Choosing sensitivity analyses for randomised trials: principles

Example

The Multicentre Aneurysm Screening Study group randomised 67,800 men to receive an invitation to an abdominal ultrasound scan or not [6]. Of those invited to receive an abdominal scan, 20% did not accept. The primary analysis was by intention to treat, thus estimating the effect of being randomised to abdominal ultrasound. Another analysis investigated the complier average causal effect, which considers what the (average) effect of treatment was in patients who would have adhered to protocol however they were randomised [7]. These questions are different, and observing different results should not shake our confidence in either. The CACE analysis was a secondary analysis, not a sensitivity analysis.

It is common for authors to compare the results of intention-to-treat with per-protocol analysis; see for example [8, 9]. While it is hard to pin down the precise question of per-protocol analysis [10], this is clearly different to the question intention-to-treat addresses. Per-protocol analysis should not therefore be considered as a sensitivity analysis for intention-to-treat but as a secondary analysis, if at all.

Example

Consider the proposal for handling missing data in Table two of Thabane et al [5]. The suggestion is to ‘analyse only complete cases’ and then ‘impute the missing data …and redo the analysis’. This will not necessarily assess how robust the results are to the missing data, as demonstrated by the following example.

In a protocol for an ongoing study, Zheng et al. describe a randomised trial aiming to assess the effect of Baduanjin exercise on physical and mental health in 222 college students [11]. The primary analysis will compare the mean lumbar muscle strength using a t-test. It is anticipated that outcomes will be missing for some participants. (The following is our illustration, and not described by the authors.) Assume that the primary analysis is in complete cases only, but the investigators wish to investigate how sensitive results are to dropping participants with missing data. They decide to use multiple imputation, where the model for imputation assumes lumbar muscle strength is normally distributed with different means but equal variances in the two treatment groups.

The imputation model described makes identical assumptions to the t-test and, with a sufficient number of imputations, the multiple imputation analysis will give near identical results. Simply imputing data does not necessarily make different assumptions. The fact that the results of two analyses are almost identical should not be reassuring: this is equivalent to being reassured that running one analysis twice gives the same results. Running two analyses which make identical assumptions gives us false confidence in the robustness of results. Note that this analysis may have value as a check that multiple imputation is working correctly, but only as a springboard to other imputation approaches.

Example

Returning to the missing data example above, if Zheng et al. were to use single (as opposed to multiple) imputation as a sensitivity analysis, as suggested in [5], this could well lead to different conclusions, despite our criticism above that the model for imputation is identical to the model for the primary analysis. Single imputation fails to allow for the uncertainty induced by missing data, and does not in general lead to valid inferences [12]. The estimated standard error of the treatment effect will be too small, implying inflation of type I error rates and under-coverage of confidence intervals. The analysis should thus not undermine the primary analysis of covariance.

Similarly, performing ‘one analysis that accounts for clustering and one that ignores it’, as proposed in [5], may be unwise. In general an analysis that accounts for clustering is used because clustering arises through the design [13]. If a cluster-randomised trial were primarily analysed allowing for the clustering, but a subsequent analysis ignoring the clustering led to different conclusions, there would be no degree of uncertainty as to which we believe. However, the best approach to account for clustering may be unclear. Hu et al. consider approaches to analysing a study with a longitudinal binary outcome [14], comparing random effects approaches with generalised estimating equations. This is reasonable because there tends to be some uncertainty as to which method is preferred.

Caveat: practical constraints

We note that there may be settings where exceptions to the third question are made for unavoidable reasons. For example, constraints on time, reliance on a methodology which is not well understood at the stage of writing, and a lack of software with the ability to run the analysis may make the ‘preferred analysis’ impractical for certain cases. This may happen in exceptional cases.

Example

The Paramedic trial is designed to assess whether survival of cardiac arrest patients can be improved by equipping ambulances with a mechanical chest compression device, compared to manual chest compressions by the crew [15]. Ambulances are randomised in a 1:2 ratio. Ambulances may move between different sites, and the crew may move between ambulances and sites, meaning the data involves cross-classified clustering. The principal analysis for this trial accounts for ambulance, but not for crew members, or the site the ambulance left from or returned to. Although an analysis which fully accounts for all three types of clustering may be preferred in theory, fitting such a model may be difficult, and might require the development of new methods and software.

We expect this issue to be rare. It arises because one analysis is preferred in theory but not in practice, and so the answer the question 3 can in fact be regarded as no.

Missing data assumptions

Consider again the trial described by Zheng et al [11]. Recall that the continuous outcome is anticipated to be missing for some participants. Suppose the primary analysis assumes data are missing at random and multiply imputes lumbar muscle strength separately for the two treatment groups, using an imputation model that also conditions on secondary (auxiliary) outcomes such as physical fitness, stress and quality of life. This primary analysis is valid under a missing at random assumption, and may give different results to analysis of the complete cases. However the assumption that missing values are missing at random is untestable. What if the data are truly missing not at random? It is considered plausible that lumbar muscle strength is less likely to be observed in individuals with lower values, and so missing values might on average be one unit lower than the observed outcomes of otherwise comparable individuals. Our sensitivity analysis might then be to subtract one from every imputed value and re-analyse the imputed data. Further sensitivity analyses could assume that this mechanism only occurred within one treatment group, that it was stronger than subtract one, or that it was in the opposite direction (add one) [16].

The sensitivity analyses are reasonable because they: 1) address the same question as the primary analysis, under different assumptions; 2) may or may not lead to different conclusions; and 3) involve different assumptions which may be plausible, although some may be less so: there is genuine uncertainty about the most plausible assumption [16].

Definitions of outcome

In a randomised trial in neutropenic patients, de Pauw et al. considered the effect of antifungal therapy on outcome [17]. The primary outcome was defined by a five-part composite endpoint, one part being ‘fever resolution’. Because fever resolution was hard to define, sensitivity analyses included using alternative definitions and feeding these into the five-part composite endpoint.

The Copers trial [18] is designed to evaluate a self-management course for patients with chronic musculoskeletal pain. The primary outcome is the mean of of three questions about Q1) the amount of pain-related disability the participant is currently experiencing, and whether the participant’s ability to Q2) work, and Q3) interact socially, has changed. Each is scored out of 10 with a high score intended to identify a negative outcome for all three questions. However, there is concern that for Q2 and Q3 some participants may be confused about whether a high or low score indicates a negative outcome. A planned sensitivity analysis is thus to redefine participants’ answers so that anyone with a score of two or lower for Q1, but eight or higher for Q2 or Q3 has their scoring reversed for Q2 and/or Q3. The primary analysis is then repeated with this definition of outcome.

Ideally, outcome variables would be unambiguously defined, but this is not always the case. For both of the above examples we regard the answer to our three questions as ‘yes’. The same question is being addressed, but assumptions about the definition of outcome are different, and it is not certain that one definition is correct.