The Alzheimer′s Disease Prediction Of Longitudinal Evolution (TADPOLE) Challenge is the most comprehensive challenge to date with regard to the number of subjects, considered features, and challenge participants. The initial objective of TADPOLE was the identification of the most predictive data, features, and methods for the progression of subjects at risk of developing Alzheimer′s. The challenge was successful in recognizing tree-based ensemble methods such as gradient boosting and random forest as the best methods for the prognosis of the clinical status in Alzheimer’s disease (AD). However, the challenge outcome was limited to which combination of data processing and methods exhibits the best accuracy; hence, it is difficult to determine the contribution of the methods to the accuracy. The quantification of feature importance was globally approached by all the challenge participant methods. In addition, TADPOLE provided general answers that focused on improving performance while ignoring important issues such as interpretability. The purpose of this study is to intensively explore the models of the top three TADPOLE Challenge methods in a common framework for fair comparison. In addition, for these models, the most meaningful features for the prognosis of the clinical status of AD are studied and the contribution of each feature to the accuracy of the methods is quantified. We provide plausible explanations as to why the methods achieve such accuracy, and we investigate whether the methods use information coherent with clinical knowledge. Finally, we approach these issues through the analysis of SHapley Additive exPlanations (SHAP) values, a technique that has recently attracted increasing attention in the field of explainable artificial intelligence (XAI).

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This work proposes a unifying framework for extending PDE-constrained Large Deformation Diffeomorphic Metric Mapping (PDE-LDDMM) with the sum of squared differences (SSD) to PDE-LDDMM with different image similarity metrics. We focused on the two best-performing variants of PDE-LDDMM with the spatial and band-limited parameterizations of diffeomorphisms. We derived the equations for gradient-descent and Gauss–Newton–Krylov (GNK) optimization with Normalized Cross-Correlation (NCC), its local version (lNCC), Normalized Gradient Fields (NGFs), and Mutual Information (MI). PDE-LDDMM with GNK was successfully implemented for NCC and lNCC, substantially improving the registration results of SSD. For these metrics, GNK optimization outperformed gradient-descent. However, for NGFs, GNK optimization was not able to overpass the performance of gradient-descent. For MI, GNK optimization involved the product of huge dense matrices, requesting an unaffordable memory load. The extensive evaluation reported the band-limited version of PDE-LDDMM based on the deformation state equation with NCC and lNCC image similarities among the best performing PDE-LDDMM methods. In comparison with benchmark deep learning-based methods, our proposal reached or surpassed the accuracy of the best-performing models. In NIREP16, several configurations of PDE-LDDMM outperformed ANTS-lNCC, the best benchmark method. Although NGFs and MI usually underperformed the other metrics in our evaluation, these metrics showed potentially competitive results in a multimodal deformable experiment. We believe that our proposed image similarity extension over PDE-LDDMM will promote the use of physically meaningful diffeomorphisms in a wide variety of clinical applications depending on deformable image registration.

Background: Several studies indicate that the anterior visual pathway provides information about the dynamics of axonal degeneration in Multiple Sclerosis (MS). Current research in the field is focused on the quest for the most discriminative features among patients and controls and the development of machine learning models that yield computer-aided solutions widely usable in clinical practice. However, most studies are conducted with small samples and the models are used as black boxes. Clinicians should not trust machine learning decisions unless they come with comprehensive and easily understandable explanations. Materials and methods: A total of 216 eyes from 111 healthy controls and 100 eyes from 59 patients with relapsing-remitting MS were enrolled. The feature set was obtained from the thickness of the ganglion cell layer (GCL) and the retinal nerve fiber layer (RNFL). Measurements were acquired by the novel Posterior Pole protocol from Spectralis Optical Coherence Tomography (OCT) device. We compared two black-box methods (gradient boosting and random forests) with a glass-box method (explainable boosting machine). Explainability was studied using SHAP for the black-box methods and the scores of the glass-box method. Results: The best-performing models were obtained for the GCL layer. Explainability pointed out to the temporal location of the GCL layer that is usually broken or thinning in MS and the relationship between low thickness values and high probability of MS, which is coherent with clinical knowledge. Conclusions: The insights on how to use explainability shown in this work represent a first important step toward a trustworthy computer-aided solution for the diagnosis of MS with OCT.