A scoping review of causal methods enabling predictions under hypothetical interventions

Background The methods with which prediction models are usually developed mean that neither the parameters nor the predictions should be interpreted causally. For many applications, this is perfectly acceptable. However, when prediction models are used to support decision making, there is often a need for predicting outcomes under hypothetical interventions. Aims We aimed to identify published methods for developing and validating prediction models that enable risk estimation of outcomes under hypothetical interventions, utilizing causal inference. We aimed to identify the main methodological approaches, their underlying assumptions, targeted estimands, and potential pitfalls and challenges with using the method. Finally, we aimed to highlight unresolved methodological challenges. Methods We systematically reviewed literature published by December 2019, considering papers in the health domain that used causal considerations to enable prediction models to be used for predictions under hypothetical interventions. We included both methodologies proposed in statistical/machine learning literature and methodologies used in applied studies. Results We identified 4919 papers through database searches and a further 115 papers through manual searches. Of these, 87 papers were retained for full-text screening, of which 13 were selected for inclusion. We found papers from both the statistical and the machine learning literature. Most of the identified methods for causal inference from observational data were based on marginal structural models and g-estimation. Conclusions There exist two broad methodological approaches for allowing prediction under hypothetical intervention into clinical prediction models: (1) enriching prediction models derived from observational studies with estimated causal effects from clinical trials and meta-analyses and (2) estimating prediction models and causal effects directly from observational data. These methods require extending to dynamic treatment regimes, and consideration of multiple interventions to operationalise a clinical decision support system. Techniques for validating ‘causal prediction models’ are still in their infancy. Supplementary Information The online version contains supplementary material available at 10.1186/s41512-021-00092-9.


Introduction
Clinical prediction models (CPMs) aim to predict current diagnostic status or future outcomes in individuals, conditional on covariates [1]. In clinical practice, CPMs may inform patients and their treating physicians of the probability of a diagnosis or a future outcome, which is then used to support decision-making. For example, QRISK [2,3] computes an individual's risk of developing cardiovascular disease within the next 10 years, based on their characteristics such as BMI, blood pressure, smoking status, and other risk factors. The National Institute for Health and Care Excellence (NICE) guidelines indicate that anyone with an estimated QRISK above 10% should be considered for statin treatment [4]. These guidelines also state that initially, patients should be encouraged to implement lifestyle changes such as smoking cessation and weight loss. However, guidelines using such clinical prediction models can be problematic for two main reasons. First, there is often a lack of clarity concerning the estimand that a clinical prediction model is targeting [5]. To inform decision making about treatment initiation, one requires predicted risks assuming no treatment is given. This might be achieved by using a 'treatment-naïve' cohort (removing all patients who take treatment at baseline) [2,3] or by incorporating treatment as a predictor variable in the model [6]. However, such approaches do not handle 'treatment drop-in': in which patients in the development cohort might start taking treatment post-baseline [7,8]. One way to attempt to account for this is to censor patients at treatment initiation; however, this assumes that treatment initiation is not informative [9]. Second, these prediction models cannot indicate which of the potential treatment options or lifestyle changes would be best in terms of lowering an individual's future cardiovascular risk, nor can they quantify the future risk if that individual was given a treatment or lifestyle change [10,11]. With the lack of randomised treatment assignment such as in the observational studies, simply 'plugging in' the hypothetical treatment or intervention via the baseline covariates will rarely, if ever, give the correct hypothetical risks [11]. For example, there may be underadjustment due to residual confounding, or overadjustment of mediators or colliders.
To correctly aid such decision-making, one needs answers to 'what-if' questions. As an example, suppose we are interested in statin interventions for primary prevention of CVD and we would like to predict the 10-year risk of CVD with or without statin interventions at an individual level. The methods used to derive CPMs do not allow for the correct use of the model in answering such 'whatif' questions, as they select and combine covariates to optimize predictive accuracy, not to predict the outcome distribution under hypothetical interventions [12,13].
Nevertheless, end-users often mistakenly compare the contribution of individual covariates (in terms of risk predictions) and seek causal interpretation of model parameters [14]. Within a potential outcomes (counterfactual) framework, an emerging class of causal predictive models could enable 'what-if' queries to be addressed, specifically calculating the predicted risk under different hypothetical interventions. This enables targeted intervention, allows correct communication to patients and clinicians, and facilitates a preventative healthcare system.
There exists a vast literature on both predictive models and causal inference. While the use of prediction modelling to enrich causal inference is becoming widespread [15], the use of causal thinking to improve prediction modelling is less well studied [16]; however, its potential is acknowledged [13]. Our aim was therefore to identify methods for developing and validating 'causal prediction' models that use causal methods to enable risk estimation of outcomes under hypothetical interventions. We aimed to identify the main methodological approaches, their underlying assumptions, targeted estimands, and potential pitfalls and challenges with using the method. Finally, we aimed to highlight unresolved methodological challenges.

Methods
We aimed to identify all studies in which a form of causal reasoning is used to enable predictions for health outcomes under hypothetical interventions. To be clear, we were not interested in causal studies where the methods can solely be used to predict average or conditional causal effects [13].
Due to the available resources for reviewing large volumes of papers, the search was restricted to the health domain. We included both methodologies proposed in statistical/machine learning literature and methodologies used in applied studies. The review process adhered to Arksey and O'Malley's [17] scoping review framework and the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement [18]. We have also followed recommendations for conducting methodology scoping reviews as suggested in Martin et al. [19].

Search strategy
We systematically reviewed the literature available up to a cut-off date on December 31, 2019. The literature search was conducted in two electronic databases: Ovid MEDLINE and Ovid Embase, and searches were tailored to each database and restricted to English language publications. The search terms were designed by considering the intersection of prediction modelling and causal inference. Pre-existing search filters were utilised where possible such as those for prediction models [20]. Details of the search terms are included in the supplementary protocol. We were also aware, a priori, of several research groups that have published work on methods in related areas (listed in the supplementary protocol). We manually searched for any relevant recent publications within the past 4 years from these groups. In addition, we conducted backward citation search checking the references of identified papers, and a forward citation search using Google Scholar, which discovered papers referencing the identified papers.

Selection of studies
After the initial search, all titles and abstracts of papers identified by the search strategy were screened for eligibility by the lead author (LL). A random 3% were screened by a second reviewer (DJ) to ensure reliability of the screening process. Any discrepancies between the reviewers were solved through mutual discussion, in consultation with a third reviewer, where needed (MS). The initial eligibility criteria, based on title and abstract screen, were as follows: (1) use causal reasoning in the context of health outcome prediction, specifically enabling prediction under hypothetical interventions; (2) describe original methodological research (e.g. peer reviewed methodological journal); or (3) applied research, which did not develop methodology, but state-of-the-art methodology was employed to address relevant causal prediction questions. We excluded studies that could only be used for causal effect estimation, and studies where standard clinical prediction models were used to infer conditional causal effects, e.g. [21]. However, we do not exclude papers that developed a novel method of allowing prediction under hypothetical intervention, even when the final goal was causal effect estimation. We excluded letters, commentaries, editorials, and conference abstracts with no information to allow assessment of proposed methods.

Extraction
Following the review aims, we extracted information from papers that were included after a full-text screening as follows: 1. Article type (summary/review, theoretical, modelling with application via simulation and/or observed data, purely applied paper); 2. Clinical topic area of analysis (e.g. CVD, HIV, cancer) for papers with application to observed data; 3. Intervention scenarios (single intervention vs multiple interventions); types of outcome and exposure examined (binary, time-to-event, count, continuous, other); 4. Information on targeted estimand and possible validation approaches for the proposed methods inferred by the review authors; stated possible sources of bias; 5. Stated assumptions; methodologies/methods used for the causal effect estimation and outcome prediction; main methodological novelty stated by the authors of identified papers; 6. Reported modelling strengths and limitations, and suggestions for the future work; 7. Availability of software/code.
The completed extraction table is available in the Supplementary File 1. Categorisation of papers was carried out during information extraction phase by synthesising the extracted information.

Results
Our database searches identified 4919 papers. We identified a further 115 papers through checking publications from known research groups, and forward and backward citation searching. Of these, 87 were retained for a fulltext screening, with 13 of these were deemed eligible for final inclusion, as listed in Table 1. The process of study identification, screening, and inclusion is summarised in the PRISMA flowchart (Fig. 1).
The identified papers covered two main intervention scenarios: single intervention [22][23][24][25][26][27] and repeated interventions over time [8,[28][29][30][31][32][33] with nearly an equal amount of papers addressing average intervention effects (defined by a contrast of means of counterfactual outcomes averaged across the population) [8,22,23,25,29,30] and conditional effects (defined as the contrast of covariate-specific means of the outcome under different intervention levels) [24,[26][27][28][31][32][33]. Across the included papers, we identified two broad categories of methodological approaches for developing causal prediction models: (1) enriching prediction models with externally estimated causal effects, such as from metaanalyses of clinical trials and (2) estimating both the prediction model and causal effects from observational data. The majority of the identified papers (10 out of 13) fell into the latter category, which can be further divided according to intervention scenarios and included methods embedded within both statistical and machine learning frameworks. Table 1 describes part of the extracted information on each paper. The complete extraction table is available in the Supplementary File 1. In addition, we will illustrate the methods identified using the statin interventions for primary prevention of CVD example introduced previously, explaining each method and showing their differences in terms of targeted questions and corresponding estimand ( Table 2).

Combining causal effects measured from external information
Three papers [22][23][24] were identified as developing models with combined information from different sources to address single treatment effect. Candido dos Reis et al. [22] and Brunner et al. [23] took a two-stage approach, in which treatment effect estimates from external sources such as RCTs and meta-analyses were first identified, then combined with prediction models to allow predictions under treatment. In the statins for CVD example, the method proposed by Candido dos Reis et al. [22] corresponds to developing a CPM including individuals who take statin at baseline, where the coefficient for the statins variable in the model is fixed to the statin effects estimated from trials. Brunner et al. [23] developed a CPM for cardiovascular risk which was then combined with an externally estimated equation of proportional risk reduction per unit LDL cholesterol reduction to aid decision making in lipid-lowering treatment usage.
In addition to the above two-stage approach borrowing causal information estimated externally into predictive models, a one-stage approach, proposed by Silva [24], was also identified where the two sources of data, interventional and observational, were jointly modelled for causal prediction. This approach was applied in a scenario where it is possible to collect interventional data such that treatments were controlled but where sample sizes might be limited. The idea was to transform observational data into informed priors under a Bayesian framework to predict the unbiased dose-response curve under a pre-defined set of interventions, or 'dose'. All the three approaches above are limited to a single intervention type and intervening at a single point in time, where, in a considered trial protocol, the intervention may follow-up for a certain length of time during which its choice is maintained (e.g. the initialisation of statin intervention). Approaches that directly apply the externally estimated causal effects into CPMs assume that the estimated causal effects are generalisable to the population in which one wishes to apply the prediction model. Equally, combining individual data from both sources (i.e. the one-stage approach) ignored the issue of sample selection bias, which was highlighted in [24]. Additionally, the one-stage approach can become computationally intensive as the size of the observational and number of treatment levels increase.
Estimating both a prediction model and causal effects from observational data A total of 10 papers discussed modelling predictions under interventions entirely from observational data. Approaches from these papers can be further divided into two categories: (1) methods considering only one intervention at a single time point [25][26][27], as discussed in Section 3.2.1, and (2) methods allowing timedependent interventions [8,[28][29][30][31][32][33], as discussed in Section 3.2.2.

Counterfactual prediction models that consider an intervention at a single point in time
In our running example, this corresponds to a decision at a single time of whether to prescribe statins for CVD prevention. It does not account for whether statins are discontinued or started at any subsequent time.
Related to average treatment effect estimation Decision-making on whether to intervene on treatment requires an unbiased estimate of the treatment effect at   baseline. Assuming that the Directed Acyclic Graph (DAG) that encodes the relationship between all the relevant variables is known, then do-calculus [34] provides an indication of whether this can be achieved in the setting of observational data with the required causal assumptions. For example, including a collider in the model (a variable caused by both treatment and outcome) will lead to biased estimates of treatment effects on the outcome. A more complex scenario appears when the collider itself cannot be directly observed, but its information is contained in other prognostic factors. Van Amsterdam et al. [25] proposed a deep learning framework to address this particular scenario. Their goal is to predict survival of lung cancer patients using CT-scan images, in which case factors such as tumor size and heterogeneity are colliders that cannot be directly observed but can be measured from the image. The authors proposed a multi-task prediction scheme embedded in a convolutional neural network (CNN) framework (a non-linear model often used with images) which can simultaneously estimate the outcome and the collider. It used a CNN to separate the unobserved collider information from images while enabling the treatment to be appropriately included as a covariate for risk prediction under intervention. As there is no modelling of interactions between treatment and other covariates, this approach only addresses average treatment effects. Van Amsterdam et al. [25] have demonstrated that deep learning can in principal be combined with insights from causal inference to estimate unbiased treatment effect for prediction. However, the causal structure applied therein was in its simplest form, and further developments are needed for more realistic clinical scenarios where, e.g. there is confounding for treatment assignment, or a treatment effect modifier exists within the image.  counterfactual prediction of E[Y (a) | X = x], a ∈ {0, 1}. In an RCT, given complete randomisation-i.e., a is independent of Y (a) and X, under consistency, one can estimate E[Y (a) | X = x] by fitting a prediction model to the treated arm (a = 1) and the control arm (a = 0), respectively. The technique is often used in estimating conditional treatment effects [21,35] or identifying subgroups from RCTs [36,37], whereas our focus is counterfactual prediction under interventions. In Alaa et al. [26], under a set of assumptions, this technique was adapted for counterfactual prediction with observational data, which used a more complex regression model to address for selection bias in the observational dataset.
Alaa et al. [26] adopted standard assumptions of unconfoundedness (or ignorability) and overlap (or positivity), which is known as the 'potential outcomes model with unconfoundedness'. Their idea is to use the signal-inwhite-noise model for the potential outcomes and estimate two target functions, the treated and the untreated, simultaneously with training data. The estimation is done through one loss function, known as the precision in estimating heterogeneous effects (PEHE), which jointly minimises the error of factual outcomes and the posterior counterfactual variance, in such a way to adjust for the bias between the treated and untreated groups. The counterfactual prediction for either treated or untreated can then be made through the estimated posterior mean of two potential outcome functions. Since the ground truth counterfactual outcomes are never available in real-world observational datasets, it is not straightforward to evaluate causal prediction algorithms and compare their performances. A semi-synthetic experimental setup was adopted in [26], where covariates and treatment assignments are real but outcomes are simulated.
For the longitudinal setting where the event history is fully observed, Arjas [27] adopted a marked point process (MPP) framework with a Bayesian non-parametric hazard model to predict the outcome under a single intervention. Point processes are distributions over sequences of time points, and a marked point process is made by attaching a characteristic (a Mark) to each point of the process [38]. The idea is to incorporate all observed events in the data, including past treatments, covariates, and outcome of interest, into a single MPP: {(T n , X n ) : n ≥ 0}, where T 0 ≤ T 1 ≤ ⋯are the ordered event times and X n is a description of the event occurring at T n . The model assumed local independence-i.e. the intensities of events (that is, the probability of an event occurring in an infinitesimal time interval) when considered relative to the histories H t are locally independent of outcome risk functions in the model. Under this assumption, in order to define a statistical model for MPP, it suffices to specify the outcome intensities with respect to H t and there is no need for other event time intensities. Prediction under hypothetical interventions can be then made by evaluating the corresponding predictive probabilities in the Bayesian posterior predictive setting given the data.
Both methods in this subsection can be computationally intensive as the number of observed samples increased. This could be ameliorated using conventional sparse approximations [26,39]. Both methods are limited to binary interventions, and prediction via treatment effect estimation can only make counterfactual prediction for outcomes with or without intervention.

Counterfactual prediction models that consider timedependent treatments and treatment-confounder feedback
Papers included in this category [8,[28][29][30][31][32][33] covered three types of approaches to deal with scenarios where the treatments of interest and confounders vary over time.
One example of such confounding is in the sequential treatment assignment setting, where doctors use a set of variable measurements, at the current time or in the past, to determine whether or not to treat, which in turn affects values of these variables at a subsequent time. For example, whether or not statins are taken at a particular time will affect cholesterol, and these subsequent cholesterol levels affect subsequent decisions about statins. The benefit of such approaches is that they allow consideration of a longer term treatment plan, such as comparing taking statins continuously for 10 years from baseline, versus not taking statins for the next 10 years. The assumptions needed for identifying unbiased treatment effects in such scenarios are consistency, positivity, and sequential ignorability.
Marginal structural models (MSMs) within a prediction model framework Consider in our running example the hypothetical risk of not taking statins for the next 10 years. To account for treatment drop-ins, i.e. treatments initiated post-baseline, one straightforward way is to censor patients at treatment initiation; however, this assumes that treatment initiation is noninformative about the baseline and time-dependent covariates. Pajouheshnia et al. [8] proposed censoring followed by reweighting using inverse probability of censoring weights (IPCW) to solve the issue of informative censoring in estimating treatment-naïve risk. The proposed method derived time-varying censoring weights by estimating the conditional probabilities of treatment initiation and then developed a weighted Cox model in the treatment-naïve pseudo-population. A more flexible way of addressing treatment drop-ins for hypothetical risk prediction is to use MSMs with inverse probability treatment weighting (IPTW), where a pseudo-population is created such that treatment selection will be unconfounded. Sperrin et al. [28] proposed combining MSM with predictive modelling approaches to adjust for confounding and generate prediction models that could appropriately estimate risk under the required treatment regimens. Following the classic development of IPTW for an MSM, the proposed methods develop two prediction models: a treatment model for computing the probability of receiving post-baseline treatments, and an outcome prediction model fitted with the derived weights and with these post-baseline treatments as well as terms for any interactions between treatment and other predictors included as predictors. By carefully defining the required estimand for the target prediction, the proposed framework could estimate risks under a variety of treatment regimens. In the statin example, this means that one can compare CVD risk under a range of different statin treatment plan, although the focus in the paper was on the 'never takes statins' hypothetical prediction. As with approaches described so far in this category, the model only considered a binary treatment (e.g. statins yes/no). The extension to multiple treatment choices for the proposed method is possible in principal, although the underlying causal structure and resulted model may become too complex.
Similarly to [28], Lim et al. [29] adopted the MSM combined with IPTW approach. Instead of using linear or logistic regression models, they embedded the concept into a deep learning framework and proposed a Recurrent Marginal Structural Network (RMSN). The model consisted of (1) a set propensity networks to compute treatment probabilities used for IPTW and (2) a prediction network used to determine the treatment response for a given set of planned interventions.
The benefit of RMSN is that, it can be configured to have multiple treatment choices and outcomes of different forms (e.g. continuous or discrete) using multiinput/multi-output RNNs. This means, in the statin example, one could consider different doses, and indeed consider alternative treatments as well. Treatment sequences can also be evaluated, and no restrictions were imposed on the prediction horizon or number of planned interventions. The use of LSTMs in computing the probabilities required for propensity weighting can also alleviate susceptibility of IPTWs to model misspecification. A drawback is that one needs a rich source of longitudinal data to train the model. Moreover, as in general in deep learning models, they lack a clear interpretation.

Methods based on balanced representation approach
Matching approaches such as MSM or RMSN combined with IPTW above adjust for bias in the treatment assignments by creating a pseudo-population where the probability of treatment assignments does not depend on the timevarying confounders. Balanced representation approach, as proposed by Bica et al. [30], instead aimed for a representation Φ of the patient history H t ¼ ðA t − 1 ; X t Þ that was not predictive of treatment assignments. That is, in the case of two treatment assignments at time t, PðΦðH t ÞjA t ¼ 0Þ ¼ PðΦðH t ÞjA t ¼ 1Þ. It can be shown that, in this way, estimation of counterfactual treatment outcomes is unbiased [40]. Bica et al. [30] proposed a counterfactual recurrent network (CRN) to achieve balancing representation and estimate unbiased counterfactual outcomes under a planned sequence of treatments (such as statins). CRN improved the closely related RMSN model proposed by Lim et al. [29] in a way that overcame the fundamental problem with IPTW, such as the high variance of the weights. As with RMSN, both models required hyperparameter tuning. As the counterfactual outcomes were never observed, hyperparameters in both models were optimised based on the error on the factual outcomes in the validation dataset. As noted by the authors in [30], more work on providing theoretical guarantees for the error on the counterfactuals is required.
Methods with g-computation for correcting timevarying confounding Three papers [31][32][33] were identified using g-computation to correct time-varying confounding and predicting treatment response curves under the potential outcome framework.
Xu et al. [31] developed a Bayesian non-parametric model for estimating conditional treatment response curves under the g-computation formula and provided posterior inference over the continuous response curves. In the statin example, this means that one can estimate cholesterol or any other continuous outcome of interest under a planned sequence of statin treatments (yes/no). The proposed method modelled the potential outcome using a generalized mixed-effects model combining the baseline progression (with no treatment prescribed), the treatment responses overtime, and noise. The goal was to obtain posterior inference for the treatment response and predict the potential outcomes given any sequence of treatments conditioned upon past treatments and covariate history. There are two limitations to the model here: (1) it assumes independent baseline progression and treatment response components, and (2) treatment response models rely on the additive treatment effects assumption and a careful choice of priors based on clinical details to be decided by domain experts.
Soleimani et al. [32] extended the approach in Xu et al. [31] in two ways: (1) to continuous-time setting with continuous-valued treatments and (2) to multivariate outcomes. This means, in the statin example, one could simultaneously predict e.g. risk of CVD, cholesterol, and systolic blood pressure (SBP) under a range of different statin treatment plans (allowing for different doses assigned at different time points). The model has its ability to capture the dynamic response after the treatment is initiated or discontinued by using linear time-invariant systems. Despite being a more flexible model than [31], this model did not overcome two limitations mentioned above.
Schulam and Saria [33] considered another continuoustime setting where both type and timing of actions may be dependent on the preceding outcome. In the statin example, this means both the statin dose and treatment time (initialisation or discontinuation) depend on the preceding cholesterol level. Here, one needs to predict how a continuous-time trajectory will progress under sequences of actions. The goal was to model action-outcome traces D ≡ {t ij , Y ij , a ij } i, j : for each individual i and irregularly sampled sequences of actions and outcomes. Schulam and Saria [33] proposed a counterfactual Gaussian process (CGP) model to model the trajectory and derived an adjusted maximum likelihood objective that learned the CGP from observational traces. The objective was derived by jointly modeling observed actions and outcomes using a marked point process (MPP). The potential outcome query can therefore be answered with the posterior predictive trajectory of the outcome model. A key limitation in this model is that it could not model heterogeneous treatment effects arising from baseline variables.
Counterfactual prediction models in this section using g-formula to correct for time-varying confounding are highly flexible and can be adopted for a variety of clinical settings. However, these methods rely on a set of strong assumptions in both discrete-time and continuous-time settings that are generally not testable; for the latter, Schulam and Saria [33] extended Robin's Sequential No Unobserved Confounders assumption to continuous-time case and also assumed Non-informative Measurement Times.

Discussion
In this study, we conducted a methodology scoping review, which has identified two main types of causal predictive modelling (methods that allow for prediction under hypothetical interventions), with the main differences between the methods being the source of data from which the causal effects are estimated. We identified that when the causal effects required for the predictions were fully estimated from the observational data, methods are available for predictions under interventions either at a single time point or varying over time. We have collated current approaches within this field and highlighted their advantages and limitations in the review.
There are recent studies that have performed a review of methods for causal inference all with different focuses: methods in the analyses of RCTs [41], methods based on graphical models [42] or DAGs [43], and methods targeting time-varying confounding [44]. Our work differs from these reviews, and, to our knowledge, is the first review to focus on methods enabling predictions under interventions (i.e. counterfactual prediction models). A recent review focused on how time-dependent treatment use should be handled when developing prediction models [8]. This clarified the targeted estimand of the clinical prediction model of interest and consider hypothetical risks under no interventions.
Our search terms, defined from the intersection of prediction modelling filters and causal inference keywords, have been made purposely broad to capture relevant literature, albeit with a high number of falsepositives driven by the heterogeneity in language across the fields. This could imply a challenge in devising a potentially more effective search strategy for identifying methodological papers on both fields, a challenge as highlighted in Martin et al. [19].
This review has synthesised a range of methods, embedded within both statistical and machine learning frameworks. These methods rely on the availability of the DAG that encodes the relationship between all the relevant variables, and a series of assumptions that make it possible to estimate counterfactual predictions from observational data. Approaches described here cover a wide range of data settings and clinical scenarios. Careful thoughts are needed before adopting these methods, and further challenges and gaps for future research remain, which we will discuss here.
Methods combining information from different sources, such as RCTs combined with observational data, provide a natural way to enable counterfactual predictions; however, challenges remain when combining these two settings. Their objectives are not necessarily complementary, leading to distinct populations included in each study (of possibly very different sample sizes), different sets of covariates being measured, and some potential measurement bias. Therefore, combining observational study with RCTs would need more careful consideration, and a good global guidance may be required. Harrell and Lazzeroni [45] laid out some initial steps one can follow toward an optimal decision making using both RCTs and electronic health record (EHR) data. We also refer the reader to the recent PATH (Predictive Approaches to Treatment effect Heterogeneity) Statement [46,47], developed to provide guidance for predictive analyses of heterogeneity of treatment effects (HTE) in clinical trials. Predictive HTE analysis aims to express treatment effects in terms of predicted risks and predict which of 2 or more treatments will be better for a particular individual, which aligns closely with our review aim here. However, as motivated by the limitations in the conventional subgroup analyses in RCTs, predictive HTE analysis has focused on regression-based prediction in randomised trials for treatment effect estimation and subgroup identification. Such techniques can be adapted for the purpose of counterfactual prediction. For example, the predictive modelling used in estimating individualised causal effect in [21,35] was applied for counterfactual prediction in the included paper [30]. However, as the primary goal in predictive HTE analyses such as [21,35] is not predicting the counterfactual outcome, we did not include them in our review, which may also be deemed as a limitation of this study.
Another obstacle in combining RCTs with observational study is that, while the estimand for causal inference is clearly defined, the prediction estimand, termed the predictimand by Van Geloven et al. [5], is often unclear in prediction models. There is an emergence of studies arguing that clearly defining the estimand in prediction is important [28,43]. Despite these challenges, and that relatively little work has been done in combining RCTs with patient observational data, it remains an opportunity to explore the interplay of these two areas, as noted in the recent survey by Bica et al. [48].
Several key challenges arise in dealing with multiple interventions. The term 'multiple treatments' has been commonly used throughout literature, especially when addressing time-varying treatments. However, the same term may refer to very distinct scenarios in different studies, and greater clarity is necessary. The first and the most often seen scenario is where multiple values/options are observed for a treatment variable, either at a single time point or over time. Treatments in this setting are indeed 'multivariate treatments'. Many approaches in this review are designated to deal with multivariate treatments [24,[30][31][32][33] or can in principal be extended to this case [25], [28]. However, except for the approach in [24], all methods assume treatment effects from different options to be independent; in [24], interactions between treatment options are modelled through the covariance matrix in the Gaussian process prior. Further methodological development could explore ways to incorporate treatment-treatment interactions into the model.
A second scenario of 'multiple treatments' is where there are interventions on several risk factors, which is substantially more complex, but also more realistic. For example, in clinical settings, one could intervene on different risk factors to prevent CVD, and possible interventions include giving antihypertensive drug or lipidlowering treatment, lifestyle changing (physical activity, smoking, and alcohol drinking), or a combination of them. As these interventions take effect on different parts of the causal structure for the outcome, changes in one factor may affect others, e.g., weight gain after smoking cessation [49]. Moreover, each clinical intervention scenario will require its own model for identifying treatment effects from observational data [11]. Recent studies on estimating causal effect under multiple interventions have explored methods such as marginal structural cox models [50] and parametric g-formula [51]. However, despite its apparent need in clinical practice as in the abovementioned example, there appears to be a lack of models for counterfactual predictions under multiple interventions, and future methodological development is required.
Treatment scenarios addressed so far in this review, both time-fixed and time-varying, are static interventions, i.e. treatment assignment under intervention does not depend on the post baseline covariates. In contrast to the static intervention is the dynamic treatment strategy, a rule in which treatments are assigned dynamically as a function of previous treatment and covariate history. Methods such as dynamic MSMs introduced by Orellana et al. [52] and independently by Van der Laan and Petersen [53], and variants of structural nested models (SNMs) introduced by Robins [54] were proposed to use observational data to estimate the optimal dynamic treatment regime. Embedding these methods within clinical prediction framework could enable counterfactual predicting under dynamic treatment allocation and support decision-making on optimal treatment rules, which presents a promising avenue for future research [55].
The most pressing problem to address for predictions under hypothetical interventions is model validation. Validation is a crucial step in prediction modelling (counterfactual or otherwise), but is challenging in the counterfactual space since that the counterfactual outcomes are not observable in the validation dataset. The included papers have by-passed this issue by noting that, models are fitted based on the error on the factual outcomes in the validation dataset. In this context, handling of treatment in validation of clinical prediction models has received some attention [56]. Pajouheshnia et al. [56] addressed the specific case of validating a prognostic model for treatment-free risk predictions in a validation set where risk-lowering treatments are used. However, further studies are required to extend the potential methods to address the more complex issue in validating counterfactual predictions, such as nondiscrete treatment types and non-parametric models as included in this review. While there is emerging research on developing a model validation procedure to estimate the performance of methods for causal effects estimation [57] and sensitivity analysis in causal inference [58], techniques are required to validate the models tailored for counterfactual prediction. Just as domain knowledge is important in causal inference before real-world deployment, it is also important in validating counterfactual prediction, and integrating data generated from RCTs and observational studies and their corresponding models provides a promising way to aid the process [48].