Multinational Assessment of Absolute Neutrophil Counts and White Blood Cell Counts Among Healthy Duffy Null Adults

ABSTRACT Background Laboratory reference intervals must reflect population diversity for accurate medical decisions. The Duffy null variant lowers absolute neutrophil counts (ANC), but existing dedicated reference intervals are based on a single African American cohort. The impact across other ethnic groups and regions remains unclear, and no white blood cell count (WBC) intervals exist for Duffy null individuals. This study aimed to establish and compare Duffy null ANC and WBC reference intervals across four continents. Methods A cross-sectional study was conducted assessing healthy Duffy null individuals from dedicated cohorts (blood donors in Namibia and Saudi Arabia, and primary care patients in the USA) and biobanks (participants from the UK and USA). Reference intervals were determined using Clinical & Laboratory Standards Institute guidelines. Results Among 7,872 participants (392 from dedicated cohorts, 7,480 from biobanks), novel ANC and WBC reference intervals were established: Namibia (820–6,370/μL; 2.51–9.85× 10 9 /L), Saudi Arabia (1,090–5,100/μL; 3.71–9.95× 10 9 /L), and the USA (1,210–5,390/μL; 3.00-9.66× 10 9 /L), with no significant differences between cohorts. Institutional reference intervals misclassified 27.9% (Namibia), 50.7% (Saudi Arabia), and 21.7% (USA) as neutropenic. Biobank analyses confirmed a significantly lower ANC in Duffy null individuals compared to Duffy non-null (p<0.0001) with no significant difference in ANC between Black and non-Black Duffy null participants. Conclusions Duffy null individuals consistently exhibit lower ANC and WBC across ethnic groups and regions. Current reference intervals overlook this variation, risking misdiagnosis and health inequities. Implementing Duffy-specific reference intervals is essential for equitable and accurate clinical decisions worldwide. Key points – Novel ANC and WBC reference intervals for Duffy null adults were established and are consistent across four continents – Current ANC reference intervals misclassify up to half of Duffy null individuals as neutropenic, contributing to global heath inequities.