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A retrospective analysis published in the journal Nature suggests that among healthy adults, the CBC (complete blood count) remains stable and fluctuates only very narrowly around individual-specific setpoints. Rather than “one size fits all” reference ranges, these setpoints are associated with mortality and disease risk, even within normal reference ranges. This new understanding may enhance the usefulness of these commonly used diagnostic tests, furthering the goals of the precision medicine-based approach to personalized care.
The authors highlight the clinical value and versatility of a CBC, yet note that wide variation exists among individuals within normal ranges. For example, a white blood count (WBC) in the upper normal range may be twice as high as one in the lower normal range. Additionally, very little research has been published on intra-individual variation in CBC indices over longer periods (e.g., months to years), especially among healthy adults, so this study also sought to monitor this variation over time.
The data for this study came from three cohorts: all adult outpatients from Mass General Brigham between three overlapping periods from 2002 to 2021, with a combined total of nearly 47,000 individuals who had had at least 5 CBCs (some cohorts had more, e.g., over 80% of participants in one of the cohorts had at least 10 isolated CBCs). They used a Gaussian mixture model to estimate setpoints for each component of the CBC, using a methodology that captures the most common or most stable values for each individual, allowing for temporary changes (such as acute illness).
They found that the individual setpoints are so specific to each person that looking at 9 indices on a CBC can distinguish a typical healthy adult from 98% of other healthy adults. Intra-individual relative variation (defined as the standard deviation divided by the mean) was smaller (2-15%) over a 20-year period than inter-individual variation (5-30%), suggesting that over a long period of time, setpoints remain the same, and that “tight regulation is a feature of normal physiology.” Only 4 CBCs were needed to accurately determine individual setpoints, so it also seems possible that physicians could apply these concepts in clinical practice for most patients.
This study also included a GWAS (genome-wide association study) component and determined that heredity is an important contributor to individual setpoints (for 9 of 10 CBC indices). For example, setpoints among first-degree relatives were highly correlated, whereas those among partners were not, indicating that similar setpoints are unlikely to be because of a shared environment.
Setpoints were also associated with mortality. Using one of the cohorts with 15 years of follow-up after setpoint determination, and importantly, only including participants whose setpoints fell within the normal range, all-cause mortality was found to be significantly associated with setpoints. This was unexpected, given that these were healthy participants with setpoints within normal limits. Yet most indices on the CBC showed monotonic relationships with mortality, except hematocrit and hemoglobin (which had the lowest mortality in the mid-range and increased at both extremes). This was replicated in two other distinct cohorts, and the associations remained after adjusting for age, sex, and over different time periods. Setpoint variability was also associated with an increased mortality risk. Overall, they estimated that at least 20% of the healthy population has between a 3 to 5% increase in all-cause mortality predicted by their setpoints.
Setpoints were also linked to disease risk. For example, an MCHC (mean corpuscular hemoglobin concentration) setpoint in the lowest quartile was linked to a greater risk of major adverse cardiovascular events, including heart attack, stroke, and heart failure. A higher WBC count was associated with an increased risk of type 2 diabetes; a higher MCV (mean corpuscular volume) was linked to an increased risk of osteoporosis; a higher RDW (red cell distribution width) was associated with an increased risk of atrial fibrillation, etc. The authors estimated that approximately 25% of the healthy population had in excess of 2 or even 5% risk for major diseases.
Setpoints were also used as markers for a more accurate diagnosis and prognosis. For instance, participants with a WBC setpoint in the upper range of normal who, at a later date, had a WBC in the lower range of normal had a one-year 6.9% elevated mortality rate. The reverse was also true, associated with a 4.5% elevated mortality rate, suggesting that deviation from the WBC setpoint (rather than an increase or decrease) carries additional mortality risk. Quite surprising was that the hazard ratios for mortality were higher when a current CBC was outside of a setpoint-derived reference interval than the ratios for population-wide reference intervals. In other words, deviating from ranges defined by personalized setpoints was more consequential than deviating from normal reference ranges. Setpoints alone and in combination with other tests (e.g., eGFR, HbA1c, ferritin, etc.) also improved disease diagnosis and prognosis. The risks associated with setpoints suggest that CBCs (and possibly other commonly utilized tests) can provide much more personalized risk assessment and may possibly opportunities for early clinical interventions.
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