Haematological setpoints are a stable and patient-specific deep phenotype

Brody H Foy; Rachel Petherbridge; Maxwell T Roth; Cindy Zhang; Daniel C De Souza; Christopher Mow; Hasmukh R Patel; Chhaya H Patel; Samantha N Ho; Evie Lam; Camille E Powe; Robert P Hasserjian; Konrad J Karczewski; Veronica Tozzo; John M Higgins

doi:10.1038/s41586-024-08264-5

Haematological setpoints are a stable and patient-specific deep phenotype

Nature. 2024 Dec 11. doi: 10.1038/s41586-024-08264-5. Online ahead of print.

Authors

Brody H Foy^{1

2

3

4}, Rachel Petherbridge^{5

6

7}, Maxwell T Roth^{5

6}, Cindy Zhang⁸, Daniel C De Souza^{5

6

7}, Christopher Mow^{5

9}, Hasmukh R Patel^{5

6}, Chhaya H Patel^{5

6}, Samantha N Ho^{5

6}, Evie Lam^{5

6}, Camille E Powe^{10

11

12

13}, Robert P Hasserjian⁶, Konrad J Karczewski^{13

14

15}, Veronica Tozzo^{5

6

7

16}, John M Higgins^{17

18

19}

Affiliations

¹ Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. brodyfoy@uw.edu.
² Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. brodyfoy@uw.edu.
³ Department of Systems Biology, Harvard Medical School, Boston, MA, USA. brodyfoy@uw.edu.
⁴ Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA. brodyfoy@uw.edu.
⁵ Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
⁸ Department of Laboratory Medicine & Pathology, University of Washington, Seattle, WA, USA.
⁹ Mass General Brigham Enterprise Research IS, Boston, MA, USA.
¹⁰ Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
¹¹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
¹² Department of Obstetrics and Gynecology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
¹³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁴ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁵ Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
¹⁷ Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA. john_higgins@hms.harvard.edu.
¹⁸ Department of Pathology, Massachusetts General Hospital, Boston, MA, USA. john_higgins@hms.harvard.edu.
¹⁹ Department of Systems Biology, Harvard Medical School, Boston, MA, USA. john_higgins@hms.harvard.edu.

PMID: 39663453
DOI: 10.1038/s41586-024-08264-5

Abstract

The complete blood count (CBC) is an important screening tool for healthy adults and a common test at periodic exams. However, results are usually interpreted relative to one-size-fits-all reference intervals^1,2, undermining the precision medicine goal to tailor care for patients on the basis of their unique characteristics^3,4. Here we study thousands of diverse patients at an academic medical centre and show that routine CBC indices fluctuate around stable values or setpoints⁵, and setpoints are patient-specific, with the typical healthy adult's nine CBC setpoints distinguishable as a group from those of 98% of other healthy adults, and setpoint differences persist for at least 20 years. Haematological setpoints reflect a deep physiologic phenotype enabling investigation of acquired and genetic determinants of haematological regulation and its variation among healthy adults. Setpoints in apparently healthy adults were associated with significant variation in clinical risk: absolute risk of some common diseases and morbidities varied by more than 2% (heart attack and stroke, diabetes, kidney disease, osteoporosis), and absolute risk of all-cause 10 year mortality varied by more than 5%. Setpoints also define patient-specific reference intervals and personalize the interpretation of subsequent test results. In retrospective analysis, setpoints improved sensitivity and specificity for evaluation of some common conditions including diabetes, kidney disease, thyroid dysfunction, iron deficiency and myeloproliferative neoplasms. This study shows CBC setpoints are sufficiently stable and patient-specific to help realize the promise of precision medicine for healthy adults.