Inherently Interpretable Multi-Label Classification Using Class-Specific Counterfactuals

Interpretability is essential for machine learning algorithms in high-stakes application fields such as medical image analysis. However, high-performing black-box neural networks do not provide explanations for their predictions, which can lead to mistrust and suboptimal human-ML collaboration. Post-hoc explanation techniques, which are widely used in practice, have been shown to suffer from severe conceptual problems. Furthermore, as we show in this paper, current explanation techniques do not perform adequately in the multi-label scenario, in which multiple medical findings may co-occur in a single image. We propose Attri-Net, an inherently interpretable model for multi-label classification. Attri-Net is a powerful classifier that provides transparent, trustworthy, and human-understandable explanations. The model first generates class-specific attribution maps based on counterfactuals to identify which image regions correspond to certain medical findings. Then a simple logistic regression classifier is used to make predictions based solely on these attribution maps. We compare Attri-Net to five post-hoc explanation techniques and one inherently interpretable classifier on three chest X-ray datasets. We find that Attri-Net produces high-quality multi-label explanations consistent with clinical knowledge and has comparable classification performance to state-of-the-art classification models.Comment: Accepted to MIDL 202

Differential effects of anti-Nogo-A antibody treatment and treadmill training in rats with incomplete spinal cord injury

Locomotor training on treadmills can improve recovery of stepping in spinal cord injured animals and patients. Likewise, lesioned rats treated with antibodies against the myelin associated neurite growth inhibitory protein, Nogo-A, showed increased regeneration, neuronal reorganization and behavioural improvements. A detailed kinematic analysis showed that the hindlimb kinematic patterns that developed in anti-Nogo-A antibody treated versus treadmill trained spinal cord injured rats were significantly different. The synchronous combined treatment group did not show synergistic effects. This lack of synergistic effects could not be explained by an increase in pain perception, sprouting of calcitonin gene-related peptide (CGRP) positive fibres or by interference of locomotor training with anti-Nogo-A antibody induced regeneration and sprouting of descending fibre tracts. The differential mechanisms leading to behavioural recovery during task-specific training and in regeneration or plasticity enhancing therapies have to be taken into account in designing combinatorial therapies so that their potential positive interactive effects can be fully expresse

High resolution MRI for quantitative assessment of inferior alveolar nerve impairment in course of mandible fractures: an imaging feasibility study

The purpose of this study was to evaluate a magnetic resonance imaging (MRI) protocol for direct visualization of the inferior alveolar nerve in the setting of mandibular fractures. Fifteen patients suffering from unilateral mandible fractures involving the inferior alveolar nerve (15 affected IAN and 15 unaffected IAN from contralateral side) were examined on a 3 T scanner (Elition, Philips Healthcare, Best, the Netherlands) and compared with 15 healthy volunteers (30 IAN in total). The sequence protocol consisted of a 3D STIR, 3D DESS and 3D T1 FFE sequence. Apparent nerve-muscle contrast-to-noise ratio (aNMCNR), apparent signal-to-noise ratio (aSNR), nerve diameter and fracture dislocation were evaluated by two radiologists and correlated with nerve impairment. Furthermore, dislocation as depicted by MRI was compared to computed tomography (CT) images. Patients with clinically evident nerve impairment showed a significant increase of aNMCNR, aSNR and nerve diameter compared to healthy controls and to the contralateral side (p < 0.05). Furthermore, the T1 FFE sequence allowed dislocation depiction comparable to CT. This prospective study provides a rapid imaging protocol using the 3D STIR and 3D T1 FFE sequence that can directly assess both mandible fractures and IAN damage. In patients with hypoesthesia following mandibular fractures, increased aNMCN R, aSNR and nerve diameter on MRI imaging may help identify patients with a risk of prolonged or permanent hypoesthesia at an early time

Climatological Study of the Short-Term Variation of the 0 C, -10 C, and -20 C Altitude Levels over the Florida Spaceport

For evaluation of the potential of cloud electrification, it is necessary to know the altitude of the 0, -10 and -20 degree Celsius levels. Cape Canaveral Air Force Station has recorded balloon launch data back to 1989. In support of rocket launches, often multiple balloons are launched within minutes of each other in the 4-6 hours leading up to launch. In the past, temperature data from sondes was typically available every hour or so through the launch countdown, allowing for frequent updates of these critical temperature thresholds. Recently, launch customers are relying on Jimsphere and wind profiler data that do not have a thermodynamic component in the latter 4-6 hours of a countdown. This study compares the altitude differences of the 0, -10 and -20 degree Celsius levels from consecutive balloon pairs not to exceed 6 hours apart. The analysis uses 9685 soundings from 1989 to 2013. Approximately 5 of the time the altitude of the temperature level in question (0, -10, -20 degrees C), varies by more than 500 feet (operationally significant threshold) within 6 hours. This study analyzes the altitude variability as a function of several meteorological parameters, such as change in sonde type, dew point depression, and solar zenith angle. Additionally, the study concludes with impacts to launch operations

CD4\u3csup\u3e+\u3c/sup\u3e T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope

Löfgren’s syndrome (LS) is an acute form of sarcoidosis characterized by a genetic association with HLA-DRB1*03 (HLA-DR3) and an accumulation of CD4+ T cells of unknown specificity in the bronchoalveolar lavage (BAL). Here, we screened related LS-specific TCRs for antigen specificity and identified a peptide derived from NAD-dependent histone deacetylase hst4 (NDPD) of Aspergillus nidulans that stimulated these CD4+ T cells in an HLA-DR3–restricted manner. Using ELISPOT analysis, a greater number of IFN-γ– and IL-2–secreting T cells in the BAL of DR3+ LS subjects compared with DR3+ control subjects was observed in response to the NDPD peptide. Finally, increased IgG antibody responses to A. nidulans NDPD were detected in the serum of DR3+ LS subjects. Thus, our findings identify a ligand for CD4+ T cells derived from the lungs of LS patients and suggest a role of A. nidulans in the etiology of LS

Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease

Chronic beryllium disease (CBD) is a granulomatous disorder characterized by an influx of beryllium (Be)-specific CD4+ T cells into the lung. The vast majority of these T cells recognize Be in an HLA-DP–restricted manner, and peptide is required for T cell recognition. However, the peptides that stimulate Be-specific T cells are unknown. Using positional scanning libraries and fibroblasts expressing HLA-DP2, the most prevalent HLA-DP molecule linked to disease, we identified mimotopes and endogenous self-peptides that bind to MHCII and Be, forming a complex recognized by pathogenic CD4+ T cells in CBD. These peptides possess aspartic and glutamic acid residues at p4 and p7, respectively, that surround the putative Be-binding site and cooperate with HLA-DP2 in Be coordination. Endogenous plexin A peptides and proteins, which share the core motif and are expressed in lung, also stimulate these TCRs. Be-loaded HLA-DP2–mimotope and HLA-DP2–plexin A4 tetramers detected high frequencies of CD4+ T cells specific for these ligands in all HLA-DP2+ CBD patients tested. Thus, our findings identify the first ligand for a CD4+ T cell involved in metal-induced hypersensitivity and suggest a unique role of these peptides in metal ion coordination and the generation of a common antigen specificity in CBD

A Polymorphism of Bactericidal/Permeability-Increasing Protein Affects Its Neutralization Efficiency towards Lipopolysaccharide

Gram-negative sepsis driven by lipopolysaccharide (LPS) has detrimental outcomes, especially in neonates. The neutrophil-derived bactericidal/permeability-increasing protein (BPI) potently neutralizes LPS. Interestingly, polymorphism of the BPI gene at position 645 (rs4358188) corresponds to a favorable survival rate of these patients in the presence of at least one allele 645 A as opposed to 645 G. When we exploited the existing X-ray crystal structure, the corresponding amino acid at position 216 was revealed as surface exposed and proximal to the lipid-binding pocket in the N-terminal domain of BPI. Our further analysis predicted a shift in surface electrostatics by a positively charged lysine (BPI216K) exchanging a negatively charged glutamic acid (BPI216E). To investigate differences in interaction with LPS, we expressed both BPI variants recombinantly. The amino acid exchange neither affected affinity towards LPS nor altered bactericidal activity. However, when stimulating human peripheral blood mononuclear cells, BPI216K exhibited a superior LPS-neutralizing capacity (IC50 12.0 ± 2.5 pM) as compared to BPI216E (IC50 152.9 ± 113.4 pM, p = 0.0081) in respect to IL-6 secretion. In conclusion, we provide a functional correlate to a favorable outcome of sepsis in the presence of BPI216K

Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases.

BACKGROUND: The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D. METHODS: We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, alpha = 0.05. RESULTS: We found no evidence of association with T1D at most of the loci studied 0.02 <P < 1.0. Only a SNP in ADAM33, rs2787094, was any evidence of association obtained, P = 0.0004 in set 1 families (relative risk (RR) = 0.78), but further support was not observed in the 4,326 cases and 4,610 controls, P = 0.57 (OR = 1.02). CONCLUSION: Polymorphisms in a variety of genes previously associated with immune-mediated disease susceptibility and/or having effects on gene function and the immune system, are unlikely to be affecting T1D susceptibility in a major way, even though some of the genes tested encode proteins of immune pathways that are believed to be central to the development of T1D. We cannot, however, rule out effect sizes smaller than OR 1.5