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Cerebrospinal fluid reference proteins increase accuracy and interpretability of biomarkers for brain diseases

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    • Contributors:
      Lund University, Faculty of Medicine, Department of Clinical Sciences, Malmö, Clinical Memory Research, Lunds universitet, Medicinska fakulteten, Institutionen för kliniska vetenskaper, Malmö, Klinisk minnesforskning, Originator; Lund University, Profile areas and other strong research environments, Lund University Profile areas, LU Profile Area: Proactive Ageing, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Lunds universitets profilområden, LU profilområde: Proaktivt åldrande, Originator; Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), MultiPark: Multidisciplinary research focused on Parkinson´s disease, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), MultiPark: Multidisciplinary research focused on Parkinson´s disease, Originator; Lund University, Faculty of Medicine, Department of Laboratory Medicine, SciLifeLab Site@Lund, SciLifeLab Site@Lund, Lunds universitet, Medicinska fakulteten, Institutionen för laboratoriemedicin, SciLifeLab Site@Lund, SciLifeLab Site@Lund, Originator; Lund University, Faculty of Science, Centre for Mathematical Sciences, Mathematics (Faculty of Engineering), Computer Vision and Machine Learning, Lunds universitet, Naturvetenskapliga fakulteten, Matematikcentrum, Matematik LTH, Datorseende och maskininlärning, Originator; Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), eSSENCE: The e-Science Collaboration, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), eSSENCE: The e-Science Collaboration, Originator; Lund University, Profile areas and other strong research environments, Strategic research areas (SRA), ELLIIT: the Linköping-Lund initiative on IT and mobile communication, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Strategiska forskningsområden (SFO), ELLIIT: the Linköping-Lund initiative on IT and mobile communication, Originator; Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: AI and Digitalization, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: AI och digitalisering, Originator; Lund University, Profile areas and other strong research environments, Lund University Profile areas, LU Profile Area: Natural and Artificial Cognition, Lunds universitet, Profilområden och andra starka forskningsmiljöer, Lunds universitets profilområden, LU profilområde: Naturlig och artificiell kognition, Originator; Lund University, Faculty of Science, Centre for Mathematical Sciences, Research groups at the Centre for Mathematical Sciences, Mathematical Imaging Group, Lunds universitet, Naturvetenskapliga fakulteten, Matematikcentrum, Forskargrupper vid Matematikcentrum, Mathematical Imaging Group, Originator; Lund University, Faculty of Engineering, LTH, LTH Profile areas, LTH Profile Area: Engineering Health, Lunds universitet, Lunds Tekniska Högskola, LTH profilområden, LTH profilområde: Teknik för hälsa, Originator
    • Abstract:
      Cerebrospinal fluid (CSF) biomarkers reflect brain pathophysiology and are used extensively in translational research as well as in clinical practice for diagnosis of neurological diseases, e.g., Alzheimer’s disease (AD). However, CSF biomarker concentrations may be influenced by non-disease related inter-individual variability. Here we use a data-driven approach to demonstrate the existence of inter-individual variability in mean standardized CSF protein levels. We show that these non-disease related differences cause many commonly reported CSF biomarkers to be highly correlated, thereby producing misleading results if not accounted for. To adjust for this inter-individual variability, we identified and evaluated high-performing reference proteins which improved the diagnostic accuracy of key CSF AD biomarkers. Our reference protein method attenuates the risk for false positive findings, and improves the sensitivity and specificity of CSF biomarkers, with broad implications for both research and clinical practice.