Considerations for Selecting Cognitive Endpoints and Psychological Patient-Reported Outcomes for Clinical Trials in Pediatric Patients With Sickle Cell Disease

Abstract

Pediatric patients with sickle cell disease (SCD) experience a range of medical complications that result in significant morbidity and mortality. Recent advances in prophylactic and curative treatment approaches have highlighted the need for sensitive and clinically-meaningful trial endpoints. The detrimental effects of cognitive and psychological difficulties on social and economic mobility are well described. Although numerous reviews have assessed cognitive outcomes in other rare genetic disorders, SCD has not received the same focus. This review describes the cognitive (i.e., executive function and processing speed) and psychological domains (i.e., depression and anxiety) that are consistently associated with SCD pathology and, therefore, may be of particular interest as clinical trial endpoints. We then discuss corresponding well-validated and reliable cognitive tests and patient-reported outcomes (PROs) that may be appropriate for clinical trials given their robust psychometric properties, ease of administration, and previous use in the SCD population. Further, we provide a discussion of potential pitfalls and considerations to guide endpoint selection. In line with the move toward patient-centered medicine, we identify specific tests (e.g., NIH Toolbox Cognition Module, Wechsler Cancellation Test) and psychological PROs (e.g., PROMIS depression and anxiety scales) that are sensitive to SCD morbidity and have the potential to capture changes that are clinically meaningful in the context of patients' day to day lives. In particularly vulnerable cognitive domains, such as executive function, we highlight the advantages of composite over single-test scores within the context of trials. We also identify general (i.e., practice effects, disease heterogeneity) and SCD-specific considerations (i.e., genotype, treatment course, and disease course, including degree of neurologic, pain, and sleep morbidity) for trial measures. Executive function composites hold particular promise as trial endpoints that are clinically meaningful, amenable to change, relatively easy to collect, and can be incorporated into the routine care of patients with SCD in various settings and countries.

Decline in Processing Speed Tells Only Half the Story: Developmental Delay in Children Living with Sickle Cell Disease

“…Our findings highlight the need to investigate whether the identified processing speed decline, particularly in the Coding subtest, is present in a current cohort of children receiving more advanced treatment methods. Future research should investigate neuroprotective treatment effects on processing speed development in young people with SCD longitudinally [ 9 , 16 , 58 , 60 , 61 ], with consideration of the role of non-verbal and visuo-spatial abilities in processing speed outcome measurement [ 55 , 56 , 57 ]. This will allow for clinically relevant replication of our longitudinal research design.…”

“…Recently, Hood et al (2022) highlighted the possible utility of domain-specific cognitive endpoints for assessing treatment effects for children and young people with SCD [ 16 ]. Alongside EF, another meaningful cognitive endpoint mentioned by Hood et al (2022) was processing speed.…”

“…However, for children and young people with a delay (sometimes due to a medical problem) or interruption in processing speed development, PSI might fall below the population average (mean = 100, SD = 15) or their premorbid baseline. Over time, PSI might either improve (recovery of skills and standardised scores that are higher than their baseline), stay the same (consistent performance or small gains in raw scores over time that are not substantial enough to impact standard scores) or decline (loss of skills which manifests as reductions in both raw and standardised scores) [ 16 ].…”

“…However, the Wechsler test in use changed (scores were re-coded), and PSI was not calculated because Symbol Search subtest scores were not included [6]. Wang et al (2001) identified no significant changes for full-scale IQ, which did not appear to be sensitive to declines in individual domains [6,16]. No other published longitudinal research has examined changes in processing speed over time in young people living with SCD.…”

Mind the gap: trajectory of cognitive development in young individuals with sickle cell disease: a cross-sectional study

“…Evaluation of raw scores is encouraged in longitudinal data as it provides a robust measure of individual change in the outcome measure, hence allowing evaluation of progress or decline for a particular individual across different time points. Exploring trajectories for raw as well as scaled scores might yield important insights when considering using cognitive endpoints in randomised clinical trials ( 33 ). Following this paradigm, we explored associations with both raw as well as scaled scores.…”