The detection of norm deviations is fundamental to clinical decision making and impacts our ability to diagnose and treat diseases effectively. Current normative modeling approaches rely on generic comparisons and quantify deviations in relation to the population average. However, generic models interpolate subtle nuances and risk the loss of critical information, thereby compromising effective personalization of health care strategies. To acknowledge the substantial heterogeneity among patients and support the paradigm shift of precision medicine, we introduce Nearest Neighbor Normativity (N3), which is a strategy to refine normativity evaluations in diverse and heterogeneous clinical study populations. We address current methodological shortcomings by accommodating several equally normative population prototypes, comparing individuals from multiple perspectives and designing specifically tailored control groups. Applied to brain structure in 36,896 individuals, the N3 framework provides empirical evidence for its utility and significantly outperforms traditional methods in the detection of pathological alterations. Our results underscore N3's potential for individual assessments in medical practice, where normativity is not merely a benchmark, but a dynamic tool that adapts to the intricacies of personalized patient care.

The authors have declared no competing interest.

This work was funded by the German Research Foundation (DFG grants HA7070/2-2, HA7070/3, and HA7070/4 to T.H.), the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Muenster (grants 22 Dan3/012/17 to U.D. and MzH 3/020/20 to T.H.) and the IMF research instrument of the medical faculty of Muenster (grant LE112409 to R.Leenings). X. Jiang was supported by the Deutsche Forschungsgemeinschaft (DFG) under Grant CRC 1450-431460824. This project was conducted with data from the German National Cohort (NAKO) (www.nako.de). The NAKO is funded by the Federal Ministry of Education and Research (BMBF) [project funding reference numbers: 01ER1301A/B/C, 01ER1511D, 01ER1801A/B/C/D and 01ER2301A/B/C], federal states of Germany and the Helmholtz Association, the participating universities and the institutes of the Leibniz Association. We thank all participants who took part in the NAKO study and the staff of this research initiative. Data collection and sharing for this project was funded by the Alzheimers Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research Development; LLC.; Johnson Johnson Pharmaceutical Research Development LLC.; Lumosity; Lundbeck; Merck Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. Data was in part provided by OASIS-3: Principal Investigators: T. Benzinger, D. Marcus, J. Morris; NIH P50AG00561, P30NS09857781, P01AG026276, P01AG003991, R01AG043434, UL1TR000448, R01EB009352. AV-45 doses were provided by Avid Radiopharmaceuticals, a wholly owned subsidiary of Eli Lilly. Data collection and sharing for this project was funded by the Frontotemporal Lobar Degeneration Neuroimaging Initiative (National Institutes of Health Grant R01 AG032306). The study is coordinated through the University of California, San Francisco, Memory and Aging Center. FTLDNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Investigators at NIFD/FTLDNI contributed to the design and implementation of FTLDNI and/or provided data, but did not participate in analysis or writing of this report (unless otherwise listed). The FTLDNI investigators included the following individuals: Howard Rosen; University of California, San Francisco (PI) Bradford C. Dickerson; Harvard Medical School and Massachusetts General Hospital Kimoko Domoto-Reilly; University of Washington School of Medicine David Knopman; Mayo Clinic, Rochester, Bradley F. Boeve; Mayo Clinic Rochester Adam L. Boxer; University of California, San Francisco, John Kornak; University of California, San Francisco Bruce L. Miller; University of California, San Francisco William W. Seeley; University of California, San Francisco Maria-Luisa Gorno-Tempini; University of California, San Francisco Scott McGinnis; University of California, San Francisco Maria Luisa Mandelli; University of California, San Francisco

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study used data from the MACS cohort, which was approved by the ethics committees of the medical faculties of the University of Marburg (07/2014) and the University of Muenster (2014-422-b-S). All procedures were performed in accordance with ethical guidelines and regulations. Participants provided written informed consent before examination and received financial compensation for participation. This study furthermore uses publicly available study data. Please see the study-specific documentations. (NAKO: nako.de/forschung, ADNI, AIBL, NIFD: ida.loni.usc.edu, OASIS3: sites.wustl.edu/oasisbrains)

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Data were obtained from the German National Cohort (NAKO), the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Open Access Series of Imaging Studies 3 (OASIS3), the Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD, and the Australian Imaging, Biomarker Lifestyle Study of Aging (AIBL). Data of the MACS study are not publicly available. All other data are available upon request via the access management systems of the respective studies. (NAKO: nako.de/forschung, ADNI, AIBL, NIFD: ida.loni.usc.edu, OASIS3: sites.wustl.edu/oasisbrains)

https://ida.loni.usc.edu

https://nako.de/forschung

https://sites.wustl.edu/oasisbrains