Relationship between diet and ankylosing spondylitis: a systematic review

Transcription

1 Relationship between diet and ankylosing spondylitis: a systematic review Research protocol November 2015 Juliane Hinz, 1,2 Hadeel M. Abbood 1 Dr. Tatiana V. Macfarlane 1 Dr. Ejaz Pathan 3 Prof. G. J. Macfarlane 4 Katy Gordon 5 1 Aberdeen Dental School and Hospital, University of Aberdeen, AB25 2ZD 2 University of Bremen, Bibliothekstraße 1, Bremen 3 Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN 4 Epidemiology Group, Institute of Applied Health Sciences, University of Aberdeen, AB25 2ZD 5 Pain Concern, Newcraighall Road, Edinburgh, EH15 3HS

2 Table of contents Introduction... 3 Rationale: Why it is important... 3 Aim... 3 Objectives... 3 Participants... 3 Outcomes... 4 Method... 4 SEARCH STRATEGY... 4 INCLUSION AND EXCLUSION CRITERIA... 4 DATA EXTRACTION... 4 QUALITY ASSESSMENT... 4 DISSEMINATION... 5 Milestones... 5 Funding... 5 References:... 6 Table of appendixes Appendix 1 Map of searching terms in MEDLINE and Embase... 7 Appendix 2 Flow diagram of study selection process... 8 Appendix 3 Data extraction form... 9 Appendix 4 Methodology Checklist 1: Systematic Reviews and Meta-analyses Appendix 5 Methodology Checklist 2: Controlled Trials Appendix 6 Methodology Checklist 3: Cohort studies Appendix 7 Methodology Checklist 4: Case-Control studies

3 Introduction Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that can affect the axial skeleton. AS is a prototype of a group of overlapping inflammatory diseases named spondyloarthropathies (Khan 2009). It leads to new bone formation, such as ankyloses of the vertebral column (Baraliakos et al. 2008). Symptoms include inflammatory back pain, asymmetrical peripheral inflammation in several peripheral joints, enthesitis, and specific organ involvement such as uveitis (Braun et al. 2007). Over a longer time-period, the disease slowly effects in progressive limitation of spinal mobility and limited chest expansion (Khan 2009). If the disease is not treated, the inflammation of the spinal joints will slowly destroy the cartilage and fibrous tissue of the surrounding structures as well as the ligaments and replace them with bone (Weisman 2011). One of the causes for AS is genetic as there is a strong association with the genetic marker HLA-B27. However the biological relationship between the gene and AS have not yet been satisfactory explained (Khan 2009). Diet has significant effects on health in general and especially on vulnerability to chronic diseases. Diet is related to obesity, heart diseases, hypertension, diabetes, osteoporosis, cancer and oral diseases. For example a high intake of carbohydrates can cause periodontitis. Periodontitis (PD) is a form of periodontal disease, which is defined as any disorder of the tissue surrounding and supporting the teeth (Pihlstrom et al. 2005). Mostly, this disorder is characterized by a gingival inflammation caused by pathogenic bacteria on the dental plaque (Pihlstrom et al. 2005). Rationale: Why it is important Patients with AS reported worsening of disease activity with certain foods, but only few studies showed an association between AS and diet (Sundström et al. 2011). Aim To assess the relationship between diet and AS. Objectives The systematic review has the following objectives: a) To investigate whether there is any evidence that patients with AS report different diet style to those without. b) To find out whether diet may affect the severity of AS. c) To investigate whether persons with particular diets are less likely to develop AS. d) To investigate if dietary interventions improve symptoms of AS. Participants The studies will be restricted to human studies. There will be no restriction to gender, socioeconomic class or ethnicity. People under 16 years will be excluded. 3

4 Outcomes Outcome measurements will be values of pain, severity of AS symptoms and the presence or absence of AS. Method Search strategy MEDLINE and Embase databases will be used for the electronic search for studies up to The search strategy terms will be grouped into two categories. Group I terms will be related to Ankylosing spondylitis (ankylosing spondylitis, Spondyloarthropath$, Spondylitis, Spondylarthropath$, spondyloarthritis) and group II will include terms associated with diet (nutrition, food, diet, Food habits, nutritional status, Vitamins, Antioxidants, fatty acids, cholesterol, carbohydrates, dietary protein, calcium, fish oils, fruit, vegetables, micronutrients). Intra-group terms will be combined with the Boolean commands OR, and Inter-group terms will be combined with AND. Two journals (Annals of the Rheumatic Diseases and Annual Review of Nutrition) will be searched manually from 2010 to Inclusion and exclusion criteria All observational studies on humans will be included (Cross-sectional, Cohort, Case-control and Case series studies). Randomized controlled trials will be included. We will include studies in any language. Data extraction After completing the database search and manual search, two independent reviewers will screen the title and the abstract of each study following the inclusion criteria. If disagreement occurs between the two reviewers, a third reviewer will be consulted. Data extraction will be done by two independent reviewers. They will extract the required data from each study. These information include: study type, population description (sample size, mean age, gender, method of recruitment), participation rate, definition of AS, type of dietary intake assessment, values that describe the relationship between AS and diet (see appendix 3). The data will be used to create tables. The tables will contain the key question of the study, type of ankylosing spondylitis diagnosis, diet assessment values. The measurement of the association between diet and ankylosing spondylitis will be quoted as reported by the authors: OR, RR, p-value, confidence interval and other analysis that can measure the association. It is planned to conduct a meta-analysis to pool the results, dependent on how big the differences between the studies will be. Quality assessment Scottish Intercollegiate Guidelines Network (SIGN) methodology checklists 1 will be performed to assess the quality of individual studies (see appendix 4 to 7). The four assessment tools will be used for systematic reviews, randomized controlled trials, cohort 1 Scottish Intercollegiate Guidelines Network (SIGN), 4

5 studies and case control studies. Two reviewers will conduct the quality assessment, if disagreement occurs, a third reviewer will be consulted. Dissemination Study protocol will be registered with PROSPERO We aim to publish this review in a peer reviewed journal. We will follow Prisma guidelines for reporting of systematic reviews Milestones Protocol finalised - November 2015 Search strategy - November 2015 Study selection November 2015 Data extraction November 2015 December 2015 Quality assessment December 2015 January 2016 Summary of results January 2016 Writing final report January 2016 Circulation of report for comments February 2016 Submission for publication - March 2016 Funding This work was supported by Erasmus, the National Ankylosing Spondylitis Society (NASS) and the University of Aberdeen. 5

6 References: Baraliakos, X., Listing, J., von der Recke, A., Braun, J. 2009, The Natural Course of Radiographic Progression in Ankylosing Spondylitis -- Evidence for Major Individual Variations in a Large Proportion of Patients, Journal of Rheumatology, vol. 36, no. 5, p Braun, J. & Sieper, J. 2007, Ankylosing Spondylitis, Lancet, vol. 369, no. 9570, pp Khan, M. 2009, Ankylosing Spondylitis in Oxford University Press, pp Pihlstrom, B. L., Michalowicz, B. S., Johnson, N. W. 2005, Periodontal diseases, Lancet, vol. 366, no. 9499, pp Roberts, K. & Flaherty, SJ Review of dietary assessment methods in public health. In Oxford: National Obesity Observational 2010, p. 3. Sundström, B., Wållberg-Jonsson, S. & Johansson, G On diet in ankylosing spondylitis, Clinical Rheumatology, vol. 30, no. 1, pp Weisman, M Ankylosing Spondylitis in Oxford University Press, pp

7 Appendix 1 Map of searching terms in MEDLINE and Embase AND All the groups results will be combined with AND Group I terms regarding ankylosing spondylitis Group II terms regarding diet 7

8 Included Eligibility Screening Identification Appendix 2 Flow diagram of study selection process Records that will be identified through database searching (n=?) Additional records that will be identified through hand-searching journals (n =?) Records screening (n =?) Excluding records due to language or validity (n =?) Records after screening (n =?) Removal of Duplication (n =?) Full-text articles assessment for eligibility (n =?) Studies that will be included in qualitative synthesis (n =?) Full-text articles excluded (n =?) - No AS - No diet - Neither AS nor diet - Not looking at relationship between AS and diet 8

9 Appendix 3 Data extraction form ID: Researcher: Title: First author s surename: Year of publication Country of study: Type of study Participants Participation rate Number: Male Female Age range: AS diagnosis criteria Diet assessment type Research Question: Is there any evidence that patients with AS report different diet style to those without? May diet affect the severity of AS? Are persons with particular diets less likely to develop AS? May dietary interventions improve symptoms of AS? Type of AS diagnosis Diet Outcome P Value Effect measure 9

10 Appendix 4 S I G N Methodology Checklist 1: Systematic Reviews and Meta-analyses SIGN gratefully acknowledges the permission received from the authors of the AMSTAR tool to base this checklist on their work: Shea BJ, Grimshaw JM, Wells GA, Boers M, Andersson N, Hamel C,. et al. Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews. BMC Medical Research Methodology 2007, 7:10 doi: / Available from [cited 10 Sep 2012] Study identification (Include author, title, year of publication, journal title, pages) Guideline topic: Key Question No: Before completing this checklist, consider: Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO reject. IF YES complete the checklist. Checklist completed by: Section 1: Internal validity In a well conducted systematic review: Does this study do it? 1.1 The research question is clearly defined and the inclusion/ exclusion criteria must be listed in the paper. If no reject 1.2 A comprehensive literature search is carried out. Not applicable If no reject 1.3 At least two people should have selected studies. 1.4 At least two people should have extracted data. 1.5 The status of publication was not used as an inclusion criterion. 1.6 The excluded studies are listed. 10

11 1.7 The relevant characteristics of the included studies are provided. 1.8 The scientific quality of the included studies was assessed and reported. 1.9 Was the scientific quality of the included studies used appropriately? 1.10 Appropriate methods are used to combine the individual study findings The likelihood of publication bias was assessed appropriately. Not applicable Not applicable 1.12 Conflicts of interest are declared. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 What is your overall assessment of the methodological quality of this review? 2.2 Are the results of this study directly applicable to the patient group targeted by this guideline? 2.3 Notes: High quality (++) Acceptable (+) Low quality (-) Unacceptable reject 0 11

12 Appendix 5 S I G N Methodology Checklist 2: Controlled Trials Study identification (Include author, title, year of publication, journal title, pages) Guideline topic: Key Question No: Reviewer: Before completing this checklist, consider: 1. Is the paper a randomised controlled trial or a controlled clinical trial? If in doubt, check the study design algorithm available from SIGN and make sure you have the correct checklist. If it is a controlled clinical trial questions 1.2, 1.3, and 1.4 are not relevant, and the study cannot be rated higher than Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist. Reason for rejection: 1. Paper not relevant to key question 2. Other reason (please specify): Section 1: Internal validity In a well conducted RCT study Does this study do it? 1.1 The study addresses an appropriate and clearly focused question. Can t say 1.2 The assignment of subjects to treatment groups is randomised. Can t say 1.3 An adequate concealment method is used. 1.4 The design keeps subjects and investigators blind about treatment allocation. Can t say Can t say 1.5 The treatment and control groups are similar at the start of the trial. 1.6 The only difference between groups is the treatment under investigation. 1.7 All relevant outcomes are measured in a standard, valid and reliable way. 1.8 What percentage of the individuals or clusters recruited into each treatment arm of the study dropped out before the study was completed? 1.9 All the subjects are analysed in the groups to which they were randomly allocated (often referred to as intention to treat analysis). Can t say Can t say Can t say Does not apply 12

13 1.10 Where the study is carried out at more than one site, results are comparable for all sites. Can t say Does not apply SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 How well was the study done to minimise bias? Code as follows: 2.2 Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, are you certain that the overall effect is due to the study intervention? 2.3 Are the results of this study directly applicable to the patient group targeted by this guideline? High quality (++) Acceptable (+) Low quality (-) Unacceptable reject Notes. Summarise the authors conclusions. Add any comments on your own assessment of the study, and the extent to which it answers your question and mention any areas of uncertainty raised above. 13

14 Appendix 6 S I G N Methodology Checklist 3: Cohort studies Study identification (Include author, title, year of publication, journal title, pages) Guideline topic: Key Question No: Reviewer: Before completing this checklist, consider: 1. Is the paper really a cohort study? If in doubt, check the study design algorithm available from SIGN and make sure you have the correct checklist. 2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist.. Reason for rejection: 1. Paper not relevant to key question 2. Other reason (please specify): Please note that a retrospective study (ie a database or chart study) cannot be rated higher than +. Section 1: Internal validity In a well conducted cohort study: Does this study do it? 1.1 The study addresses an appropriate and clearly focused question. i SELECTION OF SUBJECTS 1.2 The two groups being studied are selected from source populations that are comparable in all respects other than the factor under investigation. ii 1.3 The study indicates how many of the people asked to take part did so, in each of the groups being studied. iii 1.4 The likelihood that some eligible subjects might have the outcome at the time of enrolment is assessed and taken into account in the analysis. iv 1.5 What percentage of individuals or clusters recruited into each arm of the study dropped out before the study was completed. v 1.6 Comparison is made between full participants and those lost to follow up, by exposure status. vi ASSESSMENT Does not apply Does not apply Does not apply Does not apply 1.7 The outcomes are clearly defined. vii 14

15 1.8 The assessment of outcome is made blind to exposure status. If the study is retrospective this may not be applicable. viii 1.9 Where blinding was not possible, there is some recognition that knowledge of exposure status could have influenced the assessment of outcome. ix Does not apply 1.10 The method of assessment of exposure is reliable. x 1.11 Evidence from other sources is used to demonstrate that the method of outcome assessment is valid and reliable. xi Does not apply 1.12 Exposure level or prognostic factor is assessed more than once. xii Does not apply CONFOUNDING 1.13 The main potential confounders are identified and taken into account in the design and analysis. xiii STATISTICAL ANALYSIS 1.14 Have confidence intervals been provided? xiv SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 How well was the study done to minimise the risk of bias or confounding? High quality (++) Acceptable (+) Unacceptable reject Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, do you think there is clear evidence of an association between exposure and outcome? 2.3 Are the results of this study directly applicable to the patient group targeted in this guideline? Can t say 2.4 Notes. Summarise the authors conclusions. Add any comments on your own assessment of the study, and the extent to which it answers your question and mention any areas of uncertainty raised above. i Unless a clear and well defined question is specified in the report of the review, it will be difficult to assess how well it has met its objectives or how relevant it is to the question you are trying to answer on the basis of the conclusions. ii This relates to selection bias.* It is important that the two groups selected for comparison are as similar as possible in all characteristics except for their exposure status, or the presence of specific prognostic factors or prognostic markers relevant to the study in question. 15

16 iii This relates to selection bias.* The participation rate is defined as the number of study participants divided by the number of eligible subjects, and should be calculated separately for each branch of the study. A large difference in participation rate between the two arms of the study indicates that a significant degree of selection bias* may be present, and the study results should be treated with considerable caution. iv If some of the eligible subjects, particularly those in the unexposed group, already have the outcome at the start of the trial the final result will be subject to performance bias.* A well conducted study will attempt to estimate the likelihood of this occurring, and take it into account in the analysis through the use of sensitivity studies or other methods. v This question relates to the risk of attrition bias.*the number of patients that drop out of a study should give concern if the number is very high. Conventionally, a 20% drop out rate is regarded as acceptable, but in observational studies conducted over a lengthy period of time a higher drop out rate is to be expected. A decision on whether to downgrade or reject a study because of a high drop out rate is a matter of judgement based on the reasons why people dropped out, and whether drop out rates were comparable in the exposed and unexposed groups. Reporting of efforts to follow up participants that dropped out may be regarded as an indicator of a well conducted study. vi For valid study results, it is essential that the study participants are truly representative of the source population. It is always possible that participants who dropped out of the study will differ in some significant way from those who remained part of the study throughout. A well conducted study will attempt to identify any such differences between full and partial participants in both the exposed and unexposed groups. This relates to the risk of attrition bias.* Any unexplained differences should lead to the study results being treated with caution. vii This relates to the risk of detection bias.* Once enrolled in the study, participants should be followed until specified end points or outcomes are reached. In a study of the effect of exercise on the death rates from heart disease in middle aged men, for example, participants might be followed up until death, or until reaching a predefined age. If outcomes and the criteria used for measuring them are not clearly defined, the study should be rejected. viii This relates to the risk of detection bias.* If the assessor is blinded to which participants received the exposure, and which did not, the prospects of unbiased results are significantly increased. Studies in which this is done should be rated more highly than those where it is not done, or not done adequately. ix This relates to the risk of detection bias.* Blinding is not possible in many cohort studies. In order to asses the extent of any bias that may be present, it may be helpful to compare process measures used on the participant groups - e.g. frequency of observations, who carried out the observations, the degree of detail and completeness of observations. If these process measures are comparable between the groups, the results may be regarded with more confidence. x This relates to the risk of detection bias.* A well conducted study should indicate how the degree of exposure or presence of prognostic factors or markers was assessed. Whatever measures are used must be sufficient to establish clearly that participants have or have not received the exposure under investigation and the extent of such exposure, or that they do or do not possess a particular prognostic marker or factor. Clearly described, reliable measures should increase the confidence in the quality of the study xi This relates to the risk of detection bias.* The primary outcome measures used should be clearly stated in the study. If the outcome measures are not stated, or the study bases its main conclusions on secondary outcomes, the study should be rejected. Where outcome measures require any degree of subjectivity, some evidence should be provided that the measures used are reliable and have been validated prior to their use in the study. xii This relates to the risk of detection bias.* Confidence in data quality should be increased if exposure level is measured more than once in the course of the study. Independent assessment by more than one investigator is preferable. xiii Confounding is the distortion of a link between exposure and outcome by another factor that is associated with both exposure and outcome. The possible presence of confounding factors is one of the principal reasons why observational studies are not more highly rated as a source of evidence. The report of the study should indicate which potential confounders have been considered, and how they have been assessed or allowed for in the analysis. Clinical judgement should be applied to consider whether all likely confounders have been considered. If the measures used to address confounding are considered inadequate, the study should be downgraded or rejected, depending on how 16

17 serious the risk of confounding is considered to be. A study that does not address the possibility of confounding should be rejected. xiv Confidence limits are the preferred method for indicating the precision of statistical results, and can be used to differentiate between an inconclusive study and a study that shows no effect. Studies that report a single value with no assessment of precision should be treated with extreme caution. Rate the overall methodological quality of the study, using the following as a guide: High quality (++): Majority of criteria met. Little or no risk of bias. Results unlikely to be changed by further research. Acceptable (+): Most criteria met. Some flaws in the study with an associated risk of bias, Conclusions may change in the light of further studies. Low quality (0): Either most criteria not met, or significant flaws relating to key aspects of study design. Conclusions likely to change in the light of further studies. 17

18 Appendix 7 S I G N Methodology Checklist 4: Case-control studies Study identification (Include author, title, year of publication, journal title, pages) Guideline topic: Key Question No: Reviewer: Before completing this checklist, consider: 1. Is the paper really a case-control study? If in doubt, check the study design algorithm available from SIGN and make sure you have the correct checklist. 2. Is the paper relevant to key question? Analyse using PICO (Patient or Population Intervention Comparison Outcome). IF NO REJECT (give reason below). IF YES complete the checklist. Reason for rejection: Reason for rejection: 1. Paper not relevant to key question 2. Other reason (please specify): Section 1: Internal validity In an well conducted case control study: Does this study do it? 1.1 The study addresses an appropriate and clearly focused question. SELECTION OF SUBJECTS Can t say 1.2 The cases and controls are taken from comparable populations. Can t say 1.3 The same exclusion criteria are used for both cases and controls. Can t say 1.4 What percentage of each group (cases and controls) participated in the study? Cases: Controls: 1.5 Comparison is made between participants and non-participants to establish their similarities or differences. Can t say 1.6 Cases are clearly defined and differentiated from controls. Can t say 1.7 It is clearly established that controls are non-cases. ASSESSMENT Can t say 18

19 1.8 Measures will have been taken to prevent knowledge of primary exposure influencing case ascertainment. Can t say Does not apply 1.9 Exposure status is measured in a standard, valid and reliable way. CONFOUNDING Can t say 1.10 The main potential confounders are identified and taken into account in the design and analysis. STATISTICAL ANALYSIS Can t say 1.11 Confidence intervals are provided. SECTION 2: OVERALL ASSESSMENT OF THE STUDY 2.1 How well was the study done to minimise the risk of bias or confounding? 2.2 Taking into account clinical considerations, your evaluation of the methodology used, and the statistical power of the study, do you think there is clear evidence of an association between exposure and outcome? High quality (++) Acceptable (+) Unacceptable reject 0 Can t say 2.3 Are the results of this study directly applicable to the patient group targeted by this guideline? 2.4 Notes. Summarise the authors conclusions. Add any comments on your own assessment of the study, and the extent to which it answers your question and mention any areas of uncertainty raised above.. Unless a clear and well defined question is specified in the report of the review, it will be difficult to assess how well it has met its objectives or how relevant it is to the question you are trying to answer on the basis of the conclusions. Study participants may be selected from the target population (all individuals to which the results of the study could be applied), the source population (a defined subset of the target population from which participants are selected), or from a pool of eligible subjects (a clearly defined and counted group selected from the source population. If the study does not include clear definitions of the source population it should be rejected. All selection and exclusion criteria should be applied equally to cases and controls. Failure to do so may introduce a significant degree of bias into the results of the study. Differences between the eligible population and the participants are important, as they may influence the validity of the study. A participation rate can be calculated by dividing the number of study participants by the number of eligible subjects. It is more useful if calculated separately for cases and controls. If the participation rate is low, or there is a 19

20 large difference between the two groups, the study results may well be invalid due to differences between participants and non-participants. In these circumstances, the study should be downgraded, and rejected if the differences are very large. Even if participation rates are comparable and acceptable, it is still possible that the participants selected to act as cases or controls may differ from other members of the source population in some significant way. A well conducted case-control study will look at samples of the non-participants among the source population to ensure that the participants are a truly representative sample. The method of selection of cases is of critical importance to the validity of the study. Investigators have to be certain that cases are truly cases, but must balance this with the need to ensure that the cases admitted into the study are representative of the eligible population. The issues involved in case selection are complex, and should ideally be evaluated by someone with a good understanding of the design of case-control studies. If the study does not comment on how cases were selected, it is probably safest to reject it as a source of evidence. Just as it is important to be sure that cases are true cases, it is important to be sure that controls do not have the outcome under investigation. Control subjects should be chosen so that information on exposure status can be obtained or assessed in a similar way to that used for the selection of cases. If the methods of control selection are not described, the study should be rejected. If different methods of selection are used for cases and controls the study should be evaluated by someone with a good understanding of the design of case-control studies. If there is a possibility that case ascertainment can be influenced by knowledge of exposure status, assessment of any association is likely to be biased. A well conducted study should take this into account in the design of the study. The primary outcome measures used should be clearly stated in the study. If the outcome measures are not stated, or the study bases its main conclusions on secondary outcomes, the study should be rejected. Where outcome measures require any degree of subjectivity, some evidence should be provided that the measures used are reliable and have been validated prior to their use in the study. Confounding is the distortion of a link between exposure and outcome by another factor that is associated with both exposure and outcome. The possible presence of confounding factors is one of the principal reasons why observational studies are not more highly rated as a source of evidence. The study should indicate which potential confounders have been considered, and how they have been allowed for in the analysis. Clinical judgement should be applied to consider whether all likely confounders have been considered. If the measures used to address confounding are considered inadequate, the study should be downgraded or rejected. A study that does not address the possibility of confounding should be rejected. Confidence limits are the preferred method for indicating the precision of statistical results, and can be used to differentiate between an inconclusive study and a study that shows no effect. Studies that report a single value with no assessment of precision should be treated with extreme caution. Rate the overall methodological quality of the study, using the following as a guide: High quality (++): Majority of criteria met. Little or no risk of bias. Results unlikely to be changed by further research. Acceptable (+): Most criteria met. Some flaws in the study with an associated risk of bias, Conclusions may change in the light of further studies. Low quality (0): Either most criteria not met, or significant flaws relating to key aspects of study design. Conclusions likely to change in the light of further studies. 20