Glaucoma causes irreversible blindness. In 2020, about 80 million people worldwide had glaucoma. Existing machine learning (ML) models are limited to glaucoma prediction, where clinicians, patients, and medical experts are unaware of how data analysis and decision-making are handled. Explainable artificial intelligence (XAI) and interpretable ML (IML) create opportunities to increase user confidence in the decision-making process. This article proposes XAI and IML models for analyzing glaucoma predictions/results. XAI primarily uses adaptive neuro-fuzzy inference system (ANFIS) and pixel density analysis (PDA) to provide trustworthy explanations for glaucoma predictions from infected and healthy images. IML uses sub-modular pick local interpretable model-agonistic explanation (SP-LIME) to explain results coherently. SP-LIME interprets spike neural network (SNN) results. Using two different publicly available datasets, namely fundus images, i.e., coherence tomography images of the eyes and clinical medical records of glaucoma patients, our experimental results show that XAI and IML models provide convincing and coherent decisions for clinicians/medical experts and patients.

Explainable AI for Glaucoma Prediction Analysis to Understand Risk Factors in Treatment Planning

Summary Genome-wide association studies (GWASs) require accurate cohort phenotyping, but expert labeling can be costly, time intensive, and variable. Here, we develop a machine learning (ML) model to predict glaucomatous optic nerve head features from color fundus photographs. We used the model to predict vertical cup-to-disc ratio (VCDR), a diagnostic parameter and cardinal endophenotype for glaucoma, in 65,680 Europeans in the UK Biobank (UKB). A GWAS of ML-based VCDR identified 299 independent genome-wide significant (GWS; p ≤ 5 × 10−8) hits in 156 loci. The ML-based GWAS replicated 62 of 65 GWS loci from a recent VCDR GWAS in the UKB for which two ophthalmologists manually labeled images for 67,040 Europeans. The ML-based GWAS also identified 93 novel loci, significantly expanding our understanding of the genetic etiologies of glaucoma and VCDR. Pathway analyses support the biological significance of the novel hits to VCDR: select loci near genes involved in neuronal and synaptic biology or harboring variants are known to cause severe Mendelian ophthalmic disease. Finally, the ML-based GWAS results significantly improve polygenic prediction of VCDR and primary open-angle glaucoma in the independent EPIC-Norfolk cohort.

Large-scale machine-learning-based phenotyping significantly improves genomic discovery for optic nerve head morphology.

Abstract Glaucoma, a leading cause of irreversible blindness, is a highly heritable human disease. Previous genome-wide association studies have identified over 100 loci for the most common form, primary open-angle glaucoma. Two key glaucoma-associated traits also show high heritability: intraocular pressure and optic nerve head excavation damage quantified as the vertical cup-to-disc ratio. Here, since much of glaucoma heritability remains unexplained, we conducted a large-scale multitrait genome-wide association study in participants of European ancestry combining primary open-angle glaucoma and its two associated traits (total sample size over 600,000) to substantially improve genetic discovery power (263 loci). We further increased our power by then employing a multiancestry approach, which increased the number of independent risk loci to 312, with the vast majority replicating in a large independent cohort from 23andMe, Inc. (total sample size over 2.8 million; 296 loci replicated at P &lt; 0.05, 240 after Bonferroni correction). Leveraging multiomics datasets, we identified many potential druggable genes, including neuro-protection targets likely to act via the optic nerve, a key advance for glaucoma because all existing drugs only target intraocular pressure. We further used Mendelian randomization and genetic correlation-based approaches to identify novel links to other complex traits, including immune-related diseases such as multiple sclerosis and systemic lupus erythematosus. 

/pdf/large-scale-multitrait-genome-wide-association-analyses-3t2jncxe.pdf

Large-scale multitrait genome-wide association analyses identify hundreds of glaucoma risk loci

Purpose The Canadian Longitudinal Study on Aging (CLSA) Comprehensive cohort was established to provide unique opportunities to study the genetic and environmental contributions to human disease as well as ageing process. The aim of this report was to describe the genomic data included in CLSA. Participants A total of 26 622 individuals from the CLSA Comprehensive cohort of men and women aged 45–85 recruited between 2010 and 2015 underwent genome-wide genotyping of DNA samples collected from blood. Comprehensive quality control metrics were measured for genetic markers and samples, respectively. The genotypes were imputed to the TOPMed reference panel. Sex chromosome abnormalities were identified by copy number profiling. Classical human leukocyte antigen gene haplotypes were imputed at two-field (four-digit). Findings to date Of the 26 622 genotyped participants, 24 655 (92.6%) were identified as having European ancestry. These genomic data were linked to physical, lifestyle, medical, economic, environmental and psychosocial factors collected longitudinally in CLSA. The combined analysis, including CLSA genomic data, uncovered over 100 novel loci associated with key parameters to define glaucoma. The CLSA genomic dataset validated the contribution of a polygenic risk score to screen individuals with high fracture risk. It is also a valuable resource to directly identify common genetic variations associated with conditions related to complex traits. Taking advantage of the comprehensive interview and physical information collected in CLSA, this genomic dataset has been linked to psychosocial factors to investigate both the independent and interactive effects on cardiovascular disease. Future plans The CLSA overall is ongoing. Follow-up data will continue to be collected from participants in the current genomic subcohort, including the DNA methylation and metabolomic data. Ongoing studies focus on elucidating the role of genetic factors in cognitive decline and cardiovascular diseases. This genomic data resource is available on request through the CLSA data access application process.

/pdf/cohort-profile-genomic-data-for-26-622-individuals-from-the-h4gyledh.pdf

Cohort profile: genomic data for 26 622 individuals from the Canadian Longitudinal Study on Aging (CLSA)

Natural disaster impact assessment is of the utmost significance for post-disaster recovery, environmental protection, and hazard mitigation plans. With their recent usage in landslide susceptibility mapping, deep learning (DL) architectures have proven their efficiency in many scientific studies. However, some restrictions, including insufficient model variance and limited generalization capabilities, have been reported in the literature. To overcome these restrictions, ensembling DL models has often been preferred as a practical solution. In this study, an ensemble DL architecture, based on shared blocks, was proposed to improve the prediction capability of individual DL models. For this purpose, three DL models, namely Convolutional Neural Network (CNN), Recurrent Neural Network (RNN), and Long Short-Term Memory (LSTM), together with their ensemble form (CNN–RNN–LSTM) were utilized to model landslide susceptibility in Trabzon province, Turkey. The proposed DL architecture produced the highest modeling performance of 0.93, followed by CNN (0.92), RNN (0.91), and LSTM (0.86). Findings proved that the proposed model excelled the performance of the DL models by up to 7% in terms of overall accuracy, which was also confirmed by the Wilcoxon signed-rank test. The area under curve analysis also showed a significant improvement (~4%) in susceptibility map accuracy by the proposed strategy.

Shared Blocks-Based Ensemble Deep Learning for Shallow Landslide Susceptibility Mapping

For complex machine learning (ML) algorithms to gain widespread acceptance in decision making, we must be able to identify the features driving the predictions. Explainability models allow transparency of ML algorithms, however their reliability within high-dimensional data is unclear. To test the reliability of the explainability model SHapley Additive exPlanations (SHAP), we developed a convolutional neural network to predict tissue classification from Genotype-Tissue Expression (GTEx) RNA-seq data representing 16,651 samples from 47 tissues. Our classifier achieved an average F1 score of 96.1% on held-out GTEx samples. Using SHAP values, we identified the 2423 most discriminatory genes, of which 98.6% were also identified by differential expression analysis across all tissues. The SHAP genes reflected expected biological processes involved in tissue differentiation and function. Moreover, SHAP genes clustered tissue types with superior performance when compared to all genes, genes detected by differential expression analysis, or random genes. We demonstrate the utility and reliability of SHAP to explain a deep learning model and highlight the strengths of applying ML to transcriptome data.

/pdf/verifying-explainability-of-a-deep-learning-tissue-4jzimke67n.pdf

Verifying explainability of a deep learning tissue classifier trained on RNA-seq data.

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time-intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach we perform a systematic comparison of the distribution of VCDR and VDD, and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI based gradings increased estimates of heritability by ~50% for VCDR and VDD. Our GWAS identified more than 200 loci for both VCDR and VDD (double the number of loci from previous studies), uncovers dozens of novel biological pathways, with many of the novel loci also conferring risk for glaucoma.

/pdf/automated-ai-labelling-of-optic-nerve-head-enables-new-3d9tmdwqi3.pdf

Automated AI labelling of optic nerve head enables new insights into cross-ancestry glaucoma risk and genetic discovery in over 280,000 images from the UK Biobank and Canadian Longitudinal Study on Aging

Cupping of the optic nerve head, a highly heritable trait, is a hallmark of glaucomatous optic neuropathy. Two key parameters are vertical cup-to-disc ratio (VCDR) and vertical disc diameter (VDD). However, manual assessment often suffers from poor accuracy and is time intensive. Here, we show convolutional neural network models can accurately estimate VCDR and VDD for 282,100 images from both UK Biobank and an independent study (Canadian Longitudinal Study on Aging), enabling cross-ancestry epidemiological studies and new genetic discovery for these optic nerve head parameters. Using the AI approach, we perform a systematic comparison of the distribution of VCDR and VDD and compare these with intraocular pressure and glaucoma diagnoses across various genetically determined ancestries, which provides an explanation for the high rates of normal tension glaucoma in East Asia. We then used the large number of AI gradings to conduct a more powerful genome-wide association study (GWAS) of optic nerve head parameters. Using the AI-based gradings increased estimates of heritability by ∼50% for VCDR and VDD. Our GWAS identified more than 200 loci associated with both VCDR and VDD (double the number of loci from previous studies) and uncovered dozens of biological pathways; many of the loci we discovered also confer risk for glaucoma.

Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA

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Verifying explainability of a deep learning tissue classifier trained on RNA-seq data.

Automated AI labelling of optic nerve head enables new insights into cross-ancestry glaucoma risk and genetic discovery in over 280,000 images from the UK Biobank and Canadian Longitudinal Study on Aging

Automated AI labeling of optic nerve head enables insights into cross-ancestry glaucoma risk and genetic discovery in >280,000 images from UKB and CLSA