Discover how stable blood count setpoints unlock the future of personalized diagnostics, reshaping risk assessment and disease prediction for decades.
Study: Haematological setpoints are a stable and patient-specific deep phenotype. Image Credit: monofaction / Shutterstock
In a recent study published in the journal Nature, researchers examined the stability and clinical utility of complete blood count (CBC) setpoints in advancing personalized risk assessment and diagnostics in precision medicine.
Background
The CBC is a widely used clinical test that evaluates the hematological and immunological state of patients by measuring parameters such as red blood cells (RBCs), white blood cells (WBCs), and platelets (PLTs). It serves as a non-specific diagnostic tool for diverse medical conditions. However, the current interpretation relies on broad, population-wide reference intervals, often insensitive to subtle variations in individual physiology. Studies suggest intra-patient CBC variations are narrower over short periods, but their stability over longer durations, particularly decades, has remained unclear.
This study provides a deeper understanding of long-term hematological regulation, a key step toward precision diagnostics. Further research is needed to understand the mechanisms of hematological regulation and improve personalized diagnostic and prognostic capabilities.
About the Study
The present study analyzed CBC data from adult outpatients across three cohorts (A, B, and C) drawn from Mass General Brigham (MGB) institutions during overlapping timeframes (2002–2021, 2002–2006, and 2017–2021). Patients were eligible for inclusion if they had at least five isolated CBC measurements taken more than 90 days apart and no inpatient stays exceeding 48 hours during the study period.
To strengthen the validity of the findings, researchers excluded overlapping patients from multiple cohorts and ensured stringent quality control measures. The final cohorts comprised 12,407 patients in Cohort A, 14,371 in Cohort B, and 20,062 in Cohort C.
Data on patient demographics, CBC indices, medical procedures, prescribed medications, and clinical diagnoses were collected from the MGB Research Patient Data Registry and the Electronic Data Warehouse. Mortality data were obtained from the United States (U.S.) National Death Index and Social Security Death Master File to account for deaths occurring outside the hospital system.
The CBC indices analyzed included RBC count, WBC count, PLT count, hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean platelet volume (MPV), and red cell distribution width (RDW). Notably, advanced computational methods, such as Gaussian mixture modeling, were employed to calculate patient-specific setpoints, distinguishing transient deviations from physiological baselines.
Study Results
The analysis of CBC data from three cohorts provided clear evidence of the stability and individuality of hematological setpoints. CBC indices, including RBCs, WBCs, PLTs, HGB, HCT, MCV, MCH, MCHC, MPV, and RDW, exhibited narrow intra-patient variability over 20 years.
The long-term intra-patient coefficients of variation (CVs) were significantly lower than inter-patient CVs, confirming the existence of stable, patient-specific setpoints. These setpoints persisted despite demographic variations, including age, sex, race, and ethnicity, suggesting their regulation is a fundamental physiological characteristic.
The study demonstrated that a typical patient’s CBC indices were distinguishable from those of 98% of other healthy individuals when considering all setpoints together. Importantly, these findings were replicated in independent cohorts, enhancing their reliability.
This patient-specificity of hematological setpoints underscores their potential in precision medicine. Furthermore, the stability of these setpoints across decades enables the identification of subtle deviations that may indicate early pathological changes.
Associations between setpoints and clinical outcomes were also evident. Differences in setpoints were linked to variations in the risk of several diseases, including cardiovascular conditions, diabetes, kidney disease, and osteoporosis. Importantly, setpoint variability was also correlated with increased all-cause mortality risk, highlighting their prognostic relevance.
Retrospective analyses revealed that using setpoints improved sensitivity and specificity in diagnosing conditions like diabetes, thyroid dysfunction, and iron deficiency compared to traditional reference intervals.
The study also identified 397 genetic loci associated with CBC setpoints, with several loci being novel discoveries. These findings highlight the interplay between inherited genetic factors and acquired influences in shaping hematological regulation.
Conclusions
The study concludes that hematological setpoints derived from CBC indices are stable, patient-specific, and persist over decades in healthy individuals. These setpoints reflect a deep physiological phenotype, enabling improved sensitivity and specificity in diagnosing and predicting clinical outcomes. Their associations with disease risk and mortality highlight their potential as valuable tools in precision medicine. By incorporating these setpoints into routine clinical practice, healthcare providers could personalize diagnostic thresholds and improve risk stratification for major diseases.
Furthermore, the research underscores the need for additional studies to explore the mechanisms underlying setpoint regulation and their application in diverse clinical settings. The findings suggest that incorporating patient-specific setpoints into routine clinical practice can enhance risk stratification, personalize diagnostics, and improve the interpretation of CBC results, advancing the goal of tailored healthcare for healthy adults.