Abstract
BackgroundMore patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments. Analytical tools enable insights by linking treatment responses from different types of studies, such as randomized controlled trials (RCTs) and observational studies. Given the importance of evidence from both types of studies, our goal was to integrate these types of data into a single predictive platform to help predict response to pregabalin in individual patients with painful diabetic peripheral neuropathy (pDPN).MethodsWe utilized three pivotal RCTs of pregabalin (398 North American patients) and the largest observational study of pregabalin (3159 German patients). We implemented a hierarchical cluster analysis to identify patient clusters in the Observational Study to which RCT patients could be matched using the coarsened exact matching (CEM) technique, thereby creating a matched dataset. We then developed autoregressive moving average models (ARMAXs) to estimate weekly pain scores for pregabalin-treated patients in each cluster in the matched dataset using the maximum likelihood method. Finally, we validated ARMAX models using Observational Study patients who had not matched with RCT patients, using t tests between observed and predicted pain scores.ResultsCluster analysis yielded six clusters (287–777 patients each) with the following clustering variables: gender, age, pDPN duration, body mass index, depression history, pregabalin monotherapy, prior gabapentin use, baseline pain score, and baseline sleep interference. CEM yielded 1528 unique patients in the matched dataset. The reduction in global imbalance scores for the clusters after adding the RCT patients (ranging from 6 to 63% depending on the cluster) demonstrated that the process reduced the bias of covariates in five of the six clusters. ARMAX models of pain score performed well (R2: 0.85–0.91; root mean square errors: 0.53–0.57). t tests did not show differences between observed and predicted pain scores in the 1955 patients who had not matched with RCT patients.ConclusionThe combination of cluster analyses, CEM, and ARMAX modeling enabled strong predictive capabilities with respect to pain scores. Integrating RCT and Observational Study data using CEM enabled effective use of Observational Study data to predict patient responses.
Highlights
More patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments
Multiple interacting risk factors and comorbidities make it difficult to select the right treatment for the right patient experiencing neuropathic pain, including those with painful diabetic peripheral neuropathy. pDPN presents in up to 26% of patients with diabetes mellitus [1], with age, duration of diabetes, and poor glycemic control as major factors in its development [2]
The reduction in the imbalance scores for the clusters after adding in the Randomized controlled trial (RCT) patients suggests that the process reduced the bias of covariates notably in five of the six clusters with only Cluster 1 retaining a relatively higher imbalance of covariates
Summary
More patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments. Multiple interacting risk factors and comorbidities make it difficult to select the right treatment for the right patient experiencing neuropathic pain, including those with painful diabetic peripheral neuropathy (pDPN). From the COmbination versus Monotherapy of pregaBalin and dulOxetine in Diabetic Neuropathy Study (COMBO-DN) study, Bouhassira et al [11] analyzed neuropathic pain sensory phenotypes in patients with painful diabetic neuropathy. They confirmed the advantages of sensory phenotypes and their predictive value, and concluded that heterogeneity of the patient populations should be taken into account for delivering more customized treatment. These results are consistent with both Freeman et al [12] in terms of identifying clusters with distinct pain characteristics independent of neuropathic pain syndrome and with Baron et al [13] in terms of pain-related sensory abnormality-based profiles as a way of identifying patient subgroups for treatment
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