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1 Framing of research question using the PICOT format in randomized controlled trials of venous ulcer disease: a protocol for a systematic survey of the literature Journal: Manuscript ID bmjopen--0 Article Type: Protocol Date Submitted by the Author: -Jun- Complete List of Authors: Abbade, Luciana ; Universidade Estadual Paulista, UNESP, São Paulo, Brazil, Dermatology and Radiotherapy; McMaster University, Department of Clinical Epidemiology and Biostatistics Wang, Mei; McMaster University, Clinical Epidemiology and Biostatistics Sriganesh, Kamath; National Institute of Mental Health and Neuro Sciences, Neuroanesthesia; McMaster University, Department of Anesthesia Mbuagbaw, Lawrence; McMaster University, Department of Clinical Epidemiology & Biostatistics; Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Biostatistics Unit Thabane, Lehana; McMaster University, Department of Clinical Epidemiology & Biostatistics; Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Biostatistics Unit <b>primary Subject Heading</b>: Research methods Secondary Subject Heading: Dermatology, Cardiovascular medicine Keywords: STATISTICS & RESEARCH METHODS, WOUND MANAGEMENT, Clinical trials < THERAPEUTICS, Venous ulcers, Randomized controlled trial : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

2 Page of 0 Title: Framing of research question using the PICOT format in randomized controlled trials of venous ulcer disease: a protocol for a systematic survey of the literature Authors: Luciana P F Abbade,,, MD, PhD; Mei Wang ; Kamath Sriganesh, DM;, Lawrence Mbuagbaw;, Lehana Thabane, Affiliations:. Department of Dermatology and Radiotherapy, Botucatu Medical School, Universidade Estadual Paulista, UNESP, São Paulo, Brazil. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.. Department of Neuroanaesthesia, National Institute of Mental Health and Neurosciences, Bangalore, India.. Department of Anesthesia, McMaster University, Hamilton, ON, Canada.. Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, ON, Canada. Corresponding author: Dr Lehana Thabane Address: Biostatistics Unit, Father Sean O Sullivan Research Centre, rd Floor Martha, Room H, St. Joseph s Healthcare Hamilton, Charlton Avenue East, Hamilton, Ontario LN A, Canada. Office Telephone: -0-- ext /0 Office Fax : Address : thabanl@mcmaster.ca Word count:.; Figures: 0; Tables: 0; references: ; supplementary files: 0 Key words: statistic and research methods, wound management, clinical trial, venous ulcers, randomized controlled trial - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

3 Page of 0 Abstract Introduction: Although venous ulcers have great social and economic impact, there is a lack of evidence from randomized controlled trials (RCTs) to support appropriate management for this disease. Framing the research question using the PICOT (population; intervention; control; outcome; time-frame) format in RCTs can improve the quality of the research design. The PICOT acronym is used to formulate the research question based on the following five elements: Population, Intervention of interest, Comparator, Outcomes and the Time-frame over which the outcomes are assessed. Objectives: This study aims to assess how the PICOT format is used to frame research question, on reports of RCTs on venous ulcers and determine key factors associated with better adherence to PICOT format in framing the research question. Methods and analyses: We will conduct a systematic survey of RCTs on venous ulcers published in the National Institute of Health, PubMed database between January 0 and May. We will include all RCTs addressing therapeutic intervention for venous ulcer disease involving human subjects, and published in English language. The selection process will be carried out in duplicate by two independent investigators in two screening phases: title and abstract and full text. Investigators will resolve discrepancies by consensus. We will examine whether the five elements of PICOT format is structured as research question according a PICOT score with a possible score between 0 and. The primary outcome will be the proportion of studies that have adequately reported all PICOT elements. Dissemination: This is the first review to assess how the PICOT format is used to frame research question on management of venous ulcers in reports of RCTs. Upon completion, this review will be submitted to a peer-reviewed biomedical journal for publication and the findings will also be presented in an upcoming conference. Strengths and limitations of this study: This is the first review to assess how the PICOT format is used to frame research question based on reports of RCTs published about venous ulcers Review independently and in duplicate to evaluate the possible factors associated with better adherence to PICOT format in framing the RQ - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

4 Page of 0 Limitations: restriction of RCTs published in English, data collection from reported RCTs and not from the authors and their protocols, and limited generalizability due to the fact that RCTs are from specific field of medicine. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

5 Page of 0 Introduction Among the chronic skin ulcers, venous ulcers (VU) are the most common. It is the advanced stage of chronic venous disease and more common in Western countries.[] The prevalence of VU varies between 0.0% and %, occurring in approximately % of those over years.[] Complications arising from VU are diverse, primarily related to its chronicity and high rates of relapse after healing. In addition, the physical, social, economic and emotional burdens are frequent.[][] The overall costs with treatment of patients with VU in most Western countries, expending approximately % of their entire health care budgets.[] Although VU have great social and economic impact, there is a lack of evidence from randomized controlled trials (RCTs) to support appropriate treatment and management of patients with VU.[][] Well designed, properly conducted and appropriately reported RCTs and systematic review of good quality RCTs are considered as gold standard for providing the best evidence on the benefits and harms of different treatments for a particular disease.[] The first step in designing a RCT is the research question (RQ). The success of any research process relies, in part, on how well investigators are able to turn a clinical problem into a RQ. This is not simple task.[] The RQ determines the research architecture, strategy, and methodology.[0] A clear and focused RQ will help to determine the appropriate study design and the most appropriate methods of statistical analysis and sample size determination.[] This will minimize error, measure input and output variables appropriately, consider external and internal validities, limit bias, and also address clinical as well as statistical relevance.[] Posing a well formulated RQ will help the practitioner focus on the problem that is most important and help focus a subsequently initiated search.[] The PICO format strategy for framing RQ that was first introduced in,[] and later expanded to the acronym PICOT in 0,[] contain the following five elements: Population or sample subjects that the researcher wishes to recruit into the study, Intervention of interest, Comparator intervention or a control group to compare with the intervention of interest, Outcomes or results that will measure the effectiveness of intervention, and the Time-frame over which the outcomes are assessed.[][] In other fields of medicine, the use of the PICOT framework is sub-optimal and often associated with poor reporting of key methodological issues.[][] - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

6 Page of 0 Hypothesis We hypothesize the following: - There are less than % RCTs about VU that adequately report all the PICOT elements in their RQ, and - the compliance RQ with the PICOT format in these RCTs is likely to be better if the journal s where these RCTs are published endorse CONSORT statement, in high impact factor of the journal, in multicentre studies, with large sample size >00, report statistically significant result for primary outcome and if they are industry funded. Objectives The purpose of this review is to generate knowledge on how researchers are framing a RQ for management of VU and its impact on overall reporting of trials. The specific objectives of this study are: ) to assess how the PICOT format is used to frame RQ, objectives or hypotheses in reports of RCTs published on VU and ) to determine key factors associated with better adherence to PICOT format in framing of the RQ. Methods Study design This study will be a systematic survey of the RCTs on VU published in the National Institute of Health, PubMed database between January 0 and May. This time-frame and library were chosen primarily based on feasibility considerations, since our study is only a systematic survey. The time-frame is also part of the period during which there were several published articles addressing the completeness of reporting or adherence to various reporting guidelines.[][] Inclusion criteria: RCTs of a therapeutic intervention for VU, involving human subjects, and written in English. Exclusion criteria: Non-randomized studies, study protocols of RCTs, non-availability of full text and duplicate publications. A study will be defined as a RCT if the assignment of participants to interventions was described by words such as randomly allocated, assigned at random, or allocated by randomization, and if a control group is present. The control group could be placebo, another treatment, a different dose of the same treatment, usual care, or just no treatment.[] The search strategy will include terms for RCTs (Randomized Controlled Trial[ptyp]), venous ulcers (venous ulcers, stasis ulcers, varicose ulcers, venous stasis ulcers, - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

7 Page of 0 venous hypertension ulcers), exclusions for other type of articles (study protocol, review, systematic review, meta-analysis, cohort, case control, case series, guideline and editorial) and limits set for the specific time periods of interest (0/0/0 to /0/). The strategy that we will adopt for the search of the studies is described in Appendix. The selection process will be carried out by two independent investigators (LPFA and MW) in two screening phases: title and abstract screening and full text review. The investigators will resolve any discrepancies through consensus. First, the studies will be evaluated by reading the abstracts and only those which fulfill the inclusion and exclusion criteria will be selected. Figure demonstrates the flow diagram showing the study selection procedure. Rating the framing of the research question We will use the same methodology applied in a previous study.[] One paragraph from the introduction or methods section in full text that best described the primary RQ, hypothesis or objective will be chosen. In that paragraph, we will evaluate the framing of the RQ, regardless of whether it was formulated as a RQ, hypothesis or objective. We will examine whether the five elements of PICOT format are structured as RQ in that paragraph. The five elements were the type of patients or population relevant to the question (P), the intervention (I), the comparative intervention (C), the outcome of interest (O), and the time horizon for measuring the outcome (T). We will score each element as if it was present and as 0 if it was absent. Thus, we will create a PICOT score with a possible score between 0 and. The score represents a measure of completeness of the description of the primary RQ. Data abstraction We will use a Microsoft Excel standardized data abstraction form to extract data from each article related to the RQ. To explore the possible factors that influence the framing of the RQ additional details will also be obtained: endorsement of the CONSORT statement, journal impact factor, whether the study was conducted at single center or multicentre, total number of patients recruited in the study, whether the study was industry sponsored, whether the study reported a statistically significant results for the primary outcome and general information regarding the journal, publication date, authors, country/countries where the study was performed. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

8 Page of 0 Two reviewers (LPFA and MW) will independently abstract the data and any disagreement will be resolved through consensus. Statistical Analysis We will calculate the percentage of trials that clearly stated each PICOT element and associated % confidence interval (CI). We will report descriptive statistics on categorical data as numbers (percentages) and PICOT score as median (interquartile range [IQR]). The PICOT score will be computed as the sum of the individual elements and will range from 0 to, as described previously. For the element that had a zero count or full counts, for instance when none of or all of the included trials reported that PICOT element, the % CI will be calculated by adopting the rule of three.[] If none of n individuals within a PICOT element showed the event that we will be interested in, we could be % confident that the chance of this event occurring is at most in n. For the other PICOT elements, the % CI of the count will be calculated by making the assumption that the number of RCTs that clearly stated the element followed a binomial distribution. The probability that a RCT had clearly stated the element will set to be the observed probability in the sample. We will use Cohen s Kappa (κ) statistic to calculate chance-adjusted inter-rater agreements. Agreement will be interpreted as poor if κ 0., fair if 0. κ 0., moderate if 0. κ 0., substantial if 0. κ 0. and good if κ > 0..[] We will use generalized estimating equations (GEE)[] to determine the factors associated with adequate question formulation. Dependent variable will be PICOT score varies from 0 to. Adjustments will be made for ) whether or not the journal endorses the CONSORT statement, ) journal impact factor, ) number of centres [multicentre versus single centre], ) sample size [ 00 versus > 00], ) results of trial [if the primary outcome was statistically significant] and ) funding status [industry funded versus non-funded]. Descriptive data will be presented as counts and percentages. Data will be analyzed using Statistical Package for Social Sciences (SPSS) Version.0 (SPSS, Inc., 0, Chicago, Illinois, USA). Sample size calculation: The sample size was determined based on the primary objective of estimating the proportion of studies that have adequately reported all PICOT elements using a % - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

9 Page of 0 confidence interval. Based on prior estimate of the proportion of RCTs reporting PICOT elements of 0. from a similar study,[] we would require at least RCTs to obtain an estimate of the % CI with a margin of error of 0.0. Table provides a summary of the sample size estimates for different values of the margin of error and prior estimates of the proportion of RCTs with RQ that adequately included PICOT elements. Table : Sample size estimates E p p= prior estimate of proportion with all PICOT element; E= margin of error N=, p(-p)/ E The summary of objectives, outcomes, hypotheses and methods of analysis are depicted in Table - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

10 Page of 0 Table : Summary of objectives, outcomes, hypotheses and methods of analysis Objectives Outcomes Explanatory variables Primary: To assess how the PICOT format is used to frame RQ, objectives or hypotheses based on reports of RCTs published on VU Secondary: To determine key factors associated with better adherence to PICOT format in framing the RQ, Primary: Proportion of studies that have adequately reported all PICOT elements Hypothesis ) There are less than % RCTs about VU that reported adequately all PICOT elements in RQ ) CONSORT statement by the journal ) journal impact factor ) number of centers [multiple centers versus single center] ) sample size [ 00 versus > 00] ) results of trial [ if the primary outcome was statistically significant] ) funding status [industry funded versus non-funded]. ) The compliance of RQ in PICOT format in these RCTs will be better if the journal s endorse the CONSORT statement for RCTs, high impact factor of the journal, if the studies were multicentre, have sample size > 00, report statistically significant results for the primary outcome and are industry funded. Methods of analyses Percentage of trials that clearly stated each PICOT element and associated % confidence interval (% CI). Multivariable regression* (GEE) *This analysis will be adjusted for the number of centres, sample size, significance of results for primary outcome and source of funding - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

11 Page 0 of 0 Discussion and dissemination RCTs on VUs are the best source of high quality evidence to provide information on the relative merits of various treatments. However, these answers are threatened by the lack of well-reported clinical trials.[] Asking a good RQ is the first step to perform a good study and improve the overall study quality.[0] The question should be sufficiently clear, concise and directed to the heart of research to be developed. The success of a scientific study depends in large part on the researcher's ability to transform the clinical problem in the central research question.[] A clear and objective question is the key element essential for the implementation of the research project, and the PICOT acronym should be used to remember what the question should specify. Framing of the RQ using the PICOT format is independently associated with better overall reporting quality.[] We expect that the compliance of the RQ with PICOT format is better with high impact factor of the journal,[] endorsement of the CONSORT statement for RCTs by the journals,[] multi-sites studies,[] studies with larger sample size,[], [] and industry funding of the study.[] In conclusion, the results of this analysis will help to elucidate the extent to which the PICOT format is used to frame RQ in RCTs published about VU. In the event that use of the PICOT framework is sub-optimal, this analysis will reinforce the importance of framing a well RQ. Ethics committee approval was not sought for this review since we are dealing with published data. Upon completion, this review will be submitted to a peer-reviewed biomedical journal for publication and the findings will also be presented in an upcoming conference. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

12 Page of 0 References Robertson L, Evans C, Fowkes FGR. Epidemiology of chronic venous disease. Phlebology 0;:0. Hafner J, Baumann Conzett K. Epidemiology and pathophysiology of venous ulcers. Aktuelle Derm 0;: Park SH, Ferreira K, Santos VL. Understanding pain and quality of life for patients with chronic venous ulcers. Wounds a Compend Clin Res Pract 0;:. Lal BK. Venous ulcers of the lower extremity: Definition, epidemiology, and economic and social burdens. Semin. Vasc. Surg. ;:. Donnell Jr TFO, Passman MA, Marston WA, et al. Management of venous leg ulcers : Clinical practice guidelines of the Society for Vascular Surgery Ò and the American Venous Forum. J Vasc Surg ;:. Zenilman J, Valle MF, Malas MB, et al. Chronic Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities. Comparative Effectiveness Review No.. (Prepared by Johns Hopkins Evidence-based Practice Center under Contract No I.) AHRQ Publication No. ()-EHC. Rockville, MD Agency Healthc. Res. Qual. December. Erratum January. Lazarus G, Valle MF, Malas M, et al. Chronic venous leg ulcer treatment: Future research needs. Wound Repair Regen ;:. Sackett DL, Rosenberg WMC, Gray JAM, et al. Evidence based medicine: what it is and what it isn t. Br Med J ;:. Thabane L, Thomas T, Ye C, et al. Posing the research question: Not so simple. Can. J. Anesth. 0;:. 0 Sackett DL, Wennberg JE. Choosing the best research design for each question. BMJ ;:. Parfrey PS, Ravani P. On framing the research question and choosing the appropriate research design. Methods Mol Biol ;:. Schlosser RW, Koul R, Costello J. Asking well-built questions for evidence-based practice in augmentative and alternative communication. J Commun Disord 0;:. Richardson WS, Wilson MC, Nishikawa J, et al. The well-built clinical question: A key to evidence-based decisions. Am Coll Physicians J Club ;:A. Haynes R: Forming research questions. In: Sacket D, Guyatt G, Tugwell P, eds. Clinical Epidemiology: How to do Clinical Practice Research. Philadelphia, PA: Lippincott Williams & Wilkins 0:-. Riva JJ, Malik KM, Burnie SJ, et al. What is your research question? An introduction to the PICOT format for clinicians. J Chiropratic Assoc ;:. Rios LP, Ye C, Thabane L. Association between framing of the research question using the PICOT format and reporting quality of randomized controlled trials. BMC Med Res Methodol 0;0:. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

13 Page of 0 Borg Debono V, Zhang S, Ye C, et al. A look at the potential association between PICOT framing of a research question and the quality of reporting of analgesia RCTs. BMC Anesthesiol ;:. Samaan Z, Mbuagbaw L, Kosa D, et al. A systematic scoping review of adherence to reporting guidelines in health care literature. J Multidiscip Healthc ;:. Mbuagbaw L, Thabane, M Vanniyasingam T, Borg Debono V, et al. Improvement in the quality of abstracts in major clinical journals since CONSORT extension for abstracts: a systematic review. Contemp Clin Trials ;:. Rios LP, Odueyungbo A, Moitri MO, et al. Quality of reporting of randomized controlled trials in general endocrinology literature. J Clin Endocrinol Metab 0;:0. Eypasch E, Lefering R, Kum CK, et al. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ ;:. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics ;:. Zeger SL, Liang KY, Albert PS. Models for longitudinal data: a generalized estimating equation approach. Biometrics ;:0. Borg Debono V, Zhang S, Ye C, et al. The quality of reporting of RCTs used within a postoperative pain management meta-analysis, using the CONSORT statement. BMC Anesthesiol ;:. Lai R. Quality of Randomized Controlled Trials Reporting in the Primary Treatment of Brain Tumors. J Clin Oncol 0;:. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

14 Page of 0 Authors contributions: LPFA was involved in the search strategy, designing, testing of the data extraction form, and writing the initial draft. LT was responsible for the conception, designing of the review and critical review the final draft. KS and MW were involved in designing and testing of the data extraction form. LM contributed to improvements in the manuscript and critically revised the final draft. All authors contributed to the protocol and approved the final manuscript. Funding statement: This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. Competing interests statement: The authors do not have any competing interests to report. Data sharing statement: There are no additional data from this study. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

15 Page of 0 Appendix : Search strategy adopted for RCTs in venous ulcers between January 0 and May in PubMed database MESH (Ulcer, Varicose or Ulcers, Varicose or Varicose Ulcers or Venous Stasis Ulcers or Stasis Ulcer, Venous or Stasis Ulcers, Venous or Ulcer, Venous Stasis or Ulcers, Venous Stasis or Venous Stasis Ulcer or Venous Hypertension Ulcers or Hypertension Ulcer, Venous or Hypertension Ulcers, Venous or Ulcer, Venous Hypertension or Ulcers, Venous Hypertension or Venous Hypertension Ulcer or Venous Ulcer or Ulcer, Venous or Ulcers, Venous or Venous Ulcers or Stasis Ulcer or Stasis Ulcers or Ulcer, Stasis or Ulcers, Stasis) Final Search: articles ((("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcer"[all Fields] AND "varicose"[all Fields])) AND r[all Fields] AND ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcers"[all Fields] AND "varicose"[all Fields]) OR "ulcers, varicose"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("varicose"[all Fields] AND "ulcers"[all Fields]) OR "varicose ulcers"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "stasis"[all Fields] AND "ulcers"[all Fields]) OR "venous stasis ulcers"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("stasis"[all Fields] AND "ulcer"[all Fields] AND "venous"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("stasis"[all Fields] AND "ulcers"[all Fields] AND "venous"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcer"[all Fields] AND "venous"[all Fields] AND "stasis"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcers"[all Fields] AND "venous"[all Fields] AND "stasis"[all Fields]) OR "ulcers, venous stasis"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "stasis"[all Fields] AND "ulcer"[all Fields]) OR "venous stasis ulcer"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "hypertension"[all Fields] AND "ulcers"[all Fields]) OR "venous hypertension ulcers"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("hypertension"[all Fields] AND "ulcer"[all Fields] AND "venous"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("hypertension"[all Fields] AND "ulcers"[all Fields] AND "venous"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcer"[all Fields] AND "venous"[all Fields] AND "hypertension"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcers"[all Fields] AND "venous"[all Fields] AND "hypertension"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

16 Page of 0 "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "hypertension"[all Fields] AND "ulcer"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "ulcer"[all Fields]) OR "venous ulcer"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcer"[all Fields] AND "venous"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcers"[all Fields] AND "venous"[all Fields]) OR "ulcers, venous"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("venous"[all Fields] AND "ulcers"[all Fields]) OR "venous ulcers"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("stasis"[all Fields] AND "ulcer"[all Fields]) OR "stasis ulcer"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("stasis"[all Fields] AND "ulcers"[all Fields]) OR "stasis ulcers"[all Fields]) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcer"[all Fields] AND "stasis"[all Fields])) OR ("varicose ulcer"[mesh Terms] OR ("varicose"[all Fields] AND "ulcer"[all Fields]) OR "varicose ulcer"[all Fields] OR ("ulcers"[all Fields] AND "stasis"[all Fields]) OR "ulcers, stasis"[all Fields])) AND (Randomized Controlled Trial[ptyp] AND ("0/0/0"[PDAT] :"/0/"[PDAT])) - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

17 Page of 0 x0mm ( x DPI) - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

18 Page of 0 June, Editor-in-Chief Dear Editor Please find attached herewith a protocol paper: Framing of research question using the PICOT format in randomized controlled trials of venous ulcer disease: a protocol for a systematic survey of the literature. This is a protocol describing the methods for a systematic survey of the literature ) to assess how the PICOT (population; intervention; control; outcome; time-frame) format is used to frame research questions, objectives or hypotheses in reports of randomized controlled trials published on venous ulcers and ) to determine key factors associated with better adherence to PICOT format in framing of the research question. As in other clinical areas, appropriate framing of research questions is essential in interpreting the results and in synthesis of evidence across trials. We hope you will find the study methods sound enough to consider publishing the protocol in. This manuscript is not under consideration by any other journal. We look forward to hear from you. Yours Sincerely, Dr. Lehana Thabane Professor/Associate Chair, Clinical Epidemiology and Biostatistics, McMaster University thabanl@mcmaster.ca - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

19 Framing of research question using the PICOT format in randomized controlled trials of venous ulcer disease: a protocol for a systematic survey of the literature Journal: Manuscript ID bmjopen--0.r Article Type: Protocol Date Submitted by the Author: -Sep- Complete List of Authors: Abbade, Luciana ; Universidade Estadual Paulista, UNESP, São Paulo, Brazil, Dermatology and Radiotherapy; McMaster University, Department of Clinical Epidemiology and Biostatistics Wang, Mei; McMaster University, Clinical Epidemiology and Biostatistics Sriganesh, Kamath; National Institute of Mental Health and Neuro Sciences, Neuroanesthesia; McMaster University, Department of Anesthesia Mbuagbaw, Lawrence; McMaster University, Department of Clinical Epidemiology & Biostatistics; Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Biostatistics Unit Thabane, Lehana; McMaster University, Department of Clinical Epidemiology & Biostatistics; Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Biostatistics Unit <b>primary Subject Heading</b>: Research methods Secondary Subject Heading: Dermatology, Cardiovascular medicine Keywords: STATISTICS & RESEARCH METHODS, WOUND MANAGEMENT, Clinical trials < THERAPEUTICS, Venous ulcers, Randomized controlled trial : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

20 Page of 0 Title: Framing of research question using the PICOT format in randomized controlled trials of venous ulcer disease: a protocol for a systematic survey of the literature Authors: Luciana P F Abbade,,, MD, PhD; Mei Wang ; Kamath Sriganesh, DM;, Lawrence Mbuagbaw;, Lehana Thabane, Affiliations:. Department of Dermatology and Radiotherapy, Botucatu Medical School, Universidade Estadual Paulista, UNESP, São Paulo, Brazil. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.. Department of Neuroanaesthesia, National Institute of Mental Health and Neurosciences, Bangalore, India.. Department of Anesthesia, McMaster University, Hamilton, ON, Canada.. Biostatistics Unit, Father Sean O'Sullivan Research Centre, St Joseph's Healthcare, Hamilton, ON, Canada. Corresponding author: Dr Lehana Thabane Address: Biostatistics Unit, Father Sean O Sullivan Research Centre, rd Floor Martha, Room H, St. Joseph s Healthcare Hamilton, Charlton Avenue East, Hamilton, Ontario LN A, Canada. Office Telephone: -0-- ext /0 Office Fax : Address : thabanl@mcmaster.ca Word count:.; Figures: 0; Tables: 0; references: ; supplementary files: 0 Key words: statistic and research methods, wound management, clinical trial, venous ulcers, randomized controlled trial - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

21 Page of 0 Abstract Introduction: Although venous ulcers have a great social and economic impact, there is a lack of evidence from randomized controlled trials (RCTs) to support appropriate management for this disease. Framing the research question using the PICOT (Population; Intervention; Comparator; Outcome; Time-frame) format in RCTs can improve the quality of the research design. Objectives: To evaluate how the PICOT format is used to frame research question in reports of RCTs of venous ulcer disease and to determine the factors associated with better adherence to the PICOT format in framing the research question. Methods and analyses: We will conduct a systematic survey of RCTs on venous ulcers published in the National Institute of Health, PubMed database between January 0 and May. We will include all RCTs addressing therapeutic intervention for venous ulcer disease involving human subjects, and published in the English language. The selection process will be carried out in duplicate by two independent investigators. First, titles and abstracts will be screened, then full text articles. We will examine whether the five elements of PICOT format are used in formulating the research question and give a score between 0 and. The primary outcome will be the proportion of studies that have adequately reported all PICOT elements. Dissemination: This will be the first survey to assess how the PICOT format is used to frame research questions on the management of venous ulcers in reports of RCTs. Upon completion, this review will be submitted to a peer-reviewed biomedical journal for publication and the findings will also be presented at scientific conferences. Strengths and limitations of this study: This will be the first review to assess how the PICOT format is used to frame research questions in reports of RCTs on venous ulcers Selected articles will be reviewed independently and in duplicate to evaluate the possible factors associated with better adherence to PICOT format - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

22 Page of 0 Limitations: Only RCTs published in English will be considered. Only published information will be used. Our findings will only be generalizable to the field of venous ulcer disease. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

23 Page of 0 Introduction Among the chronic skin ulcers, venous ulcers (VU) are the most common. It is the advanced stage of chronic venous disease and more common in Western countries.[] The prevalence of VU varies from 0.0% to %, occurring in approximately % of people over years.[] The prevalence of VUs varies substantially between studies due to differences in diagnostic methods, epidemiological characteristics of the patients and whether or not foot ulcers are included.[, ] The primary risk factors for VU include old age, phlebitis and deep venous thrombosis. [, ] Complications arising from VU are diverse, primarily related to its chronicity. The main complications are critical colonization and contact dermatitis.[, ] More severe complications include cellulitis, osteomyelitis, and malignant change.[, ] High rates of relapse after healing is other problem with annual recurrence rates varying between % and %.[0-]. In addition VU comes with physical, social, economic and emotional burden.[][] The overall cost of VU treatment in most Western countries is approximately % of their entire health care budgets.[] Although VU has great social and economic impact, there is a lack of evidence from randomized controlled trials (RCTs) to support the management of patients with VU. A recent systematic review of the trials on comparative effectiveness of advanced wound dressings, antibiotics, and surgical management of chronic VU concluded that many of the trials had serious methodological flaws - they were small trials with limited statistical power, which in turn limited their ability to provide conclusive results. [] Furthermore, a critical assessment of the evidence in this review revealed that more trials are needed to evaluate the effects of advanced wound dressings, systemic antibiotics, and surgical interventions, compared with either one another or to a mandatory compression system established as the standard of care for treatment or management of patients with VU.[] Well designed, properly conducted and appropriately reported RCTs summarized in a systematic review are considered the gold standard for providing the best evidence on the benefits and harms of different treatments for a particular disease.[] The first step in designing a RCT is the research question (RQ). The success of any research process relies, in part, on how well the investigators are able to turn a clinical problem into a RQ. This is not simple task.[] The RQ determines the research architecture, strategy and methodology.[] A clear and focused RQ will help to determine the appropriate study design and the most - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

24 Page of 0 appropriate methods of statistical analysis and sample size [] A well formulated research question helps to minimize error, measure input and output variables appropriately, consider external and internal validities, limit bias, and also address clinical as well as statistical relevance.[] Posing a well formulated RQ will help the practitioner focus on the problem that is most important.[] The PICO format strategy for framing RQs that was first introduced in,[] and later expanded to the acronym PICOT in 0,[] contain the following five elements: Population or sample subjects that the researcher wishes to recruit into the study, Intervention of interest, Comparator intervention or a control group to compare with the intervention of interest, Outcomes or results that will measure the effectiveness of intervention, and the Time-frame over which the outcomes are assessed.[][] In other fields of medicine, the use of the PICOT framework is sub-optimal and often associated with poor reporting of key methodological issues.[][] Hypotheses We hypothesize the following: )Less than % of the RCTs on VU use all the PICOT elements in their RQ,[] ) the RQ is more likely to follow the PICOT format if the RCT is published in a journal that endorses the CONSORT statement,[-] or has a high impact factor,[][] is a multicentre study,[] has a large sample size (>00 participants),[-] reports statistically significant result for the primary outcome[] and if they are industry funded. [][] These six factors were chosen based on evidence from previous research that show them to be related with better overall reporting quality []. Furthermore, the framing of the RQ using the PICOT format has also been shown to be independently associated with better reporting quality.[] Objectives The purpose of this review is to generate knowledge on how researchers are framing RQs in trials on the management of VU and to provided recommendations for improvement. The specific objectives of this study are: ) to assess how the PICOT format is used to frame RQs in reports of RCTs published on VU and ) to determine the factors associated with better adherence to the PICOT format in framing of the RQ. Methods Study design - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

25 Page of 0 This study will be a systematic survey of the RCTs on VU published in the National Institute of Health, PubMed database between January 0 and May. This time-frame and library were chosen primarily based on feasibility considerations. This timeframe is also part of the period during which there have been several published articles addressing the completeness of reporting or adherence to various reporting guidelines.[][] Inclusion criteria: RCTs of a therapeutic intervention for VU, involving human subjects, and written in English. Exclusion criteria: Non-randomized studies, study protocols of RCTs and abstracts. A study will be defined as a RCT if the assignment of participants to interventions was described by phrases such as randomly allocated, assigned at random, or allocated by randomization, and if a control group is present. The control group could be placebo, another treatment, a different dose of the same treatment, usual care, or just no treatment.[] The search strategy will include terms for RCTs (Randomized Controlled Trial[ptyp]), venous ulcers (venous ulcers, stasis ulcers, varicose ulcers, venous stasis ulcers, venous hypertension ulcers) and exclusions for other types of articles (study protocol, review, systematic review, meta-analysis, cohort, case control, case series, guideline and editorial) and limits set for the specific time periods of interest (0/0/0 to /0/). The strategy that we will adopt for the search is described in Appendix. The selection process will be carried out by two independent investigators (LPFA and MW) in two screening phases: title and abstract screening and full text review. The investigators will resolve any discrepancies through consensus. First, the studies will be evaluated by reading the abstracts and only those which fulfill the inclusion and exclusion criteria will be selected for further screening. Figure is a flow diagram showing the study selection procedures. Rating the framing of the research question We will use the same methodology applied in a previous study.[] One paragraph from the introduction or methods section in the full text that best describes the primary RQ, hypothesis or objective will be chosen. In that paragraph, we will evaluate the framing of the RQ, regardless of whether it was formulated as a RQ, hypothesis or objective. We will examine whether the five elements of the PICOT format are used. The five elements - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

26 Page of 0 are the type of patients or population relevant to the question (P), the intervention (I), the comparative intervention (C), the outcome of interest (O), and the time horizon for measuring the outcome (T). We will score each element as if it was present and as 0 if it was absent. Thus, we will create a PICOT score ranging from 0 and. The score will represent a measure of completeness of the description of the primary RQ. Data abstraction We will use a Microsoft Excel standardized data abstraction form to extract data from each article. To explore the possible factors that influence the framing of the RQ additional details will also be obtained: endorsement of the CONSORT statement, journal impact factor, whether the study was conducted at single center or multicentre, total number of patients recruited in the study, whether the study is industry sponsored, whether the study reported a statistically significant result for the primary outcome. Two reviewers (LPFA and MW) will independently abstract the data and any disagreement will be resolved through consensus. If consensus can t be reached, a third author (LT) will be contacted. Statistical Analysis The primary outcome will be the percentage of studies that have adequately reported all PICOT elements and the secondary outcomes will be the percentage of reporting each PICOT item. We will calculate the percentage of trials that clearly stated each PICOT element and associated % confidence interval (CI). We will report descriptive statistics on categorical data as numbers (percentages) and PICOT score as median (interquartile range [IQR]). The PICOT score will be computed as the sum of the individual elements and will range from 0 to, as described previously. For the elements that have a zero count or full counts, for instance when none of or all of the included trials reported that PICOT element, the % CI will be calculated by adopting the rule of three.[] The rule of three states that: if none of n individuals reports the item of interest, we can be % confident that the chance of this event occurring is at most in n. For the other PICOT elements, the % CI of the count will be calculated by assuming a binomial distribution. The probability that a RCT had clearly stated the element will set to be the observed probability in the sample. We will use Cohen s Kappa (κ) statistic to calculate chance-adjusted inter-rater agreements. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.

27 Page of 0 Agreement will be interpreted as poor if κ 0., fair if 0. κ 0., moderate if 0. κ 0., substantial if 0. κ 0. and good if κ > 0..[] We will use generalized estimating equations (GEE)[] to determine the factors associated with adequate question formulation. The dependent variable will be the PICOT score, ranging from 0 to. Adjustments will be made for ) whether or not the journal endorses the CONSORT statement, ) journal impact factor, ) number of centres [multicentre versus single centre], ) sample size [ 00 versus > 00], ) results of trial [if the primary outcome was statistically significant] and ) funding status [industry funded versus other sources of funding]. Data will be analyzed using Statistical Package for Social Sciences (SPSS) Version.0 (SPSS, Inc., 0, Chicago, Illinois, USA). Sample size calculation: The sample size was determined based on the primary objective: estimating the proportion of studies that adequately report all PICOT elements using a % confidence interval. Based on a prior estimate of the proportion of RCTs reporting PICOT elements of 0. from a similar study,[] we would require at least RCTs to obtain an estimate of the % CI with a margin of error of 0.0. Table provides a summary of the sample size estimates for different values of the margin of error and prior estimates of the proportion of RCTs with RQ that adequately included PICOT elements. Table : Sample size estimates p E p= prior estimate of proportion with all PICOT element; E= margin of error N=, p(-p)/ E The summary of objectives, outcomes, hypotheses and methods of analysis are depicted in Table. - : first published as 0./bmjopen--0 on November. Downloaded from on October by guest. Protected by copyright.