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Bayesian network metaanalysis methods for combining individual participant data and aggregate data from single arm trials and randomised controlled trials
BMC Medical Research Methodology volume 22, Article number: 186 (2022)
Abstract
Background
Increasingly in network metaanalysis (NMA), there is a need to incorporate nonrandomised evidence to estimate relative treatment effects, and in particular in cases with limited randomised evidence, sometimes resulting in disconnected networks of treatments. When combining different sources of data, complex NMA methods are required to address issues associated with participant selection bias, incorporating singlearm trials (SATs), and synthesising a mixture of individual participant data (IPD) and aggregate data (AD). We develop NMA methods which synthesise data from SATs and randomised controlled trials (RCTs), using a mixture of IPD and AD, for a dichotomous outcome.
Methods
We propose methods under both contrastbased (CB) and armbased (AB) parametrisations, and extend the methods to allow for both within and acrosstrial adjustments for covariate effects. To illustrate the methods, we use an applied example investigating the effectiveness of biologic diseasemodifying antirheumatic drugs for rheumatoid arthritis (RA). We applied the methods to a dataset obtained from a literature review consisting of 14 RCTs and an artificial dataset consisting of IPD from two SATs and AD from 12 RCTs, where the artificial dataset was created by removing the control arms from the only two trials assessing tocilizumab in the original dataset.
Results
Without adjustment for covariates, the CB method with independent baseline response parameters (CBunadjInd) underestimated the effectiveness of tocilizumab when applied to the artificial dataset compared to the original dataset, albeit with significant overlap in posterior distributions for treatment effect parameters. The CB method with exchangeable baseline response parameters produced effectiveness estimates in agreement with CBunadjInd, when the predicted baseline response estimates were similar to the observed baseline response. After adjustment for RA duration, there was a reduction in acrosstrial heterogeneity in baseline response but little change in treatment effect estimates.
Conclusions
Our findings suggest incorporating SATs in NMA may be useful in some situations where a treatment is disconnected from a network of comparator treatments, due to a lack of comparative evidence, to estimate relative treatment effects. The reliability of effect estimates based on data from SATs may depend on adjustment for covariate effects, although further research is required to understand this in more detail.
Background
Traditionally, metaanalysis of randomised controlled trials (RCTs) has been used to quantitatively pool published evidence on the effectiveness of a treatment, or a network of treatments through network metaanalysis (NMA), across trials with similar characteristics (e.g. patient population, trial design and conduct) [1–3]. In the published literature, results from a trial are usually reported as aggregate data (AD) summarising the average treatment effect. Synthesising evidence from RCTs has been considered a gold standard as randomised treatment allocation minimises the risk of confounding in treatment effect estimates.
In circumstances where randomised evidence is limited, nonrandomised evidence, such as data from singlearm trials (SATs), may have to be considered in determining treatment effectiveness [4]. Such cases are becoming increasingly common in health technology assessment (HTA), as new technologies receive accelerated approval from regulatory agencies based on SATs leading to disconnected networks of treatments [5]. This creates an issue for reimbursement decisionmaking by HTA bodies where the interest is in unbiased estimates of relative treatment effects. Consequently, there is a need for synthesis methods which combine randomised and nonrandomised evidence, whilst addressing issues associated with the latter, such as susceptibility to confounding and the lack of evidence from a comparator arm in the case of SATs [6].
For a particular trial, individual participant data (IPD) may be available recording the effect of the treatment on outcomes of interest, as well as a set of covariates, for each participant. Metaanalysis incorporating IPD has been shown to overcome issues associated with detecting treatmentcovariate interactions, and prognostic effects, compared to a metaregression of AD only [7, 8]. Moreover, it accounts for variability in covariate values across participants within a trial, allowing within and acrosstrial interactions to be estimated separately which mitigates the risk of aggregation bias [9, 10]. However, the availability of IPD is often subject to a datasharing agreement with the trial sponsor which often involves a lengthy, complex process due to regulatory considerations (e.g. data protection and privacy). Furthermore, access to IPD may be particularly challenging when data are required from a number of trials, and for trials assessing different treatments developed by different manufacturers. Consequently, IPD are unlikely to be available for all trials in the synthesis and methods have been developed which combine a mixture of IPD and AD [11–14]. Populationadjustment methods have been developed to estimate a relative treatment effect for the specific situation where IPD are available for a trial assessing a particular treatment and only AD are available for another trial assessing a comparator, which is a common occurrence in HTA [15]. Such methods make the assumption that the treatment effect is equivalent in the two study populations at each level of a set of effect modifiers [16]. More recently, multilevel network metaregression methods have been proposed which extend the populationadjustment methods beyond the twostudy case, and also avoid the issue of aggregation bias by using IPD to inform the covariate distributions in the AD model [17]. Similarly, methods have been proposed which use IPD to estimate regression coefficients for effect modifiers, and synthesise IPD and AD via either a hierarchical model or by constructing empirical prior distributions [18].
Extensions to metaanalysis, which allow the synthesis of SATs and RCTs, have been proposed which assume that baseline response parameters are exchangeable (rather than independent) across trials [19]. This approach has been developed to a NMA context using a mixture of IPD and AD and a contrastbased approach to NMA [20]. Armbased NMA methods, which parametrise absolute treatment effects across trial arms, also allow SATs to be incorporated into a synthesis of RCTs in a pairwise metaanalysis [21] and a NMA context [22, 23]. Under a Bayesian framework, these methods allow data from SATs to provide information on the pooled treatment effect and betweenstudy heterogeneity parameters via a prior distribution, and can be downweighted according to commensurability with RCT data [24]. These methods have been criticised for compromising randomised treatment allocation and introducing bias in treatment effect estimates from RCTs [25, 26]. However, they may be helpful to include when the only evidence available for a treatment is from SATs, and the increase in risk of bias associated with the exchangeability assumption may have little impact in practice [27, 28]. Alternative methods seek to match similar trial arms based on reported characteristics and either entering the matched pairs into the NMA directly or by pluggingin the baseline response estimate from a matched trial to estimate a relative treatment effect from SATs [29, 30].
In this paper, we develop methods to synthesise SATs and twoarm RCTs, using a mixture of IPD and AD, for a dichotomous outcome. We consider methods with and without adjustment for a covariate effect. We build on contrast and armbased NMA methods [22, 23] to incorporate SATs, and use sharedparameters to synthesise IPD and AD [13, 14]. We apply the developed methods using mixture of IPD and AD from RCTs assessing the effectiveness of biologic diseasemodifying antirheumatic drugs (bDMARDs) as treatments for rheumatoid arthritis (RA), as an applied example. We describe the IPD and AD datasets used in the applied example in “Applied example: assessing biologics for treating rheumatoid arthritis (RA)” section, before detailing the methods for a Bayesian implementation in “Methods” section, and reporting the results from the application in “Results” section. In “Discussion” section, we discuss issues related to the use of the methods and suggest how these can be investigated further.
Applied example: assessing biologics for treating rheumatoid arthritis (RA)
In this paper, we consider a casestudy in rheumatoid arthritis (RA); a chronic autoimmune condition causing joint inflammation in (mostly) elderly patients. The American College of Rheumatology (ACR) response criteria provide a measure of patient response to treatment, with an ACR20 outcome representing a 20% improvement in RA symptoms as defined by the criteria [31]. A number of bDMARDs (hereafter referred to as biologics) have been developed to offer a choice of treatment strategies in managing the disease [32].
Table 1 summarises the original dataset used in the applied example. Data were available from 14 RCTs, each assessing the effectiveness of a firstline biologic versus placebo as treatment for RA, with 5,821 participants in total. In 9 trials, a biologic was allocated to multiple trial arms (ranging from two to four arms) in order to assess different dosage regimens. For this applied example, these data were aggregated and considered as from a single trial arm. There was not significant variability in dosage regimens across trials assessing a particular biologic. All trial arms consisted of participants receiving methotrexate as background therapy. IPD were available for two trials of tocilizumab [33, 34], whilst only AD were available for the remaining trials [35–49]. An ACR20 response was considered as an outcome to measure treatment effectiveness, with IPD providing responder status for each participant and AD providing the number of participants achieving a response in each trial arm. We considered RA duration (in years) as a covariate in our models, as there was evidence of an association between baseline response and RA duration present in the exploratory analysis of the IPD. Table 1 lists the mean RA duration at baseline in each trial arm.
Figure 1 illustrates the network structure in terms of the evidence available for each treatment comparison. The network consists of trials assessing four biologics; infliximab, tocilizumab, golimumab, and adalimumab. Each trial compared a biologic therapy versus placebo, and there were no trials comparing biologics headtohead.
In this paper, we consider methods which can be applied to synthesise data from SATs and RCTs, in a NMA context. For the applied example, an artificial dataset was created by removing the placebo arms from the two tocilizumab trials. As a result, the artificial dataset included two SATs assessing tocilizumab. The aim of the synthesis was to compare the effectiveness of tocilizumab with infliximab, golimumab, and adalimumab, in terms of the ACR20 outcome.
Methods
In this section, we describe Bayesian NMA methods used to synthesise data from SATs and twoarm RCTs, under both contrast and armbased model parametrisations. We focus on onestage methods which synthesise IPD and AD in a single model, as opposed to twostage methods where IPD are first aggregated and then synthesised with AD. We assume data are available as IPD from N^{IPD} SATs followed by AD from N^{AD} twoarm RCTs, and let j=1,...,N^{IPD},...,N^{IPD}+N^{AD} index both trial sets. We start by describing the likelihood functions used to model a dichotomous outcome using IPD and AD, then describe methods under a contrastbased parametrisation, followed by methods under an armbased parametrisation. Under each parametrisation, we describe methods without adjustment for covariates and methods which include a covariate to adjust for its effect.
Likelihood models for a dichotomous outcome
Let Y_{ijk} represent a dichotomous outcome indicating responder status (i.e. responder 1, nonresponder 0) for participant i in trial j assigned to treatment k. Then, for trials from which IPD are available, we assume that the outcome Y_{ijk} is a Bernoulli random variable,
where p_{ijk} represents the probability of response for each participant.
Similarly, let n_{jk} and r_{jk} represent the numbers of participants and responders, respectively, in trial j allocated treatment k. Then, for trials from which only AD are available, the number of responders in each arm r_{jk} is assumed to follow a Binomial distribution,
where p_{jk} is the probability of response in each trial arm. For both datatypes, we employ the logit link function to transform response probabilities onto the linear predictor scale on which treatment effects can be assumed to be linearly additive.
The number of responders in each arm r_{jk} is the sum over the participantlevel Bernoulli outcomes Y_{ijk}, which are assumed to be identicallydistributed. If there are unobserved participantlevel covariates which influence the individual response probabilities p_{ijk}, then the corresponding outcomes Y_{ijk} are unlikely to be identicallydistributed. Thus, the AD likelihood in Eq. (2) is the correct aggregate version of the IPD likelihood in Eq. (1) only if there are no important unobserved participantlevel covariates.
Contrastbased (CB) methods
Here, we describe methods under a contrastbased parametrisation where treatment effects are expressed relative to a baseline response (i.e. the outcome observed in the control arm). We denote B as index for the baseline treatment in each trial.
Methods without covariates
We start by describing methods which only model the response data and do not include data on covariates, as an intermediate step so that it is clear how these methods can be extended to incorporate covariate adjust ment in “Methods with covariateadjustment” section. The IPD and AD models are equivalent, but are described separately to clarify how sharedparameters allow both datasets to contribute to the estimation of the treatment effect.
For IPD, the model is given by,
where ϕ_{j} represents the log odds of a response on the baseline treatment B in trial j, δ_{jBk} is the log odds ratio of effect on treatment k relative to B, and I_{ijk} is a participantlevel treatment indicator variable (i.e. treatment 1, baseline 0).
Similarly, for AD, the model can be written as,
where ϕ_{j} and δ_{jBk} have the same interpretation as for the IPD model (3), and I_{jk} is an armlevel treatment indicator variable.
The treatment effects δ_{jBk} are assumed to be exchangeable across trials comparing treatment k with B,
with d_{Bk} representing the pooled log odds ratio. The betweenstudy heterogeneity in the treatment effects is quantified by the standard deviation parameter σ. Here, σ is assumed to be common across treatment comparisons as we consider methods for application in cases where data are limited.
The pooled effects d_{Bk} can be represented in terms of basic parameters by assuming consistency within the network d_{Bk}=d_{1k}−d_{1B} (d_{11}=0). Thus, effect estimates can be obtained indirectly for treatment comparisons for which there are no trials providing a headtohead estimate. We place a noninformative Normal prior distribution on each of the basic parameters d_{1k}∼N(0,10^{2}) and the baseline response parameters ϕ_{j}∼N(0,10^{2}). Hong et al. place a noninformative Uniform prior distribution for the betweenstudy heterogeneity parameter, σ∼U(0,10). However, we note that this prior distribution may be weaklyinformative in a synthesis with few trials [50] and σ∼U(0,2) has been recommended as a more appropriate prior distribution [51] which we use here (The results of a sensitivity analysis using σ∼U(0,10) are reported in Appendix E for comparison).
Traditionally, NMA methods have been applied to synthesise data from RCTs which assume independent baseline response parameters ϕ_{j} [3]. This accounts for differences in prognostic factors between trials, and ensures that the impact of randomised treatment allocation is reflected in the treatment effect estimates. However, such an approach is restricted to trials with two or more arms and the interest here is to incorporate data from SATs into the synthesis. Therefore, we assume exchangeable baseline response parameters as in [19],
where m_{ϕ} represents the mean baseline response, and σ_{ϕ} quantifies betweenstudy heterogeneity in the baseline response. The benefit of this assumption is that it allows a baseline response to be predicted, and a treatment effect to be estimated, for each SAT in the synthesis so that pooled estimates are based on all of the available evidence. The cost of this assumption is that randomisation is compromised for RCTs in the synthesis, which will bias treatment effect estimates where there is significant betweenstudy heterogeneity (which may be due to differences in prognostic factors) in baseline response estimates. We specify a noninformative Normal prior distribution for the mean baseline response parameter m_{ϕ}∼N(0,10^{2}), and a noninformative Uniform prior distribution for the betweenstudy heterogeneity parameter σ_{ϕ}∼U(0,2). We label the methods with independent and exchangeable baseline response parameters by CBunadjInd and CBunadjEx, respectively.
Alternatively, the CBunadjInd method can be implemented in two stages to predict baseline response estimates for SATs in the synthesis, whilst maintaining the effects of randomisation and limiting bias in treatment effect estimates for RCTs. In the first stage, the CBunadjEx method is applied to the data from the set of RCTs in the synthesis. The posterior estimates for the mean and standard deviation parameters (i.e. \(\hat {m}_{\phi }\) and \(\hat {\sigma }_{\phi }\)), describing the distribution of the baseline response across RCTs, are recorded. In the second stage, the CBunadjInd method is applied to synthesise SATs and RCTs, where an informative Normal prior distribution is placed on the baseline response parameters corresponding to SATs (i.e. \(\phi _{j} \sim N\left (\hat {m}_{\phi }, \hat {\sigma }_{\phi }^{2}\right)\)). This prior distribution is informed by the posterior estimates recorded from the first stage of the method, which is equivalent to using the posterior predictive distribution of the baseline response across RCTs. The posterior predictive distribution, as opposed to the posterior distribution, is recommended by Dias et al. to account for betweenstudy heterogeneity [52]. Ultimately, pooled treatment effect estimates, and inference, are based only on the second stage of the method. Thus, SATs are incorporated into the synthesis and contribute to the pooled treatment effect estimates, whilst the assumption of independent baseline response parameters ensures randomisation in RCTs is not compromised.
Methods with covariateadjustment
Studylevel adjustment only
Here, we consider methods which include a covariate to adjust the baseline response. We begin by extending the CBunadjEx method to adjust for a covariate at the triallevel, and let \(\bar {x}_{j}\) represent the mean covariate value summarising participants in trial j. We use the superscripts A and W to denote across and withintrial effects, respectively. For IPD, the extended model is given by,
where ϕ_{j} represents the log odds of response on baseline treatment B when \(\bar {x}_{j}\) is equal to zero, and α^{A} is the change in the log odds for a unit increase in \(\bar {x}_{j}\). Thus, α^{A} represents a triallevel covariate effect, accounting for the association between the baseline response ϕ_{j} and the mean covariate \(\bar {x}_{j}\), across trials. Here, there is no adjustment for the interaction between the relative treatment effect and the mean covariate, and so δ_{jBk} represents a marginal treatment effect.
Similarly, for AD, the extended model can be described by,
where ϕ_{j} and α^{A} have the same interpretation as for the IPD model (7). A noninformative Normal prior distribution is recommended for the acrosstrial covariate effect parameter α^{A}∼N(0,10^{2}), and we label this method CBadjEx.
Participantlevel and studylevel adjustment
In this paper, we consider methods to synthesise a mixture of IPD and AD. IPD allows participantlevel and triallevel covariate effects to be estimated separately, avoiding aggregation bias which may occur when the assumption that these effects are equivalent does not hold [8]. We extend the CBadjEx method in Eq. (7) to adjust for the covariate both at the participantlevel and the triallevel. We let x_{ijk} represent the covariate value for participant i in trial j allocated treatment k. For IPD, the extended model is given by,
where α^{W} is the change in the log odds of a response on baseline treatment B for a unit increase in \(\left (x_{ijk}  \bar {x}_{j} \right)\). Thus, α^{W} represents a common (participantlevel) covariate effect within a trial. A noninformative Normal prior distribution is recommended for withintrial covariate effect parameter α^{W}∼N(0,10^{2}), and we label this method CBadjEbEx (where Eb denotes that this method accounts for ecological aggregation bias  the difference between the across and withintrial covariate effects).
Armbased (AB) methods
Hong et al. have proposed NMA models under an armbased parametrisation, where treatment effects are expressed as the absolute effects across trial arms, using either IPD [22] or AD [23]. Here, we extend their models to synthesise a mixture of IPD and AD.
Methods without covariates
We begin by describing models with outcome data only. For IPD, the model is given by,
where θ_{k} represents the pooled log odds of response on treatment k, and ν_{jk} are error terms (i.e. the difference between the log odds of response on treatment k in trial j and the pooled log odds of response on treatment k). A noninformative Normal prior distribution is suggested for each pooled response parameter θ_{k}∼N(0,10^{2}).
Similarly, for AD, the model is described by,
where θ_{k} and ν_{jk} have the same interpretation as for the IPD model (10).
The error terms ν_{jk} are assumed to be exchangeable across trials,
where τ quantifies the betweenstudy heterogeneity and is assumed to be common. A noninformative Uniform prior distribution is recommended for the betweenstudy heterogeneity parameter τ∼U(0,2).
The application in this paper considers a synthesis of SATs and twoarm RCTs, and we make an additional assumption regarding the heterogeneity observed in the latter. For each twoarm RCT, we let k_{1} and k_{2} denote the treatment assigned in arms 1 and 2, respectively. Then, the error terms are assumed to follow a bivariate distribution,
with covariance matrix \(\boldsymbol {\Sigma }_{k_{1} k_{2}}\). The responses observed in arms from RCTs are likely to be similar (compared to two SATs), due to the balance in prognostic factors achieved by randomised treatment allocation [53]. The similarity is represented by a common distribution, which is a bivariate distribution in the case of data from twoarm RCTs, accounting for the correlation between treatment arms. A noninformative Uniform prior distribution is suggested for the correlation parameter in the covariance matrix ρ∼U(−1,1). We label this method as ABunadj.
Methods with covariateadjustment
Studylevel adjustment only
Here, we extend the ABunadj method to allow adjustment for a covariate. We begin by adjusting the absolute treatment effect in each arm for the average value of the covariate \(\bar {x}_{jk}\) across participants in trial j and treatment arm k. For IPD, the extended model is given by,
where θ_{k} represents the pooled log odds of response to treatment k when \(\bar {x}_{jk}\) is equal to zero, and β^{A} is the change in the pooled log odds for a unit increase in \(\bar {x}_{jk}\). Thus, β^{A} represents the covariate effect across trial arms. Under the armbased parametrisation, we follow the approach by Hong et al. and adjust for the armlevel mean covariate to account for differences between arms within each trial, in addition to differences between trials [22]. In some cases, data on the armlevel mean covariate \(\bar {x}_{jk}\) may not be available from the published trial report, in which case adjustment would be restricted to the reported mean triallevel covariate \(\bar {x}_{j}\).
Similarly, for AD, the extended model can be written as,
where θ_{k} and β^{A} have the same interpretation as for the IPD model (14). We suggest a noninformative Normal prior distribution for the armlevel covariate effect parameter β^{A}∼N(0,10^{2}), and we label this method ABadj.
Participantlevel and studylevel adjustment
In a similar way to that described for the contrastbased methods, the covariate effect at the participantlevel may differ from the effect at the armlevel. To avoid the aggregation bias which is introduced as a result of this difference, we extend the ABadj method in Eq. (14) to separate the across and withintrial covariate effects. For IPD the extended model is given by,
where β^{W} represents the change in the pooled log odds for a unit increase in \(\left (x_{ijk}  \bar {x}_{jk} \right)\). We place a noninformative Normal distribution on the withintrial covariate effect parameter β^{W}∼N(0,10^{2}). We label this method ABadjEb.
Implementation and software
All methods were applied by fitting models in Stan [54], using Markov chain Monte Carlo (MCMC) sampling to estimate Bayesian posterior distributions for model parameters. Each implementation consisted of four MCMC chains, where 1,000 iterations were used as an initial burnin period for each chain. Posterior estimates were based on 1,000 samples per chain, and checked for sensitivity to changes in initial values. The effective sample size and \(\hat {R}\) statistics were extracted for an initial assessment to identify signs of chain nonconvergence, and further checks were made by inspecting trace and autocorrelation plots [55].
Results
In this section, we report the results from applying the methods described in “Methods” section to the datasets described in “Applied example: assessing biologics for treating rheumatoid arthritis (RA)” section. All methods were applied to both the original dataset (consisting of 14 RCTs) and the artificial dataset (consisting of two SATs and 12 RCTs from the original dataset). In tables and figures, where a method was applied to the original dataset it is labelled with the suffix 1, and where it was applied to the artificial dataset it is labelled with the suffix 2 (e.g. the contrastbased unadjusted method with independent baseline response parameters applied to the original dataset is labelled CBunadjInd1). Under the contrastbased parametrisation, the methods require a reference treatment to be specified for which we chose placebo. We report the results for the methods without covariates first, and then report the results from applying the methods with adjustment on the baseline response using RA duration (years) as a covariate.
Methods without covariates
Contrastbased methods
The contrastbased methods without adjustment for covariates are described in “Methods without covariates” section, and consist of the methods with independent and exchangeable baseline response parameters, CBunadjInd and CBunadjEx, respectively. Figure 2 presents the posterior median and 95% credible interval (CrI) estimates for the basic parameters d_{1k}, representing log odds ratios (ORs) comparing biologics versus placebo in terms of the ACR20 outcome, for each method when applied to the original and artificial datasets.
Considering the application to the original dataset first, the CBunadjInd method estimates the OR comparing tocilizumab versus placebo to be 3.94 (95% CrI: 1.99, 8.25). This indicates that, in the population represented by the set of trials in the synthesis, a random sample of participants allocated tocilizumab have on average almost four times the odds of achieving an ACR20 response compared to a similar sample of participants allocated placebo. When the CBunadjInd method was applied to the artificial dataset, using a twostage approach (see final paragraph in “Methods without covariates” section), the OR was estimated to be 3.10 (1.34, 6.82). This suggests that the effectiveness of tocilizumab is underestimated in the artificial dataset compared to the original dataset, albeit with significant overlap in CrIs. This result can be explained by the difference in the observed baseline response in the original dataset and the baseline response predicted by the CBunadjInd method when applied to the artificial dataset. Figure A.1 (Appendix A) presents the posterior estimates of the baseline response parameters ϕ_{j} representing the log odds of achieving an ACR20 response on placebo in each trial. For trials one and two, assessing tocilizumab versus placebo, the predicted baseline response overestimates the observed baseline response in the original dataset, which inversely impacts the basic parameter estimates.
Considering the application to the original dataset, the CBunadjEx method estimates the OR comparing tocilizumab versus placebo to be 3.86 (2.20, 6.89). This estimate is in agreement with the estimate from the CBunadjInd method applied to the original dataset, indicating that the exchangeability assumption had little impact on the baseline response estimates. Figure A.1 (Appendix A) confirms that there is little difference in baseline response estimates between CBunadjInd and CBunadjEx for trials one and two. When applied to the artificial dataset, CBunadjEx estimates the OR to be 3.10 (1.40, 6.96). This result is consistent with the estimate from applying CBunadjInd to the artificial dataset using the twostage approach, but underestimates the OR in the original dataset. This suggests that the disagreement in the effect estimates for tocilizumab is due to the difference between the observed and predicted baseline response estimates, and that the exchangeability assumption had little impact on the results. There is significant overlap in the CrIs corresponding to the effect estimates across all applications, which indicates that the disagreement introduced by using data from SATs (i.e. removing data from an RCT control arm) is relatively limited for this example. Figure 2 also shows that uncertainty increases in treatment effect estimates corresponding to tocilizumab when the control arms are removed, but there is no change in uncertainty for the effect estimates corresponding to the other treatments.
Figure 2 suggests that the exchangeability assumption has a greater impact on effect estimates for adalimumab. Considering the application to the original dataset, the CBunadjInd method estimates an OR of 4.90 (2.39, 9.78) for adalimumab versus placebo. In contrast, the CBunadjEx method estimates an OR of 4.18 (2.44, 7.17). A similar disagreement is observed in the artificial dataset where the CBunadjInd method estimates an OR of 4.81 (2.34, 9.78), whilst CBunadjEx estimates an OR of 4.10 (2.34, 6.96). This indicates that the exchangeability assumption introduces a disagreement in the effect estimates for adalimumab in both datasets. Figure A.1 (Appendix A) shows that the baseline response estimates corresponding to trials assessing adalimumab versus placebo (in particular, trials four and six) are significantly shifted toward the mean baseline response (represented by the dashedline). This suggests that the exchangeability assumption can lead to disagreement in effect estimates, particularly where there is significant betweenstudy heterogeneity in baseline response estimates. It follows that adjusting the baseline response by including covariates, to account for betweenstudy heterogeneity, could mitigate disagreement in effect estimates introduced by the exchangeability assumption. Despite evidence of disagreement in effect estimates there is significant overlap in CrIs, suggesting that the impact of assuming exchangeability is relatively limited for this example.
Armbased methods
The armbased method without covariateadjustment ABunadj is described in “Methods without covariates” section. Figure 3 presents the posterior median and 95% CrI estimates for the pooled absolute effects θ_{k} representing the log odds of achieving an ACR20 outcome associated with each intervention.
Considering the application to the original dataset first, ABunadj estimates the pooled log odds on placebo to be 0.88 (1.10, 0.67). This implies that, in a population represented by the trials in the synthesis, a random sample of participants allocated placebo would on average have a probability of achieving an ACR20 response of 0.29 (0.25, 0.34). For tocilizumab, the pooled log odds is estimated to be 0.33 (0.17, 0.81), which corresponds to a response probability of 0.58 (0.46, 0.69). This suggests that tocilizumab is significantly more effective than placebo, in terms of the ACR20 outcome, and is consistent with the results from the contrastbased methods. When ABunadj was applied to the artificial dataset, the pooled log odds on placebo was estimated to be 0.83 (1.09, 0.57), representing a response probability of 0.30 (0.25, 0.36). This is very similar to the estimate of the pooled response probability for ABunadj applied to the original dataset. The pooled log odds on tocilizumab is estimated to be 0.28 (0.26, 0.82), corresponding to a response probability of 0.57 (0.44, 0.69). Here, the result slightly underestimates the effect estimate from the original dataset. This indicates that the removal of data on placebo response, in trials assessing tocilizumab versus placebo, impacted the pooled response estimate for tocilizumab. This may be because the ABunadj method assumes that response estimates are correlated at the betweenstudy level, where the correlation ρ was estimated to be 0.29 (0.42, 0.80) for the application to the original dataset, and 0.31 (0.40, 0.84) for the application to the artificial dataset. There is significant overlap in CrIs for each intervention associated with each dataset, which suggests the impact of the removal of data was limited in this example.
Table B.2 (Appendix B) lists posterior median and 95% CrI estimates for the model parameters corresponding to each application of ABunadj. The betweenstudy heterogeneity τ was estimated to be 0.34 (0.22, 0.53) when ABunadj was applied to the original dataset, which is slightly smaller than the estimate of 0.35 (0.23, 0.55) from the application to the artificial dataset.
Methods with covariateadjustment
Contrastbased methods
In this section, we report the results from applying methods which include an adjustment of the baseline response for RA duration. We begin by considering the results from the contrastbased methods with exchangeable baseline response parameters. Figure 4 presents the posterior median and 95% CrI estimates for the unadjusted and adjusted log ORs, corresponding to the contrastbased methods applied to the artificial dataset.
For tocilizumab, the OR estimated by the CBadjEx method, which included adjustment for the mean RA duration, was 3.00 (1.42, 6.42) which suggests that in a trial of newlydiagnosed RA patients (i.e. mean RA duration equal to zero years), participants allocated tocilizumab have approximately three times greater odds of achieving an ACR20 response compared to a similar group of participants allocated placebo. This result underestimates the unadjusted OR 4.10 (2.34, 6.96) estimated by the CBunadj method, which represents the average effect of tocilizumab across varying levels of RA duration. This difference in results indicates that the effect of tocilizumab may vary with RA duration, and Table B.3 (Appendix B) confirms the presence of an across trial covariate effect (α^{A}) of 0.10 (0.20, 0.00). This implies that the effect of a biologic versus placebo in a trial in which a sample of patients have had RA for an average of two years will be approximately 10% (100×(1−exp(−0.10))) smaller than in a trial in which a similar sample of patients have had RA for an average of one year.
The CBadjEbEx method, which also includes an adjustment for the withintrial covariate effect of RA duration, estimates an OR of 2.94 (1.34, 6.30) comparing tocilizumab versus placebo. This result is in strong agreement with the CBadjEx method, which suggests a lack of a covariate effect at the participantlevel. Table B.3 (Appendix B) lists the withintrial covariate effect (α^{W}) estimate as 0.00 (0.02, 0.01). The difference between across and withintrial covariate effect estimates indicates aggregation bias, and may be due to a difference in the distribution of RA duration within trials and the distribution of mean RA duration across trials. Figure 4 also presents the posterior estimates for the unadjusted log OR (comparing tocilizumab versus placebo) from the contrastbased method with independent baseline response parameters (CBunadjInd) applied to the original dataset. The unadjusted OR, estimated in the artificial dataset, underestimates the unadjusted OR estimated in the original dataset, and this difference does not decrease after adjustment for the covariate effect of RA duration. This shows that the adjustment has not mitigated the disagreement in results between the original and artificial datasets. Figure A.2 (Appendix A) presents the posterior estimates for the baseline response corresponding to each method. For trials one and two, there is little difference in the estimates before and after adjustment. This could be due to the fact that RA duration does not explain heterogeneity in the baseline response.
For adalimumab versus placebo, the adjusted OR estimated by the CBadjEx method was 4.39 (2.53, 8.00). This estimate is more consistent with the unadjusted OR from the original dataset, estimated by CBunadjInd to be 4.90 (2.39, 10.07). In Figure A.2 (Appendix A), the adjusted baseline response estimates in trials four, five, and six (i.e. trials assessing adalimumab versus placebo) show some discrepancy with respect to the unadjusted baseline response estimates from the original dataset.
Table B.3 (Appendix B) shows that there is a reduction in betweenstudy heterogeneity in baseline response (σ_{ϕ}) after adjusting for the mean RA duration, from 0.33 (0.15, 0.60) estimated by CBunadjEx to 0.28 (0.12, 0.56) estimated by CBadjEx. This indicates that the inclusion of mean RA duration is explaining some of the heterogeneity in baseline response, although there is little change in the mean baseline response m_{ϕ}.
Armbased methods
Figure 5 presents the posterior median and 95% CrI estimates for the unadjusted and adjusted armbased methods, applied to the artificial dataset. For placebo, the unadjusted pooled log odds of achieving an ACR20 response was estimated to be 0.83 (1.08, 0.58), corresponding to a response probability of 0.30 (0.25, 0.36). This result was relatively unchanged after adjustment for mean RA duration at the armlevel, where the adjusted pooled log odds were estimated to be 0.85 (1.09, 0.61) and the corresponding response probability was 0.30 (0.25, 0.36). Similarly, the adjustment did not seem to have an impact on effect estimates for tocilizumab, where the unadjusted pooled log odds were estimated to be 0.28 (0.26, 0.82) and the adjusted pooled log odds were 0.27 (0.24, 0.80). In contrast, the effect on adalimumab was larger after adjustment indicating the presence of a covariate effect across trials. The unadjusted pooled log odds of response were 0.59 (0.10, 1.07) corresponding to a response probability of 0.64 (0.52, 0.74), whilst the adjusted pooled log odds of response were 0.46 (0.04, 0.91) corresponding to a response probability of 0.61 (0.49, 0.71). Table B.4 (Appendix B) lists the posterior estimates for the acrosstrial covariate effect β^{A}, estimated by the ABadj method to be 0.06 (0.14, 0.02). This suggests that there is a decrease of approximately 6% in the pooled log odds of achieving an ACR20 response, for each additional year a sample of patients spend diagnosed with RA. There does not appear to be evidence of a withintrial covariate effect β^{W}, which is estimated by the ABadjEb method to be 0.00 (0.02, 0.01). Although there does not seem to be a noticeable difference in the betweenstudy heterogeneity (τ) before and after adjustment, the correlation ρ decreases from 0.31 (0.40, 0.87) to 0.23 (0.49, 0.82).
Table B.5 (Appendix B) lists deviance information criterion (DIC) statistics, a measure of model fit [56] where smaller values are preferred, for each method applied to the artificial dataset. There does not seem to be a significant difference in model fit between the arm and contrastbased methods. The inclusion of RA duration as a covariate did not provide a significant reduction in DIC.
Discussion
In this paper, we develop contrast and armbased methods for NMA synthesising SATs and RCTs, using a mixture of IPD and AD, for a dichotomous outcome. We also extended these methods to adjust the baseline response for a covariate, to account for within and acrosstrial covariate effects. We applied the methods to a dataset of 14 RCTs assessing biologics versus placebo for RA and an artificial dataset, including two SATs (assessing tocilizumab), generated from the original dataset of 14 RCTs by removing the control arm in the two tocilizumab trials. Placebo was designated as the reference treatment for the network, and so the contrastbased methods assumed a fixed baseline treatment across trials. The contrastbased unadjusted methods underestimated the treatment effect for tocilizumab versus placebo, when applied to the artificial dataset compared to the original dataset. This difference appeared to be caused by an overestimate of the predicted baseline response for the SATs. The contrastbased methods with exchangeable baseline response parameters showed disagreement with the methods assuming independent parameters, in treatment effect estimates for adalimumab, in both datasets. This disagreement seemed to be caused by a shift toward the mean baseline response associated with the exchangeability assumption for the baseline response parameters. Despite these discrepancies, there was large overlap in posterior distributions for treatment effect parameters between applications to the two datasets. Under both the contrast and armbased parametrisation, there was some evidence of an acrosstrial covariate effect associated with mean RA duration, but a withintrial covariate effect was not detected. However, the adjustment appeared to make little difference to the treatment effect estimates. The armbased methods showed greater agreement in effect estimates between the applications to the two datasets.
Our applied example enabled an assessment of the developed methods to synthesise SATs and RCTs against a synthesis of RCTs alone. A similar approach was used by Beliveau et al. [27], where connected networks of RCTs were disconnected by removing data from trials, to understand the impact of assuming exchangeable baseline response parameters to connect the disconnected networks. In the majority of cases, the exchangeability assumption seemed to make relatively little difference to the results, as posterior distributions for treatment effect parameters showed large overlap. This is consistent with the findings from our applied example, where there was also significant overlap in posterior distributions for treatment effect parameters in the artificial and original datasets, although the effect estimate for tocilizumab had greater precision in the original dataset where more data were available. Despite this, there was a shift in effect estimates associated with assuming exchangeable baseline response parameters, due to the influence of the mean baseline response (e.g. for adalimumab). To better understand this discrepancy, we also applied the contrastbased method with independent baseline response parameters to the artificial dataset using a twostage approach. This approach is recommended by Dias et al. [52] to ensure treatment effect estimates are not influenced by assumptions regarding the baseline response. This mitigated the discrepancy associated with assuming exchangeable baseline response parameters, and the results were more consistent with the application to the original dataset for adalimumab. However, the discrepancy remained for treatment effect estimates associated with tocilizumab, indicating that the predicted baseline response in the artificial dataset was not consistent with the observed baseline response in the original dataset. This implies that incorporating SATs into a NMA to estimate relative treatment effects depends significantly on how representative the mean baseline response across the RCTs in the synthesis is of the hypothetical baseline response for the participants in the SATs. This highlights the importance of considering whether each trial in the synthesis is informative about the target population in the SATs [52]. It also suggests that explaining betweenstudy heterogeneity in the baseline response, by including covariates to account for differences in prognostic factors in trial participants, could improve the predicted baseline response. Thus, incorporating SATs into a synthesis may be beneficial when decisionmakers require relative effect estimates for a particular treatment, and are reluctant to delay the decision until a RCT has been undertaken. A review of HTA submissions found an increasing use of data from SATs in recent years, particularly to provide evidence on an external patient cohort to determine relative treatment effectiveness [57]. Malottki et al. conducted a multiple technology appraisal of five biologics as secondline treatment for RA [58], in which they identified five RCTs and 28 SATs relevant to the decision problem. Only two biologics were compared headtohead via an indirect comparison based on two RCTs and the SATs were not included in any quantitative synthesis, resulting in large uncertainty in effectiveness estimates.
When seeking to combine data from SATs and RCTs in a metaanalysis (or NMA), particularly in a decisionmaking context, it can be beneficial to implement a range of methods to understand how alternative parametrisations influence the results. A comparison of arm and contrastbased methods requires the calculation of additional quantities as a function of model parameters. For armbased methods, a pooled relative treatment effect can be calculated from the pooled armlevel outcomes, d_{1k}=θ_{k}−θ_{1}. For contrastbased methods, a pooled absolute treatment effect can be calculated from the mean baseline response and the pooled relative treatment effect, θ_{k}=m_{ϕ}+d_{ik}.
We also applied methods which included adjustment for a covariate, to account for betweenstudy heterogeneity in baseline response, considering RA duration to be a prognostic factor associated with ACR20 response. In the artificial dataset, an acrosstrial covariate effect was associated with mean RA duration. The results indicate that the adjustment provided a small reduction in betweenstudy heterogeneity, but this did not make treatment effect estimates more consistent with those from the application to the original dataset. The residual betweenstudy heterogeneity estimated after adjustment suggested the presence of unmeasured prognostic factors. Despite some evidence of an acrosstrial covariate effect, there was no evidence of a withintrial covariate effect, indicating the presence of aggregation bias. The difference between these findings may be due to the impact of unmeasured covariates, associated with both an ACR20 response and mean RA duration across trials. An exploratory analysis of the IPD, corresponding to the two tocilizumab trials for which it was available (see Table 1), was undertaken to assess the distribution of RA duration across patients within each trial. The distribution of RA duration within each trial did not differ significantly from the distribution of mean RA duration across the other 12 RCTs (listed in Table 1). Here, the goal of the adjustment for RA duration was to use data from RCTs to predict baseline response estimates more representative (compared to the unadjusted estimates) of the patient population in the SATs. Whilst we focus on adjustment on the baseline response, other authors have looked at how a treatment effect varies with respect to a trial characteristic (treatmentcovariate interaction) [59], via metaregression or network metaregression. Populationadjustment methods, such as matchingadjustment indirect comparison and simulated treatment comparison methods, have been proposed for a similar goal where IPD are available for one trial and only AD are available for another [16]. Similarly, NMA methods have been developed which combine IPD and AD whilst accounting for a nonlinear association between the treatment effect and a particular covariate to mitigate aggregation bias [60]. More recently, Hong et al. propose NMA methods using AD to define a prior distribution for pooled treatment effect and treatmentcovariate interaction parameters estimated from IPD, whilst downweighting the AD via a power term or a commensurability parameter, which also avoid introducing aggregation bias into the synthesis [61].
Due to the limited data available in the artificial dataset, we assumed a common withintrial covariate effect parameter. An assumption of independent withintrial covariate effects may have accounted for the difference in covariate distributions between the two trials for which IPD were available. Thom et al. were unable to detect acrosstrial covariate effects in a similar application due to limited data [20]. In our applied example, there were no trials comparing biologics headtohead, preventing an assessment of inconsistency via the recommended methods [62]. Due to this, and the limited data, we did not consider adjustment of treatment effects for potential effect modifiers.
In this paper, we made the assumption that the intervention arms in RCTs assessing tocilizumab versus placebo were representative of SATs assessing tocilizumab. In practice, the populations represented by the trials may differ due to factors associated with trial design (e.g. participant inclusion criteria). A better assessment of the methods would be provided by a simulation study, where data are simulated for a network of RCTs and then a subset of data corresponding to participants in control arms are removed, to provide a more accurate representation of data from SATs. This would allow the methods to be applied in a greater number of scenarios to understand how differences in trial populations can influence treatment effect estimates when incorporating SATs into a network. Furthermore, many of the trials considered in the applied example consisted of multiple intervention arms, from which data were combined to create a single intervention arm. The proposed methods can be extended for application to multiarm RCTs, by considering withintrial correlation between treatment effects relative to a common baseline treatment [51].
Conclusion
In this paper, we propose contrast and armbased NMA methods which allow the incorporation of SATs into a synthesis of RCTs, to estimate relative treatment effectiveness when there is no alternative (due to a disconnected network). Further work is required to understand how adjustment for covariate effects can be incorporated to predict a more representative baseline response estimate for SATs, and treatment effect estimates more consistent with randomised evidence.
Availability of data and materials
The datasets analysed during the study are included in this published article (Table 1, applicable only to data extracted from published manuscripts). For eligible studies qualified researchers may request access to individual patient level clinical data through a data request platform. At the time of writing this request platform is Vivli (https://vivli.org/ourmember/roche/). For up to date details on Roche’s Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here: https://go.roche.com/data_sharing.
Abbreviations
 NMA:

Network metaanalysis
 SAT:

Single arm trial
 IPD:

Individual participant data
 AD:

Aggregate data
 RCT:

Randomised controlled trial
 CB:

Contrast based
 AB:

Arm based
 RA:

Rheumatoid arthritis
 HTA:

Health technology assessment
 bDMARD:

biologic disease modifying anti rheumatic drug
 ACR:

American College of Rheumatology
 MCMC:

Markov chain Monte Carlo
 CrI:

Credible interval
 OR:

Odds ratio
 DIC:

Deviance information criterion
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Acknowledgements
This research used the ALICE/SPECTRE High Performance Computing Facility at the University of Leicester. The authors would like to thank Roche for providing access to the individual participant data used in the analysis.
Funding
JS was supported by UK National Institute for Health Research (NIHR) Doctoral Research Fellowship [award no. NIHR300190]. LW was supported by NIHR Methods Fellowship [award no. RMFI201708027] and subsequently by NIHR Predoctoral Fellowship [NIHR301013]. KRA and SB were supported by the UK Medical Research Council [grant no. MR/R025223/1]. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funding bodies played no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.
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Contributions
JS and SB conceptualised the study. JS, LW, and SG undertook the data curation. JS undertook the formal analysis and contributed the original draft of the manuscript. SB, KRA and CG provided supervision for JS. SG and RDR provided additional methodological advice. All authors contributed to manuscript revisions and approved the final manuscript.
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Competing interests
JS, SG, LW, RDR, and CG do not have conflict of interest. SB has served as a paid consultant providing methodological advice to NICE, Roche and RTI Health Solutions, has received payments for educational events from Roche, and has received research funding from European Federation of Pharmaceutical Industries & Associations (EFPIA) and Johnson & Johnson. KRA has served as a paid consultant, providing methodological advice, to; Abbvie, Amaris, Allergan, Astellas, AstraZeneca, Boehringer Ingelheim, BristolMeyers Squibb, CreativCeutical, GSK, ICON/Oxford Outcomes, Ipsen, Janssen, Eli Lilly, Merck, NICE, Novartis, NovoNordisk, Pfizer, PRMA, Roche and Takeda, and has received research funding from Association of the British Pharmaceutical Industry (ABPI), European Federation of Pharmaceutical Industries & Associations (EFPIA), Pfizer, Sanofi and Swiss Precision Diagnostics. He is a Partner and Director of Visible Analytics Limited, a healthcare consultancy company.
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Additional file 1
Supplementary material for: bayesian network metaanalysis methods for combining individual participant data and aggregate data from single arm trials and randomised controlled trials. Includes: Figures A.12, Tables B.15, Stan programming code for models.
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Singh, J., Gsteiger, S., Wheaton, L. et al. Bayesian network metaanalysis methods for combining individual participant data and aggregate data from single arm trials and randomised controlled trials. BMC Med Res Methodol 22, 186 (2022). https://doi.org/10.1186/s1287402201657y
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DOI: https://doi.org/10.1186/s1287402201657y