Lauren E. Merz

The Duffy null variant is found in 10% of the United States population, and results in distinct absolute neutrophil counts (ANC) and white blood cell count (WBC) RIs. Investigators from twenty-three institutions completed a collaborative assessment of ANC and WBC in healthy Duffy-null pediatric and adult participants. This report summarizes a roadmap for developing and implementing Duffy-null RIs and infrastructure. Through consensus, we identified the following key themes: 1) Identifying Stakeholders and Funding, 2) Collecting Samples, 3) Testing for Duffy Status, 4) Implementing Duffy-Specific Policies and Tools, and 5) Educating Providers and Duffy-null individuals. Across themes, we outline challenges and opportunities relevant to the development and implementation of Duffy-null infrastructure. We provide examples from community and academic practice settings as well as sites with geographic, size, funding, and population diversity. This roadmap will support healthcare systems, hospitals, and laboratories in developing and implementing Duffy-specific infrastructure.

Most reference intervals (RI) for absolute neutrophil count (ANC) and white blood cell count (WBC) in the United States (US) are not representative of people with the Duffy null phenotype (10% of the US population), which leads to misdiagnoses and inequity in care. We aimed to verify the adult Duffy null ANC RI and develop WBC and ANC RIs for pediatrics. 1,412 healthy Duffy null participants from 23 sites were included. All sites agreed on eligibility criteria. Otherwise, this was a pragmatic design with site-specific variation in collection approach. ANC and WBC were stratified into 5 age categories: 6 months-2 years, 3-6 years, 7-12 years, 13-17 years, and 18+ years. RI were calculated by Clinical and Laboratory Standards Institute guidelines. Duffy null-specific ANC RI were 0.53-4.50×109/L (6 months-2 years, n=184), 0.78-4.67×109/L (3-6 years, n=160), 0.87-5.34×109/L (7-12 years, n=190), 0.90-4.89×109/L (13-17 years, n=216), and 1.03-7.30×109/L (18+ years, n=662). 25% of adults had ANC <2.00×109/L and 24-53% of children had ANC <1.50×109/L. Sensitivity analyses did not show any significant differences in ANC RI when accounting for blood draw type, setting, collection site, hematology analyzer, or hemoglobin and platelet counts. This study provides the first report of Duffy null-specific pediatric ANC and WBC RI, as well as a large-scale verification of adult Duffy null-specific ANC and WBC RI. Adoption of Duffy null-specific RIs is necessary for the accurate interpretation of laboratory values that will support appropriate and equitable medical decision-making.

The Duffy-null phenotype is reported in ∼1 in 10 individuals in the United States and results in absolute neutrophil counts (ANC) that are 40% to 50% lower than most institutional reference intervals. Misinterpretation of normal ANC values for this population leads to avoidable diagnostic testing and referrals. We aimed to evaluate the economic value of serologic Duffy testing vs no testing obtained alongside other recommended blood work at 9 to 12 months of age, using a Markov cohort design incorporating all levels of currently practiced diagnostic neutropenia workups across scenario analyses. The analysis was conducted from a US societal perspective over a lifetime horizon across all accepted willingness-to-pay thresholds. The primary outcome was the incremental net monetary benefit (iNMB) in US dollars ($) per quality-adjusted life-year. Duffy testing was favored in the base-case and all scenario analyses, with iNMB ranging from $2.18 to $92.77 per child tested for Duffy status. The cost of Duffy serological testing, the cost of the neutropenia workup, and the prevalence of low ANC were the 3 parameters with the greatest variation that affected the iNMB. Probabilistic analyses showed that universal testing was favored in 100%, 100%, 100%, 95%, and 100% of 10 000 iterations in the base-case, full workup, annual follow-up, minimal workup, and targeted testing scenarios, respectively. The Duffy-null prevalence threshold required for universal testing to be cost-effective was 7.6%, 1.6%, 1.3%, and 9.0%, respectively, and 4.9% for targeted testing. At these thresholds, universal serologic Duffy testing would align with cost-effective implementation in at least 20 states in the United States today.

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 4 continents. A cross-sectional study was conducted assessing healthy Duffy-null individuals from dedicated cohorts (blood donors in Namibia, Saudi Arabia, and the United Kingdom; primary care patients in the United States) and biobanks (participants from the United Kingdom and the United States). Among 8018 participants (880 from dedicated cohorts and 7138 from biobanks), novel ANC and WBC reference intervals were established (Namibia [ANC, 820/μL to 6370/μL; WBC, 2.51 × 109/L to 9.85 × 109/L]; Saudi Arabia [ANC, 1140/μL to 5290/μL; WBC, 3.72 × 109/L to 10.71 × 109/L]; United Kingdom (ANC, 1185/μL to 5462/μL; WBC, 3.1 × 109/L to 8.8 × 109/L]; the United States [ANC, 1210/μL to 5390/μL; WBC, 3.00 × 109/L to 9.66 × 109/L]), with no significant differences between cohorts. Institutional reference intervals misclassified 27.9% (Namibia), 50.9% (Saudi Arabia), 26.0% (United Kingdom), and 21.7% (the United States) as neutropenic. Biobank analyses confirmed no significant difference in ANC between Black and non-Black Duffy-null participants. 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.