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Current biomarkers for AD diagnosis require expensive neuroimaging or invasive cerebrospinal fluid sampling, thus precluding early detection. Blood-based biomarker discovery in Alzheimer\u2019s can facilitate less-invasive, routine diagnostic tests to aid early intervention. Therefore, we propose \u201cc-Diadem\u201d (constrained dual-input Alzheimer\u2019s disease model), a novel deep learning classifier which incorporates KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway constraints on the input genotyping data to predict disease, i.e., mild cognitive impairment (MCI)\/AD or cognitively normal (CN). SHAP (SHapley Additive exPlanations) was used to explain the model and identify novel, potential blood-based genetic markers of MCI\/AD.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We developed a novel constrained deep learning neural network which utilizes SNPs (single nucleotide polymorphisms) and microarray data from ADNI (Alzheimer\u2019s Disease Neuroimaging Initiative) to predict the disease status of participants, i.e., CN or with disease (MCI\/AD), and identify potential blood-based biomarkers for diagnosis and intervention. The dataset contains samples from 626 participants, of which 212 are CN (average age 74.6\u2009\u00b1\u20095.4\u00a0years) and 414 patients have MCI\/AD (average age 72.7\u2009\u00b1\u20097.6\u00a0years). KEGG pathway information was used to generate constraints applied to the input tensors, thus enhancing the interpretability of the model. SHAP scores were used to identify genes which could potentially serve as biomarkers for diagnosis and targets for drug development.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>Our model\u2019s performance, with accuracy of 69% and AUC of 70% in the test dataset, is superior to previous models. The SHAP scores show that SNPs in PRKCZ, PLCB1 and ITPR2 as well as expression of HLA-DQB1, EIF1AY, HLA-DQA1, and ZFP57 have more impact on model predictions.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>In addition to predicting MCI\/AD, our model has been interrogated for potential genetic biomarkers using SHAP. From our analysis, we have identified blood-based genetic markers related to Ca<jats:sup>2+<\/jats:sup> ion release in affected regions of the brain, as well as depression. The findings from our study provides insights into disease mechanisms, and can facilitate innovation in less-invasive, cost-effective diagnostics. To the best of our knowledge, our model is the first to use pathway constraints in a multimodal neural network to identify potential genetic markers for AD.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12920-023-01675-9","type":"journal-article","created":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T09:02:09Z","timestamp":1697187729000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["c-Diadem: a constrained dual-input deep learning model to identify novel biomarkers in Alzheimer\u2019s disease"],"prefix":"10.1186","volume":"16","author":[{"given":"Sherlyn","family":"Jemimah","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1868-1003","authenticated-orcid":false,"given":"Aamna","family":"AlShehhi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"for the Alzheimer\u2019s Disease Neuroimaging Initiative","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,10,13]]},"reference":[{"key":"1675_CR1","volume-title":"World Alzheimer Report 2021: Journey through the diagnosis of dementia","author":"S Gauthier","year":"2021","unstructured":"Gauthier S, Rosa-Neto P, Morais JA, Webster C. 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