{"doi":"10.1002/ejp.1835","title":"Yes, no, maybe: Replication and the importance of methodology","abstract":"This journal recently published a paper by Rong et al., entitled ‘Persistent moderate to severe pain and long-term cognitive decline’. (Rong et al., 2021). The authors demonstrate that, to a small but statistically significant degree, older adults with persistent moderate-to-severe pain (an approximation for chronic pain) experience a faster rate of late-life cognitive decline than older adults without pain. Given these findings, should clinicians be alert for accelerated cognitive decline in older adults with chronic pain? Rong et al. argue yes. But, interestingly, using the same data source, an earlier study by Veronese et al., (2018) concluded that there was no evidence for an effect. What are we to make of this? Rong and Veronese both used the English Longitudinal Study of Ageing (ELSA), a large population-based study of English older adults, to measure whether there exists evidence for a faster rate of cognitive decline in participants who report moderate-to-severe pain. Veronese et al. conducted a short-term analysis (2 years of cognitive change) and concluded that pain was not associated with accelerated cognitive decline. In contrast, Rong et al. found a highly statistically significant association that was replicated in multiple subgroup/sensitivity analyses. Rather than being inherently contradictory, important differences in the analytic methods and the handling of non-response likely explain the differing conclusions of Rong and Veronese. Rong adopted an analytic strategy similar to that of Whitlock et al., (2017), my group, when we studied the impact of persistent pain on cognition in an aligned cohort of US older adults, reaching qualitatively identical conclusions on the primary outcome of interest. Thus, Rong et al. externally replicated and, concurrently, internally repudiated the existing manuscripts, elegantly demonstrating the self-correcting and iterative nature of science. Whilethere were differences between Rong and Whitlock in elements of the study, including the way cognitive tests were handled, the adjustment covariates, andthe characterization of persistent pain, the overall analytic approach was thesame between the two studies: a linear mixed effects model with random effectsat the participant level, allowing for a different rate of change over time(i.e. slope) for those with persistent pain. This is an intuitive strategy which does not assume that everyone experiences the same underlying rate of cognitive decline or the same ‘acceleration’ (with apologies for causal language!) with chronic pain. Studying a long duration of cognitive test results—10 years in Whitlock et al, and 12 years in Rong et al—allows for more precise estimates, and may explain similarities between Rong and Whitlock's conclusions. Rong goes further, as well, to look for a dose–response relationship between pain severity and rate of decline (it does exist), to test whether there was a difference in young-old versus older-old individuals (there was not) and to test whether certain anatomic pain sites behave differently (they do not). There is one other crucial difference between the approach of Rong versus that of Veronese: the handling of non-response. In any longitudinal study, some participants drop out—often because of death or because they no longer wish to participate. In an analysis of chronic pain and cognition, it must be assumed that that dropout is strongly associated with either the primary predictor (pain) and/or the primary outcome (cognition). That is, older adults who are constantly in pain, or who are cognitively unable to participate in testing, may be more likely to die, may elect to stop contributing cognition data, or may exit the study. This will, as Rong notes, most likely bias the findings to the null (i.e. create a bias that makes it more likely to conclude there was no association)—the most affected participants, who would strengthen the association between chronic pain and low cognition, drop out and c","journal":"European Journal of Pain","year":2021,"id":205340,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":45327,"name":"Elizabeth L. Whitlock","orcid":"0000-0002-6868-4301","position":0,"is_corresponding":true}],"reference_count":3,"raw_metadata":null,"created_at":"2026-07-18T23:51:33.996102Z","pmid":"34216525","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}