Time- and Race-Specific Haematological Reference Intervals for Healthy Volunteer Trials: A Retrospective Analysis of Pooled Data From Multiple Phase I Trials

Abstract

Most UK hospitals, laboratories, and research institutions use uniform reference intervals (RI) that do not take into account known diurnal and racial variation in total white blood cells (WBC) count and its constituent parameters. These risks of excluding potentially suitable ethnic minority volunteers from participating in phase I clinical trials could call into question the validity of a trial's findings or limit its scientific applications and ability to accurately observe drug effects upon WBC parameters. This study pools data from multiple phase I trials, assesses the effects of race and time of day on WBC count, and compares it to the existing literature to establish race and time-specific RIs. A total 13,332 venous blood samples obtained from 7,157 healthy male and female volunteers at the time of screening or admission (predosing) who took part in 35 phase I trials over a period of seven years were pooled and the data were analyzed using generalised estimating equation models. Adjusted RI of total WBC count and its individual parameters were then calculated according to time of day (morning vs. evening) for both black and nonblack populations. This study indicates that black individuals on average had lower total WBC, neutrophil, monocyte, eosinophil, and basophil counts than individuals from nonblack racial groups. Black volunteers had higher mean lymphocyte counts relative to their nonblack counterparts. These differences were deemed statistically significant. Statistically significant increases in total WBC, neutrophil, lymphocyte, and monocyte counts were also observed over the course of daily sampling. Eosinophil counts decreased during this time period, but this finding was only statistically significant in the nonblack population. Despite an observed mild diurnal increase in basophil count in both populations, this was not considered statistically significant. This high-powered study adds significant weight to the known evidence for diurnal and racial variation in WBC parameters. Importantly, it proposes specific RIs that more precisely reflect race and time of day. These could ensure increased participation of black volunteers in clinical trials for improved population representation. Furthermore, the proposed RIs allow for more

Risk of common infections in people with inflammatory bowel disease in primary care: a population-based cohort study

“…This continuous modelling approach maximises power by avoiding arbitrary dichotomisation and enables our results to be generalisable, given the variability in normal reference range values for haematological parameters in different settings. 60 As with all observational studies of this type, a limitation of our analysis is that we were unable to determine any causal associations, and although results were consistent with extensive sensitivity analysis we cannot rule out unobserved confounding as an explanation of our findings, especially given the relatively modest effect sizes observed. Data recording and capture bias might be another study limitation, as symptomatic individuals with IBD may have specific patterns of care meaning they present more frequently to clinicians, who may also investigate infections in people with IBD more proactively.…”

From race‐based to race‐conscious medicine: proceed with care

“…Pathology test interpretation is often guided by reference intervals and some are influenced by race. 2 There is a potential for result misinterpretation in racial minority groups who are assumed to have the same reference as the majority. Coates and colleagues 2 highlighted the risks of using uniform reference intervals for total white blood cells (WBC) count and associated parameters without considering racial differences.…”

“…In contrast, Blacks had higher average lymphocyte counts. 2 The risks of excluding racial minority individuals from Phase 1 clinical trials could raise questions on the validity of a trial's findings. 2 The use of race-specific reference intervals might ensure increased Black participation in trials for better population representation and ultimately the application of trial findings across different racial groups in clinical practice.…”

“…2 The risks of excluding racial minority individuals from Phase 1 clinical trials could raise questions on the validity of a trial's findings. 2 The use of race-specific reference intervals might ensure increased Black participation in trials for better population representation and ultimately the application of trial findings across different racial groups in clinical practice. 2 Surks and Boucai 3 cautioned that the traditional 'one size fits all' method for determining thyroid-stimulating hormone (TSH) reference intervals does not reflect TSH distribution of a specific racial group.…”

Lessons from my Elders on Recruitment and Retention into Health Research

“…The stakes are high; the underrepresentation of minority groups in research leads to clinical guidelines and US Preventive Services Task Force (USPSTF) recommendations, laboratory reference ranges, "best" practices, insurance authorization guidelines, and health care policies that can be suboptimal or even harmful to those groups whose data are missing from the knowledge base on which they were developed. [16][17][18][19] We must do better. Author's note: Following the final submission of this brief report, I learned of the passing of another elder and a giant in the field of minority aging, Dr. James Jackson, principal investigator of the Michigan Center for Urban African American Aging Research (MCU-AAAR), a founding RCMAR Center, who passed away on September 1, 2020 at the age of 77.…”