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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
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
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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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References
1 Robertson L, Evans C, Fowkes FGR. Epidemiology of chronic venous disease. Phlebology 2008;23:103–11.
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.
10 Sackett DL, Wennberg JE. Choosing the best research design for each question. BMJ 1997;315:20–7.
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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
Med Res Methodol 2010;10:11.
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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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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
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
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"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 ("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
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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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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
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
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"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 ("2009/01/01"[PDAT] : "2016/05/31"[PDAT]))
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