framing of research question using the picot format in...

For peer review only

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: BMJ Open

Manuscript ID bmjopen-2016-013175

Article Type: Protocol

Date Submitted by the Author: 24-Jun-2016

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

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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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,1,2,5

MD, PhD; Mei Wang2; Kamath Sriganesh, DM;

3,4 Lawrence

Mbuagbaw;2,5 Lehana Thabane

2,5

Affiliations:

1. Department of Dermatology and Radiotherapy, Botucatu Medical School, Universidade

Estadual Paulista, UNESP, São Paulo, Brazil

2. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton,

ON, Canada.

3. Department of Neuroanaesthesia, National Institute of Mental Health and Neurosciences,

Bangalore, India.

4. Department of Anesthesia, McMaster University, Hamilton, ON, Canada.

5. 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, 3rd Floor Martha, Room

H325, St. Joseph’s Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario L8N 4A6,

Canada.

Office Telephone: 1-905-522-1155 ext 33720/34905

Office Fax : 1-905-528-7386

Email Address : [email protected]

Word count: 1.877; Figures: 01; Tables: 02; references: 25; supplementary files: 01

Key words: statistic and research methods, wound management, clinical trial, venous ulcers,

randomized controlled trial

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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 2009 and

May 2016. 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 5. The primary outcome will

be the proportion of studies that have adequately reported all 5 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

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• 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.

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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.[1] The

prevalence of VU varies between 0.06% and 2%, occurring in approximately 4% of those

over 65 years.[2]

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.[3][4] The overall costs with treatment of patients with VU in most

Western countries, expending approximately 1% of their entire health care budgets.[5]

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.[6][7]

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.[8]

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.[9] The RQ determines the research architecture,

strategy, and methodology.[10] 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.[9] 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.[11]

Posing a well formulated RQ will help the practitioner focus on the problem that

is most important and help focus a subsequently initiated search.[12] The PICO format

strategy for framing RQ that was first introduced in 1995,[13] and later expanded to the

acronym PICOT in 2006,[14] 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.[9][15]

In other fields of medicine, the use of the PICOT framework is sub-optimal and

often associated with poor reporting of key methodological issues.[16][17]

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Hypothesis

We hypothesize the following: 1- There are less than 25% RCTs about VU that

adequately report all the 5 PICOT elements in their RQ, and 2- 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 >100, 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: 1) to assess how the PICOT format is used to frame RQ,

objectives or hypotheses in reports of RCTs published on VU and 2) 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 2009 and May 2016. 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.[18][19]

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.[20]

The search strategy will include terms for RCTs (Randomized Controlled

Trial[ptyp]), venous ulcers (venous ulcers, stasis ulcers, varicose ulcers, venous stasis ulcers,

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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 (01/01/2009 to 31/05/2016). The

strategy that we will adopt for the search of the studies is described in Appendix 1. 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 1 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.[16] 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 1 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

5. 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.

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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 95% 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 5 individual elements and

will range from 0 to 5, as described previously17. 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 95% CI will be calculated by adopting the rule of three.[21] If none of n

individuals within a PICOT element showed the event that we will be interested in, we could

be 95% confident that the chance of this event occurring is at most 3 in n. For the other

PICOT elements, the 95% 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 ≤ 0.2, fair if 0.21 ≤ κ ≤ 0.4, moderate

if 0.41 ≤ κ ≤0.6, substantial if 0.61 ≤ κ ≤ 0.8 and good if κ > 0.8.[22]

We will use generalized estimating equations (GEE)[23] to determine the factors

associated with adequate question formulation. Dependent variable will be PICOT score

varies from 0 to 5. Adjustments will be made for 1) whether or not the journal endorses the

CONSORT statement, 2) journal impact factor, 3) number of centres [multicentre versus

single centre], 4) sample size [≤ 100 versus > 100], 5) results of trial [if the primary outcome

was statistically significant] and 6) 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 16.0 (SPSS, Inc., 2009, 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 5 PICOT elements using a 95%

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confidence interval. Based on prior estimate of the proportion of RCTs reporting 5 PICOT

elements of 0.20 from a similar study,[16] we would require at least 61 RCTs to obtain an

estimate of the 95% CI with a margin of error of 0.10. Table 1 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 5 PICOT elements.

Table 1: Sample size estimates

E

p

0.15 0.20 0.30

0.05 196 246 323

0.10 49 61 81

0.15 22 27 36

p= prior estimate of proportion with all 5 PICOT element; E= margin of error

N= 1,962 p(1-p)/ E

2

The summary of objectives, outcomes, hypotheses and methods of analysis are

depicted in Table 2

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Table 2: Summary of objectives, outcomes, hypotheses and methods of analysis

Objectives Outcomes Explanatory

variables

Hypothesis Methods of analyses

Primary: To assess how the PICOT format is used to frame RQ, objectives or hypotheses based on reports of RCTs published on VU

Primary: Proportion of studies that have adequately reported all 5 PICOT elements

1) There are less than 25% RCTs about VU that reported adequately all 5 PICOT elements in RQ

Percentage of trials that clearly stated each PICOT element and associated 95% confidence interval (95% CI).

Secondary: To determine key factors associated with better adherence to PICOT format in framing the RQ,

1) CONSORT statement by the journal

2) journal impact factor

3) number of centers [multiple centers versus single center]

4) sample size [≤ 100 versus > 100]

5) results of trial [ if the primary outcome was statistically significant]

6) funding status [industry funded versus non-funded].

2) 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 > 100, report statistically significant results for the primary outcome and are industry funded.

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

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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.[7] Asking a good RQ is the first step to perform a good

study and improve the overall study quality.[10] 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.[9]

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.[16] We expect that the compliance of the RQ with PICOT

format is better with high impact factor of the journal,[18] endorsement of the CONSORT

statement for RCTs by the journals,[18] multi-sites studies,[18] studies with larger sample

size,[18],[24] and industry funding of the study.[25]

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.

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2 Hafner J, Baumann Conzett K. Epidemiology and pathophysiology of venous ulcers. Aktuelle Derm 2009;35:216–20

3 Park SH, Ferreira K, Santos VL. Understanding pain and quality of life for patients with chronic venous ulcers. Wounds a Compend Clin Res Pract 2008;20:309–20.

4 Lal BK. Venous ulcers of the lower extremity: Definition, epidemiology, and economic and social burdens. Semin. Vasc. Surg. 2015;28:3–5.

5 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 2014;60:3–59.

6 Zenilman J, Valle MF, Malas MB, et al. Chronic Venous Ulcers: A Comparative Effectiveness Review of Treatment Modalities. Comparative Effectiveness Review No. 127. (Prepared by Johns Hopkins Evidence-based Practice Center under Contract No. 290-2007-10061-I.) AHRQ Publication No. 13(14)-EHC121. Rockville, MD Agency Healthc. Res. Qual. December 2013. Erratum January 2014.

7 Lazarus G, Valle MF, Malas M, et al. Chronic venous leg ulcer treatment: Future research needs. Wound Repair Regen 2014;22:34–42.

8 Sackett DL, Rosenberg WMC, Gray JAM , et al. Evidence based medicine: what it is and what it isn’t. Br Med J 1996;312:71–2.

9 Thabane L, Thomas T, Ye C, et al. Posing the research question: Not so simple. Can. J. Anesth. 2009;56:71–9.

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12 Schlosser RW, Koul R, Costello J. Asking well-built questions for evidence-based practice in augmentative and alternative communication. J Commun Disord 2007;40:225–38.

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14 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 2006:3-14.

15 Riva JJ, Malik KM, Burnie SJ, et al. What is your research question ? An introduction to the PICOT format for clinicians. J Chiropratic Assoc 2012;56:167–71.

16 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

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17 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 2013;13:44.

18 Samaan Z, Mbuagbaw L, Kosa D, et al. A systematic scoping review of adherence to reporting guidelines in health care literature. J Multidiscip Healthc 2013;6:169–88.

19 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 2014;38:245–50.

20 Rios LP, Odueyungbo A, Moitri MO, et al. Quality of reporting of randomized controlled trials in general endocrinology literature. J Clin Endocrinol Metab 2008;93:3810–6.

21 Eypasch E, Lefering R, Kum CK, et al. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995;311:619–20.

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24 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

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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.

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Appendix 1: Search strategy adopted for RCTs in venous ulcers between January 2009 and May

2016 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: 157 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


("varicose"[All Fields] AND "ulcers"[All Fields]) OR "varicose ulcers"[All Fields]) OR ("varicose


("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


("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


("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


"varicose ulcer"[All Fields] OR ("ulcer"[All Fields] AND "venous"[All Fields] AND "hypertension"[All


"varicose ulcer"[All Fields] OR ("ulcers"[All Fields] AND "venous"[All Fields] AND "hypertension"[All


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"varicose ulcer"[All Fields] OR ("venous"[All Fields] AND "hypertension"[All Fields] AND "ulcer"[All


"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


("ulcers"[All Fields] AND "stasis"[All Fields]) OR "ulcers, stasis"[All Fields])) AND (Randomized Controlled

Trial[ptyp] AND ("2009/01/01"[PDAT] : "2016/05/31"[PDAT]))

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254x190mm (96 x 96 DPI)

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June 23, 2016

Editor-in-Chief

BMJ Open

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 1) 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 2) 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

BMJ Open. 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

E-mail: [email protected]

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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: BMJ Open

Manuscript ID bmjopen-2016-013175.R1

Article Type: Protocol

Date Submitted by the Author: 14-Sep-2016

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


BMJ Open on 3 June 2018 by guest. P

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jopen.bmj.com

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MJ O

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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,1,2,5 MD, PhD; Mei Wang2; Kamath Sriganesh, DM;3,4 Lawrence Mbuagbaw;2,5 Lehana Thabane2,5

Affiliations:

1. Department of Dermatology and Radiotherapy, Botucatu Medical School, Universidade Estadual Paulista, UNESP, São Paulo, Brazil

2. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada.

3. Department of Neuroanaesthesia, National Institute of Mental Health and Neurosciences, Bangalore, India.

4. Department of Anesthesia, McMaster University, Hamilton, ON, Canada. 5. 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, 3rd Floor Martha,

Room H325, St. Joseph’s Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario

L8N 4A6, Canada.

Office Telephone: 1-905-522-1155 ext 33720/34905

Office Fax : 1-905-528-7386

Email Address : [email protected]

Word count: 1.986; Figures: 01; Tables: 02; references: 44; supplementary files: 01

Key words: statistic and research methods, wound management, clinical trial, venous ulcers, randomized controlled trial

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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 2009 and

May 2016. 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 5. The primary outcome will be the proportion of studies that have adequately reported

all 5 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

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• 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.

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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.[1] The

prevalence of VU varies from 0.06% to 2%, occurring in approximately 4% of people over

65 years.[2] 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.[3, 4] The primary risk factors for VU include old age, phlebitis and deep

venous thrombosis. [1, 5]

Complications arising from VU are diverse, primarily related to its chronicity.

The main complications are critical colonization and contact dermatitis.[6, 7] More severe

complications include cellulitis, osteomyelitis, and malignant change.[8, 9] High rates of

relapse after healing is other problem with annual recurrence rates varying between 26% and

69%.[10-12]. In addition VU comes with physical, social, economic and emotional

burden.[13][14] The overall cost of VU treatment in most Western countries is approximately

1% of their entire health care budgets.[15]

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. [16] 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.[17]

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.[18] 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.[19] The RQ determines the research architecture, strategy and methodology.[20]

A clear and focused RQ will help to determine the appropriate study design and the most

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appropriate methods of statistical analysis and sample size [19] 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.[21]

Posing a well formulated RQ will help the practitioner focus on the problem that

is most important.[22] The PICO format strategy for framing RQs that was first introduced in

1995,[23] and later expanded to the acronym PICOT in 2006,[24] 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.[19][25]

In other fields of medicine, the use of the PICOT framework is sub-optimal and

often associated with poor reporting of key methodological issues.[26][27]

Hypotheses

We hypothesize the following: 1)Less than 25% of the RCTs on VU use all the 5

PICOT elements in their RQ,[26] 2) the RQ is more likely to follow the PICOT format if the

RCT is published in a journal that endorses the CONSORT statement,[28-32] or has a high

impact factor,[30][33] is a multicentre study,[34] has a large sample size (>100

participants),[35-37] reports statistically significant result for the primary outcome[38] and if

they are industry funded. [35][39] These six factors were chosen based on evidence from

previous research that show them to be related with better overall reporting quality [40].

Furthermore, the framing of the RQ using the PICOT format has also been shown to be

independently associated with better reporting quality.[26]

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: 1) to assess how the PICOT format is

used to frame RQs in reports of RCTs published on VU and 2) to determine the factors

associated with better adherence to the PICOT format in framing of the RQ.

Methods

Study design

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This study will be a systematic survey of the RCTs on VU published in the

National Institute of Health, PubMed database between January 2009 and May 2016. This

time-frame and library were chosen primarily based on feasibility considerations. This time-

frame 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.[40][41]

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.[35]

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 (01/01/2009 to 31/05/2016). The

strategy that we will adopt for the search is described in Appendix 1. 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 1 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.[26] 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

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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 1 if it was present and as 0 if it was absent.

Thus, we will create a PICOT score ranging from 0 and 5. 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 5 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 95% 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 5 individual elements and

will range from 0 to 5, as described previously17. 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 95% CI will be calculated by adopting the rule of three.[42] The rule of three

states that: if none of n individuals reports the item of interest, we can be 95% confident that

the chance of this event occurring is at most 3 in n. For the other PICOT elements, the 95%

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.

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Agreement will be interpreted as poor if κ ≤ 0.2, fair if 0.21 ≤ κ ≤ 0.4, moderate if 0.41 ≤ κ ≤

0.6, substantial if 0.61 ≤ κ ≤ 0.8 and good if κ > 0.8.[43]

We will use generalized estimating equations (GEE)[44] to determine the factors

associated with adequate question formulation. The dependent variable will be the PICOT

score, ranging from 0 to 5. Adjustments will be made for 1) whether or not the journal

endorses the CONSORT statement, 2) journal impact factor, 3) number of centres

[multicentre versus single centre], 4) sample size [≤ 100 versus > 100], 5) results of trial [if

the primary outcome was statistically significant] and 6) funding status [industry funded

versus other sources of funding].

Data will be analyzed using Statistical Package for Social Sciences (SPSS)

Version 16.0 (SPSS, Inc., 2009, 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 5 PICOT elements using a 95% confidence

interval. Based on a prior estimate of the proportion of RCTs reporting 5 PICOT elements of

0.20 from a similar study,[26] we would require at least 61 RCTs to obtain an estimate of the

95% CI with a margin of error of 0.10. Table 1 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 5 PICOT elements.

Table 1: Sample size estimates

E

p

0.15 0.20 0.30

0.05 196 246 323

0.10 49 61 81

0.15 22 27 36

p= prior estimate of proportion with all 5 PICOT element; E= margin of error

N= 1,962 p(1-p)/ E

2

The summary of objectives, outcomes, hypotheses and methods of analysis are

depicted in Table 2.

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Table 2: Summary of objectives, outcomes, hypotheses and methods analysis

Objectives Outcomes Explanatory

variables

Hypotheses Methods of analyses

Primary: To assess how the PICOT format is used to frame RQ, objectives or hypotheses based on reports of RCTs published on VU

Primary: Proportion of studies that have adequately reported all 5 PICOT elements

1) There are less than 25% RCTs about VU that adequately report all 5 PICOT elements in the RQ

Percentage of trials that clearly state each PICOT element and associated 95% confidence interval (95% CI).

Secondary: To determine the factors associated with better adherence to PICOT format in framing the RQ

1) CONSORT endorsement by the journal

2) journal impact factor

3) number of centers [multiple centers versus single center]

4) sample size [≤ 100 versus > 100]

5) results of trial [ if the primary outcome was statistically significant]

6) funding status [industry funded versus other].

2) The use of the PICOT format will be better if the journals in which it is published endorses the CONSORT statement , has a high impact factor, is amulticenter study, has a sample size > 100, reports statistically significant results for the primary outcome and is industry funded.

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

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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-designed and reported clinical trials.[17] Asking a good RQ is the first step in

conducting a good study and improves the overall quality of the study.[20] 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 part on the researcher's ability to transform the

clinical problem in the central research question.[19]

The results of this analysis will help to elucidate the extent to which the PICOT

format is used to frame RQ in RCTs published on VU. In the event that use of the PICOT

framework is sub-optimal, this analysis will reinforce the importance of framing a good 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 at scientific

conferences.

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30 Ethgen M, Boutron L, Steg PG, et al. Quality of reporting internal and external validity data from randomized controlled trials evaluating stents for percutaneous coronary intervention. BMC Med Res Methodol 2009;9:24.

31 Kiehna EN, Starke RM, Pouratian N, et al. Standards for reporting randomized controlled trials in neurosurgery. J Neurosurg 2011;114:280–5.

32 Zhong Y, Zhou W, Jiang H, et al. Quality of reporting of two-group parallel randomized controlled clinical trials of multi-herb formulae: A survey of reports indexed in the Science Citation Index Expanded. Eur. J. Integr. Med. 2011;3.

33 Montané E, Vallano A, Vidal X, et al. Reporting randomised clinical trials of analgesics after traumatic or orthopaedic surgery is inadequate: a systematic review. BMC Clin Pharmacol 2010;10:2.

34 Balasubramanian SP, Wiener M, Alshameeri Z, et al. Standards of reporting of randomized controlled trials in general surgery: can we do better? Ann Surg 2006;244:663–7.

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35 Rios LP, Odueyungbo A, Moitri MO, et al. Quality of reporting of randomized controlled trials in general endocrinology literature. J Clin Endocrinol Metab 2008;93:3810–6.

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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.

Figure legend:

Figure 1: Flow diagram showing study selection procedure

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90x90mm (300 x 300 DPI)

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Appendix 1: Search strategy adopted for RCTs in venous ulcers between January 2009 and May

2016 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: 157 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


("ulcers"[All Fields] AND "varicose"[All Fields]) OR "ulcers, varicose"[All Fields])) OR ("varicose


("varicose"[All Fields] AND "ulcers"[All Fields]) OR "varicose ulcers"[All Fields]) OR ("varicose


("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


("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


("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


"varicose ulcer"[All Fields] OR ("hypertension"[All Fields] AND "ulcers"[All Fields] AND "venous"[All


"varicose ulcer"[All Fields] OR ("ulcer"[All Fields] AND "venous"[All Fields] AND "hypertension"[All


"varicose ulcer"[All Fields] OR ("ulcers"[All Fields] AND "venous"[All Fields] AND "hypertension"[All


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"varicose ulcer"[All Fields] OR ("venous"[All Fields] AND "hypertension"[All Fields] AND "ulcer"[All


"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


("ulcers"[All Fields] AND "stasis"[All Fields]) OR "ulcers, stasis"[All Fields])) AND (Randomized Controlled

Trial[ptyp] AND ("2009/01/01"[PDAT] : "2016/05/31"[PDAT]))

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