Propensity Score-Based Approaches to Confounding by Indication in Individual Patient Data Meta-Analysis: Non-Standardized Treatment for Multidrug Resistant Tuberculosis

Background In the absence of randomized clinical trials, meta-analysis of individual patient data (IPD) from observational studies may provide the most accurate effect estimates for an intervention. However, confounding by indication remains an important concern that can be addressed by incorporating individual patient covariates in different ways. We compared different analytic approaches to account for confounding in IPD from patients treated for multi-drug resistant tuberculosis (MDR-TB). Methods Two antibiotic classes were evaluated, fluoroquinolones—considered the cornerstone of effective MDR-TB treatment—and macrolides, which are known to be safe, yet are ineffective in vitro. The primary outcome was treatment success against treatment failure, relapse or death. Effect estimates were obtained using multivariable and propensity-score based approaches. Results Fluoroquinolone antibiotics were used in 28 included studies, within which 6,612 patients received a fluoroquinolone and 723 patients did not. Macrolides were used in 15 included studies, within which 459 patients received this class of antibiotics and 3,670 did not. Both standard multivariable regression and propensity score-based methods resulted in similar effect estimates for early and late generation fluoroquinolones, while macrolide antibiotics use was associated with reduced treatment success. Conclusions In this individual patient data meta-analysis, standard multivariable and propensity-score based methods of adjusting for individual patient covariates for observational studies yielded produced similar effect estimates. Even when adjustment is made for potential confounding, interpretation of adjusted estimates must still consider the potential for residual bias.


Rationale
3 Describe the rationale for the review in the context of what is already known.

Objectives 4
Provide an explicit statement of the questions being addressed with reference, as applicable, to participants, interventions, comparisons, outcomes and study design (PICOS). Include any hypotheses that relate to particular types of participant-level subgroups. Methods

Protocol and registration 5
Indicate if a protocol exists and where it can be accessed. If available, provide registration information including registration number and registry name. Provide publication details, if applicable.
Eligibility criteria 6 Specify inclusion and exclusion criteria including those relating to participants, interventions, comparisons, outcomes, study design and characteristics (e.g. years when conducted, required minimum follow-up). Note whether these were applied at the study or individual level i.e. whether eligible participants were included (and ineligible participants excluded) from a study that included a wider population than specified by the review inclusion criteria. The rationale for criteria should be stated. State the process for determining which studies were eligible for inclusion.

Data collection processes
10 Describe how IPD were requested, collected and managed, including any processes for querying and confirming data with investigators. If IPD were not sought from any eligible study, the reason for this should be stated (for each such study).
If applicable, describe how any studies for which IPD were not available were dealt with. This should include whether, how and what aggregate data were sought or extracted from study reports and publications (such as extracting data independently in duplicate) and any processes for obtaining and confirming these data with investigators.

Data items 11
Describe how the information and variables to be collected were chosen. List and define all study level and participant level data that were sought, including baseline and follow-up information. If applicable, describe methods of standardising or translating variables within the IPD datasets to ensure common scales or measurements across studies.

IPD integrity A1
Describe what aspects of IPD were subject to data checking (such as sequence generation, data consistency and completeness, baseline imbalance) and how this was done.
Risk of bias assessment in individual studies.

12
Describe methods used to assess risk of bias in the individual studies and whether this was applied separately for each outcome. If applicable, describe how findings of IPD checking were used to inform the assessment. Report if and how risk of bias assessment was used in any data synthesis.

Specification of outcomes and effect measures
13 State all treatment comparisons of interests. State all outcomes addressed and define them in detail. State whether they were pre-specified for the review and, if applicable, whether they were primary/main or secondary/additional outcomes. Give the principal measures of effect (such as risk ratio, hazard ratio, difference in means) used for each outcome.

14
Describe the meta-analysis methods used to synthesise IPD. Specify any statistical methods and models used. Issues should include (but are not restricted to):  Use of a one-stage or two-stage approach.  How effect estimates were generated separately within each study and combined across studies (where applicable).  Specification of one-stage models (where applicable) including how clustering of patients within studies was accounted for.  Use of fixed or random effects models and any other model assumptions, such as proportional hazards.  How (summary) survival curves were generated (where applicable).  Methods for quantifying statistical heterogeneity (such as I 2 and  2 ).  How studies providing IPD and not providing IPD were analysed together (where applicable).  How missing data within the IPD were dealt with (where applicable). n/a p7 p7 p7 p7 p7 p9-10 p10-14

Exploration of variation in effects A2
If applicable, describe any methods used to explore variation in effects by study or participant level characteristics (such as estimation of interactions between effect and covariates). State all participant-level characteristics that were analysed as potential effect modifiers, and whether these were pre-specified.

Risk of bias across studies
15 Specify any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to not obtaining IPD for particular studies, outcomes or other variables.

Additional analyses 16
Describe methods of any additional analyses, including sensitivity analyses. State which of these were pre-specified.

Study selection and IPD obtained 17
Give numbers of studies screened, assessed for eligibility, and included in the systematic review with reasons for exclusions at each stage. Indicate the number of studies and participants for which IPD were sought and for which IPD were obtained. For those studies where IPD were not available, give the numbers of studies and participants for which aggregate data were available. Report reasons for non-availability of IPD. Include a flow diagram.

Study characteristics 18
For each study, present information on key study and participant characteristics (such as description of interventions, numbers of participants, demographic data, unavailability of outcomes, funding source, and if applicable duration of follow-up). Provide (main) citations for each study. Where applicable, also report similar study characteristics for any studies not providing IPD.

IPD integrity A3
Report any important issues identified in checking IPD or state that there were none.

Risk of bias within studies 19
Present data on risk of bias assessments. If applicable, describe whether data checking led to the up-weighting or downweighting of these assessments. Consider how any potential bias impacts on the robustness of meta-analysis conclusions.

Results of individual studies 20
For each comparison and for each main outcome (benefit or harm), for each individual study report the number of eligible participants for which data were obtained and show simple summary data for each intervention group (including, where applicable, the number of events), effect estimates and confidence intervals. These may be tabulated or included on a forest plot.

Results of syntheses 21
Present summary effects for each meta-analysis undertaken, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified, and report the numbers of studies and participants and, where applicable, the number of events on which it is based.
When exploring variation in effects due to patient or study characteristics, present summary interaction estimates for each characteristic examined, including confidence intervals and measures of statistical heterogeneity. State whether the analysis was pre-specified. State whether any interaction is consistent across trials.
Provide a description of the direction and size of effect in terms meaningful to those who would put findings into practice.

Risk of bias across studies 22
Present results of any assessment of risk of bias relating to the accumulated body of evidence, including any pertaining to the n/a n/a n/a p10-14 p7 Ref 19 p7 Suppl Table 2 p7, Ref 19 p14-17 Tables  5-6 Suppl Table 2 availability and representativeness of available studies, outcomes or other variables.

Additional analyses 23
Give results of any additional analyses (e.g. sensitivity analyses). If applicable, this should also include any analyses that incorporate aggregate data for studies that do not have IPD. If applicable, summarise the main meta-analysis results following the inclusion or exclusion of studies for which IPD were not available.

Summary of evidence 24
Summarise the main findings, including the strength of evidence for each main outcome.

Strengths and limitations 25
Discuss any important strengths and limitations of the evidence including the benefits of access to IPD and any limitations arising from IPD that were not available.

Conclusions 26
Provide a general interpretation of the findings in the context of other evidence.

Implications A4
Consider relevance to key groups (such as policy makers, service providers and service users). Consider implications for future research.

Funding 27
Describe sources of funding and other support (such as supply of IPD), and the role in the systematic review of those providing such support.
A1 -A3 denote new items that are additional to standard PRISMA items. A4 has been created as a result of re-arranging content of the standard PRISMA statement to suit the way that systematic review IPD meta-analyses are reported.
© Reproduced with permission of the PRISMA IPD Group, which encourages sharing and reuse for non-commercial purposes n/a p17 p20 pp20-21 p21 p23