors of research , and journals that include them among their target audiences ( n=45 ) . Results Our systematic review identified that factors such as interactions between research ers and health care policy-makers and timing/timeliness appear to increase the prospect s for research use among policy-makers . Our interviews with health care managers and policy-makers suggest that they would benefit from having information that is relevant for decisions highlighted for them ( e.g. context ual factors that affect a review 's local applicability and information about the benefits , harms/risks and costs of interventions ) and having review s presented in a way that allows for rapid scanning for relevance and then grade d entry ( such as one page of take-home messages , a three-page executive summary and a 25-page report ) . Managers and policy-makers have mixed views about the helpfulness of recommendations . Our analysis of websites found that context ual factors were rarely highlighted , recommendations were often provided and grade d entry formats were rarely used . Conclusions Research ers could help to ensure that the future flow of systematic review s will better inform health care management and policy-making by involving health care managers and policy-makers in their production and better highlighting information that is relevant for decisions . Research funders could help to ensure that the global stock of systematic review s will better inform health care management and policy-making by supporting and evaluating local adaptation processes such as developing and making available online more user-friendly ‘ front ends ’ for potentially relevant systematic review An extensive and growing number of review s of the published literature demonstrate that health research publications have frequent deficiencies . Of particular concern are poor reports of r and omised trials , which make it difficult or impossible for readers to assess how the research was conducted , to evaluate the reliability of the findings , or to place them in the context of existing research evidence . As a result , published reports of trials often can not be used by clinicians to inform patient care or to inform public health policy , and the data can not be included in systematic review s. Reporting guidelines are design ed to identify the key information that research ers should include in a report of their research . We describe the history of reporting guidelines for r and omised trials culminating in the CONSORT Statement in 1996 . We detail the subsequent development and extension of CONSORT and consider related initiatives aim ed at improving the reliability of the medical research literature Prediction relates to estimating the probability of something currently unknown . In the context of medical research , prediction typically concerns either diagnosis ( probability of a certain condition being present but not yet detected ) or prognosis ( probability of an outcome developing in the future ) ( 13 ) . Prognosis applies not only to sick persons or those with an established diagnosis but also to , for example , pregnant women at risk for diabetes ( 4 ) . Prediction research includes predictor finding studies , prediction model studies ( development , validation , and extending or updating ) , and prediction model impact studies ( 1 ) . Predictor finding studies ( also known as risk factor or prognostic factor studies ) aim to identify which predictors ( such as age , disease stage , or biomarkers ) independently contribute to the prediction of a diagnostic or prognostic outcome ( 1 , 5 ) . Prediction model studies aim to develop , vali date , or up date ( for example , extend ) a multivariable prediction model . A prediction model uses multiple predictors in combination to estimate probabilities to inform and often guide individual care ( 2 , 6 , 7 ) . These models can predict an individual 's probability of either currently having a particular outcome or disease ( diagnostic prediction model ) or having a particular outcome in the future ( prognostic prediction model ) . Both types of model are widely used in various medical domains and setting s ( 810 ) , as evidence d by the large number of models developed in cancer ( 11 , 12 ) , neurology ( 13 , 14 ) , and cardiovascular disease ( 15 ) . Prediction models are sometimes described as  risk prediction models , predictive models , prediction indices or rules , or risk scores ( 2 , 7 ) . An example is QRISK2 for predicting cardiovascular risk ( 16 ) . Prediction model impact studies evaluate the effect of using a model to guide patient care compared with not using such a model . They use a comparative design , such as a r and omized trial , to study the model 's effect on clinical decision making , patient outcomes , or costs of care ( 1 ) . Systematic review s have a key role in evidence -based medicine and the development of clinical guidelines ( 1719 ) . They are considered to provide the most reliable form of evidence for the effects of an intervention or diagnostic test ( 20 , 21 ) . Systematic review s of prediction models are a relatively new and evolving area but are increasingly undertaken to systematic ally identify , appraise , and summarize evidence on the performance of prediction models ( 1 , 6 , 22 ) . Assessing the quality of included studies is a crucial step in any systematic review ( 20 , 21 ) . The QUIPS ( Quality In Prognosis Studies ) tool has been developed to assess risk of bias ( ROB ) in predictor finding ( prognostic factor ) studies ( 23 ) . Research ers can use the revised Cochrane ROB Tool ( ROB 2.0 ) ( 24 ) to investigate the method ological quality of prediction model impact studies that use a r and omized comparative design , or ROBINS-I ( Risk Of Bias In Nonr and omized Studies of Interventions ) for those that use a nonr and omized comparative design ( 25 ) . As more prediction model studies and systematic review s of such studies are used as evidence for clinical guidance , a tool facilitating quality assessment for individual prediction model studies is urgently needed . We present PROBAST ( Prediction model Risk Of Bias ASsessment Tool ) , a tool to assess the ROB and concerns regarding the applicability of diagnostic and prognostic prediction model studies . PROBAST can be used to assess studies of model development and model validation , including those updating a prediction model ( Box 1 [ 26 ] ) . We refer to the accompanying explanation and elaboration document ( 27 ) , for detailed explanations of how to use PROBAST and how to judge ROB and applicability . Box 1 . Types of diagnostic and prognostic modeling studies or reports addressed by PROBAST . Adopted from the TRIPOD ( Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis ) and CHARMS ( CHecklist for critical Appraisal and data extraction for systematic Review s of prediction Modelling Studies ) guidance ( 7 , 26 ) . PROBAST = Prediction model Risk Of Bias ASsessment Tool . Methods : Development of PROBAST Development of PROBAST was based on a 4-stage approach for developing health research reporting guidelines : define the scope , review the evidence base , use a Web-based Delphi procedure , and refine the tool through piloting ( 28 ) . Guidelines explicitly aim ed at the development of quality assessment tools were not available at the time ( 29 ) . Development Stage 1 : Scope and Definitions A steering group of 9 experts in prediction model studies and development of quality assessment tools agreed on key features of the desired scope of PROBAST . A panel of 38 experts with different background s further refined the scope during the Web-based Delphi procedure . PROBAST was design ed mainly to assess primary studies included in a systematic review . The group agreed that PROBAST would assess both risk of bias and concerns regarding applicability of a study evaluating a multivariable prediction model to be used for individualized diagnosis or prognosis . A domain-based structure was adopted , similar to that used in other ROB tools , such as ROB 2.0 ( 24 ) , ROBINS-I ( 25 ) , QUADAS-2 ( Quality Assessment of Diagnostic Accuracy Studies 2 ) ( 30 ) , and ROBIS ( 31 ) . We agreed that PROBAST should cover primary studies that develop , vali date , or up date multivariable prediction models aim ing to make individualized predictions of a diagnostic or prognostic outcome ( Box 1 ) . Studies that use multivariable modeling techniques to identify predictors ( such as risk or prognostic factors ) associated with an outcome but do not attempt to develop , vali date , or up date a model for making individualized predictions are not covered by PROBAST ( 5 ) . Therefore , PROBAST is not intended for predictor finding studies or prediction model impact studies . Studies of diagnostic and prognostic models often use different terms for predictors and outcomes ( Box 2 ) . A multivariable prediction model is defined as any combination or equation of 2 or more predictors for estimating probability or risk for an individual ( 6 , 7 , 3234 ) . Box 2 . Differences between diagnostic and prognostic prediction model studies . PROBAST = Prediction model Risk Of Bias ASsessment Tool . Development Stage 2 : Review of Evidence We used the following 3 approaches to build an evidence base to inform the development of PROBAST : identifying relevant method ological review s in the area of prediction model research ( November 2012 to January 2013 ) , asking members of the steering group to identify relevant method ological studies ( January 2013 to March 2013 ) , and using the Delphi procedure to ask members of the wider group to identify additional evidence ( February 2012 to July 2014 ) . Identified literature was used to guide the scope and produce an initial list of signaling questions to consider for inclusion in PROBAST ( 1 , 2 , 57 , 26 , 3340 ) . We grouped signaling questions into common themes to identify possible domains . Additional literature provided as part of the Web-based surveys informed development of the explanation and elaboration document . Development Stage 3 : Web-Based Delphi Procedure We used a modified Delphi process to gain feedback and agreement on the scope , structure , and content of PROBAST . Web-based surveys were developed to gather structured feedback for each round . The 38-member Delphi group comprised method ological experts in prediction model research and development of quality assessment tools , experienced systematic review ers , commissioners , and representatives of reimbursement agencies . We included various stakeholders to ensure that the views of end users , method ological experts , and decision makers were represented . The Delphi process consisted of 7 rounds . Round 1 asked about the scope of the tool , and participants agreed to focus on prediction model studies and follow a domain-based structure . Round 2 aim ed to identify relevant domains and agree on which to include . The signaling questions for domains were refined in rounds 3 to 5 . Respondents used a 1-to-5 Likert scale to rate each proposed signaling question for inclusion . They could also suggest rephrasing , provide supporting evidence ( such as references to relevant studies ) , and suggest missing signaling questions . Round 6 refined the domains and introduced further optional guidance for using PROBAST . In the last round , participants received the agreed draft version of PROBAST and had the opportunity to provide any final feedback . Development Stage 4 : Piloting and Refining the Tool We held 6 workshops on PROBAST at consecutive annual Cochrane Colloquia ( Quebec , Canada , 2013 ; Hyderabad , India , 2014 ; Vienna , Austria , 2015 ; Seoul , South Korea , 2016 ; Cape Town , South Africa , 2017 ; and Edinburgh , United Kingdom , 2018 ) . We also held numerous consecutive workshops with MSc and PhD students ( for example , the master 's program in epidemiology at Utrecht University [ Utrecht , the Netherl and s ] and the Evidence -Based Health Care program at Oxford University [ Oxford , United Kingdom ] ) . In these workshops , we piloted the then-current version of PROBAST to gather feedback on practical issues associated with using the tool so that we could further refine and subsequently vali date it . Finally , more than 50 review groups have already piloted PROBAST versions , including the final version , in their review s. Topics included cancer , cardiology , endocrinology , pulmonology , and orthopedics . All feedback received from these initiatives was used to further inform the content and structure of PROBAST , wording of the signaling questions , and content of the guidance documents ( 27 ) . Results : The PROBAST Tool What Does PROBAST Assess ? PROBAST assesses both risk of bias and concerns regarding applicability of primary studies that developed or vali date d multivariable prediction models for diagnosis or prognosis ( Boxes 1 and 2 )
No single measure was identified for use across the range of FND symptoms in adults .
Across r and omised controlled trials ( k=40 ) and observational treatment studies ( k=40 ) , outcome measures most often assessed core FND symptom change .
Other domains measured commonly were additional physical and psychological symptoms , life impact ( ie , quality of life , disability and general functioning ) and health economics/cost-utility ( eg , healthcare re source use and quality -adjusted life years ) .
CONCLUSIONS There are few well-vali date d FND-specific outcome measures .
OBJECTIVES We aim ed to identify existing outcome measures for functional neurological disorder ( FND ) , to inform the development of recommendations and to guide future research on FND outcomes .