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Do patients with chronic low-back pain experience a loss of health-related quality of life? A protocol for a systematic review and meta-analysis

Introduction Health-related quality of life in chronic low back pain (LBP) is an important issue since various individual factors such as perceived loss of autonomy, inability to continue daily life and anxiety can contribute to maintenance or deterioration of this condition. Health-related quality of life is also important because it can predict the probability of recovery or recrudescence over time. In the literature, there is no systematic review on this topic. The present paper describes a protocol of the first systematic review and meta-analysis aimed at summarising the data on health-related quality of life in patients with chronic LBP compared with healthy controls. Gender, age and comorbidity of psychiatric disorders (mood or anxiety disorders) will be explored as moderators. Studies will be included if they used a case–control design comparing adults with chronic LBP to healthy controls on health-related quality of life through validated interviews/questionnaires. Methods and analysis According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses, a systematic review and meta-analysis will be conducted from 10th to 17th January 2020. Independent reviewers will search published/unpublished studies through electronic databases (Scopus, PubMed, EMBASE and the Cochrane Library) and additional sources, will extract the data and assess the methodological quality through the Newcastle-Ottawa Scale. Random-effect meta-analysis will be carried out by calculating effect sizes as Cohen’s d indices. Publication bias will be assessed and moderators of the effect sizes will be investigated through weighted least squares meta-regression. The knowledge whether health-related quality of life is better or worse as a function of some individual characteristics may suggest personalised care pathways according to a precision medicine approach. Ethics and dissemination The current review does not require ethics approval. The results will be disseminated through publications in peer-reviewed journals. PROSPERO registration number CRD42019131749

March 2017 for which I received a fee. I am chief investigator or coinvestigator on multiple previous and current research grants from the UK National Institute for Health Research (NIHR) , Arthritis Research UK and I am a co-investigator on grants funded by the Australian NHMRC. As an NIHR senior investigator, I receive research support from NIHR. I have received travel expenses, and honoraria, for speaking at conferences from the professional organisations hosting the conferences. I am a director and shareholder of Clinvivo Ltd that provides electronic data collection for health services research. I am part of an academic partnership with Serco Ltd. I have accepted an honorarium from the consortium for advanced research training in Africa. I am an editor of the NIHR journal series, and a member of the NIHIR Journal editors Group for which I receive a fee. I am co-investigator on two studies, funded by NIHR, that receive support in kind from Stryker Ltd. I have published multiple papers on low back pain some of which are referenced in this paper.

GENERAL COMMENTS
Thank you for asking me to comment on this systematic review protocol. I have some substantial concerns both about style and substance that the authors may wish to address. 1. It is a long paper that could be shortened substantially without detracting from scientific merit. In particular, I think, that the background and discussion are far too long. The background provides a rather rambling and disjointed overview of the literature on chronic disease and the health impact of low back pain. It is not clear that this is needed. Essentially the key points are that low back pain is very common, it has a major on quality of life, but this has not been quantified in a recent systematic review. Over 1,000 words are not needed to say this. Similarly the discussion could be substantially shortened allowing the reader to focus on what is proposed; the core of the paper. 2. The authors present sections of various definitions of low back pain. I suggest they need to absolutely clear that what they are interested in is chronic non-specific low back pain. This means being specific about which specific causes of low back pain are excluded and why. For example, in the background they include degenerative disc disease as a specific cause of low back pain. Most authorities, including the authors of the paper they cite to support this point, would not regard this a specific cause of low back pain. I think they also need to be very clear on how they are going to manage papers including populations with radicular pain. Firstly will studies pure populations of radicular pain be included/excluded and secondly how will studies with mixed populations be analysed. 3. The inclusion criteria for cases and controls are muddled and will be difficult to implement. For cases they mix up two definitions one with back pain present for 4 weeks and one with back pain present for 12 weeks. In reality most papers will not apply either of these definitions and the authors will need to use whatever definitions are provided in the papers. In which case I suggest that the authors will simply accept the definitions given in the original papers and report these as an outcome of the review. 4. For the people with low back pain they appear to be accepting self-report of presence of low back pain, but for the control groups they appear to be requiring a physician examination to confirm absence of low back pain. It is not possible to ascertain presence or absence of pain on examination. Also, of course, most health professionals who treat low back pain are not physicians. 5. The decision criteria for inclusion of health related quality of life measures are unclear. In table one eligible measures are listed whilst in text it is reported than any measure with reported psychometric properties will be used. If criteria based on adequate performance in validation studies is required for a measure to be included on the analysis then these do need to be specified. I suggest that the choice of outcome is also an outcome of this study and that the reviewers should then comment upon the validation work, if any available for that measure. Overall a very well written protocol for the paper "Do patients with chronic low back pain experience a loss of health-related quality of life? A protocol for a systematic review and meta-analysis." The rational for the paper is well written. The methodology is very detailed and sufficient for both the systematic review and meta-analysis. I like that you are examining the studies for publication bias with a funnel plot. I have two small points to consider in your methodology. Response: We warmly thank the Reviewer for this positive feedback, for the precious encouragement and for the appreciation of the strengths of our work. 1.On page 9 you state that studies will be included if "they used case-control design (the study may use any other design if it reports the necessary data to compute effect sizes according to inclusion criteria "b")". What other study designs would be included? Cohort studies, cross-sectional studies? Table 3 lists cross-sectional, case-control and longitudinal studies. The types of studies referred to by "other designs" should be included in this part of the manuscript and not just table 3. Response: We have included the other designs in the "Eligibility criteria" paragraph, as requested by the Reviewer.
2.Can you comment on page 12 on the reliability of the Newcastle-Ottawa Quality Assessment Scale that you are using to assess risk of bias in the studies? This information would be helpful if available.
It is good to see you will be attempting to contact the authors of each paper. Response: As requested, we have added contacting the authors of each paper in the "Information sources and search strategy" paragraph as a further strategy to locate eligible studies.
Reviewer: 2 BIYU SHEN (CHINA) 1. The topic of this article has clinical significance 2. The content is complete, the steps are standardized Response: We warmly thank the Reviewer for providing this positive feedback and for nicely appreciating the strengths of our work.
Reviewer: 3 Martin Underwood (Warwick Clinical trials Unit) 1. It is a long paper that could be shortened substantially without detracting from scientific merit. In particular, I think, that the background and discussion are far too long. The background provides a rather rambling and disjointed overview of the literature on chronic disease and the health impact of low back pain. It is not clear that this is needed. Essentially the key points are that low back pain is very common, it has a major on quality of life, but this has not been quantified in a recent systematic review. Over 1,000 words are not needed to say this. Similarly, the discussion could be substantially shortened allowing the reader to focus on what is proposed; the core of the paper. Response: We agree with this point raised by the Reviewer. To meet this request and make the Introduction shorter, we have removed the entire "Health-related quality of life as a roadmap in the management of chronic diseases" paragraph. In addition, we have eliminated some statements at the end of the Introduction and at the beginning of the Discussion section to make the manuscript more readable and focused on the point. 2. The authors present sections of various definitions of low back pain. I suggest they need to absolutely clear that what they are interested in is chronic non-specific low back pain. This means being specific about which specific causes of low back pain are excluded and why. For example, in the background they include degenerative disc disease as a specific cause of low back pain. Most authorities, including the authors of the paper they cite to support this point, would not regard this a specific cause of low back pain. I think they also need to be very clear on how they are going to manage papers including populations with radicular pain. Firstly, will studies pure populations of radicular pain be included/excluded and secondly how will studies with mixed populations be analysed. Response: We agree with the points raised by the Reviewer. As requested, we have added a definition of chronic non-specific low back pain in the Introduction section. In addition, we have removed degenerative disc disease as a specific cause of low back pain. We have added "inflammatory disorders" among the specific causes of low back pain. We also revised criterion "b" by specifying that studies will be included if conducted on chronic non-specific low back pain whereas studies on chronic specific low back pain will be excluded. Finally, with regard to populations with radicular pain we have revised the eligibility criteria thoroughly to make them clearer and consistent with the Reviewer's comments. Specifically, we have stated that studies on chronic LBP associated with radicular pain will be included since the most accepted definitions of LBP include also radicular pain (Dionne et al., 2008;Olivera et al., 2018). However, studies conducted on radiculopathy or radicular pain alone without chronic LBP (e.g., sciatica, sciatic pain) will be excluded since these conditions are different from chronic non-specific LBP (Bardin et al., 2017;Maher et al., 2017). Studies on mixed samples including patients with chronic LBP and radiculopathy will be excluded, unless the data on these two types of conditions are analyzed separately. 3. The inclusion criteria for cases and controls are muddled and will be difficult to implement. For cases they mix up two definitions one with back pain present for 4 weeks and one with back pain present for 12 weeks. In reality most papers will not apply either of these definitions and the authors will need to use whatever definitions are provided in the papers. In which case I suggest that the authors will simply accept the definitions given in the original papers and report these as an outcome of the review. Response: We agree with the Reviewer. As requested, we have changed this point by specifying that we will accept the definitions of low back pain provided in the included studies and we will report these as an outcome of the review. Please, see the revision made in "c" in the Eligibility Criteria paragraph. 4. For the people with low back pain they appear to be accepting self-report of presence of low back pain, but for the control groups they appear to be requiring a physician examination to confirm absence of low back pain. It is not possible to ascertain presence or absence of pain on examination. Also, of course, most health professionals who treat low back pain are not physicians. Response: We agree with this point raised by the Reviewer. As requested, in the Eligibility Criteria we have removed the criterion based on a physician examination as a method of ascertaining the presence or absence of pain. In addition, we have changed the eligibility criteria of the controls accordingly, i.e. they had to be recruited from the general population. 5. The decision criteria for inclusion of health related quality of life measures are unclear. In table one eligible measures are listed whilst in text it is reported than any measure with reported psychometric properties will be used. If criteria based on adequate performance in validation studies is required for a measure to be included on the analysis then these do need to be specified. I suggest that the choice of outcome is also an outcome of this study and that the reviewers should then comment upon the validation work, if any available for that measure. Response: As requested by the Reviewer, we have revised this section. Firstly, we have removed the sentence where we stated that any measure will be used. Subsequently, we have specified that the choice of the measures will be an outcome of the review. Third, we have also specified more thoroughly the criteria based on adequate performance in validation studies. Specifically, we have stated that the measure should present at least an acceptable value of internal consistency as suggested by a Cronbach's alpha coefficient equal to or higher than .70 which is the gold standard for adequate internal consistency according to the guidelines provided by Nunnally (1978). This should be reported in the validation study. As requested by the Reviewer, we have also added a description of the validation work for each measure in Table 1 (please, see revised Table 1). Reference: Nunnally, J. C. (1978). Psychometric theory (2nd ed.). New York: McGraw-Hill. 6. Reviewers need to clear if they are measuring overall health related quality of life or psychological wellbeing. Most of the focus of the manuscript is on overall quality of life. However, at the start of the discussion there is a focus on the psychological impact of low back pain. If this is what they are interested in, then a different review is needed. Response: We agree with this point highlighted by the Reviewer. As requested, we have specified more thoroughly that the focus of the review is on overall quality of life and not on the psychological impact of low back pain. Therefore, we have removed the sentences focused on the psychological impact of low back pain at the start of the Discussion section. We have also removed the measures related to psychological wellbeing from the "Eligibility Criteria" paragraph. 7. It is proposed to pool data from different outcome measures. This is not safe as different measures are measuring different constructs. The Psychological General Wellbeing Index, for example, is measuring something very different than the physical component score of the SF-36. Quite how it is proposed to include data from measures such as the SF-36 family that provide eight domains or two component scores and measure with a single score is not stated. I suggest that the authors simply pool data share the same measure or family of measures is used. Response: We agree with this point suggested by the Reviewer. We have modified the procedure of data pooling by stating that we will pool the data from the same scale of the same measure (e.g., SF-36 Mental Health Scale). This change has been added in the "Summary measures" paragraph. In addition, as requested by the Reviewer, we have included only measures closely related to quality of life and we have removed all the measures related to wellbeing or psychological wellbeing because this construct is different from quality of life. 8. Studies are likely to be so heterogenous that any meaningful pooling is not practical and the likelihood of a narrative review of their findings needs to be recognized. Response: We recognize this point highlighted by the Reviewer. To address this potential issue, we have added a sentence in the "Discussion and Conclusions" section stating that we can expect that studies are so heterogenous that any meaningful pooling is a difficult step and the case for a narrative review may be a better strategy. 9. I think the authors are confusing moderator variables with predictor variables. Moderators are factors that predict response to treatment and not part of this review. Response: As requested by the Reviewer, we have replaced the term "moderator(s)" with "predictor(s)" throughout the manuscript.
Reviewer: 4 Eva Denison (The Norwegian Institute of Public Health, Norway) 1. The abstract says "weighted least simple meta-regression" -shouldn't that be weighted least squares meta-regression, as is stated in the Methods section? Response: We have corrected this point in the Abstract accordingly, as requested by the Reviewer. 2. Eligibility criteria, (e): Please consider whether it is necessary to state that a case-control design is required, instead of sticking to the criterion stated under (b). Response: We have specified the necessary types of research designs and we have removed the sentence related to the criterion stated under (b), as requested by the Reviewer. 3. Evaluation of study quality: Please clarify whether the cutoff limits for high, medium, and low quality on the NOQAS was established by the authors of NOQAS or by the authors of the current protocol. Also please describe actions if consensus is not reached. Response: We understand the comment provided by the Reviewer. However, unfortunately, the NOS does not provide cut-off limits and the scope of our protocol does allow us to establish them. The scores on the NOS will only be managed as a continuous variable: this has been highlighted as a main limitation of the review. In addition, we have added a description of the actions if consensus is not reached in the "Evaluation of study quality" paragraph. 4. Publication bias: Please consider other reasons for funnel plot asymmetry than publication bias, and also justify use of trim and fill procedure in relation to other tests, see Sterne et al 2011 (attached). Even if Sterne et al discuss Reporting bias in RCTs, their suggestions may be useful in the present review. Response: As requested by the Reviewer, we have added some statements in the "Publication bias" paragraph discussing other reasons for funnel plot asymmetry. In addition, following the Reviewer's suggestion, the Trim and Fill procedure has been replaced with the Egger test which has been considered as a more suitable to test for funnel plot asymmetry, as recommended by the guidelines provided in Sterne et al. (2011). 5. As far as I understand, the suggested synthesis methods are appropriate. However, in my experience, meta-analysis of case control data (or similar) may warrant Close collaboration with a statistician. Response: We recognize the importance of this point and we agree with the Reviewer's comment. A senior statistician is one of the coauthors of the paper and a close collaboration with him will be a relevant part of the meta-analytical work. To highlight this point, we have added a sentence about this in the "Meta-analytic procedure" paragraph. 6. Please elaborate on consequences of potential small number of studies for exploration of heterogeneity and publication bias. Response: We have clarified this point in two ways, i.e. (1) by specifying in the "Moderator coding and analysis" paragraph that sources of heterogeneity will be explored if at least 6 to 10 studies are included, as requested by the guidelines recommended by Fu et al. (2011); (2) by highlighting that a small number of studies will be a major limitation of the review which does not allow us to explore the sources of heterogeneity in the "Discussion and conclusions" paragraph.

GENERAL COMMENTS
I would still like to see mention of the inter-rater reliability of the Newcastle-Ottawa Quality Assessment Scale. Otherwise well written paper.

Martin Underwood
Warwick CTU UK I was Chair of the NICE accreditation advisory committee until March 2017 for which I received a fee. I am chief investigator or coinvestigator on multiple previous and current research grants from the UK National Institute for Health Research (NIHR) , Arthritis Research UK and I am a co-investigator on grants funded by the Australian NHMRC. As an NIHR senior investigator, I receive research support from NIHR. I have received travel expenses, and honoraria, for speaking at conferences from the professional organisations hosting the conferences. I am a director and shareholder of Clinvivo Ltd that provides electronic data collection for health services research. I am part of an academic partnership with Serco Ltd. I have accepted an honorarium from the consortium for advanced research training in Africa. I am an editor of the NIHR journal series, and a member of the NIHIR Journal editors Group for which I receive a fee. I am co-investigator on two studies, funded by NIHR, that receive support in kind from Stryker Ltd. I have published multiple papers on low back pain some of which are referenced in this paper.

GENERAL COMMENTS
I an happy with the changes made.

Eva Denison
The Norwegian Institute of Public Health