Ordered Counterfactual Explanation by Mixed-Integer Linear Optimization

Post-hoc explanation methods for machine learning models have been widely used to support decision-making. One of the popular methods is Counterfactual Explanation (CE), also known as Actionable Recourse, which provides a user with a perturbation vector of features that alters the prediction result. Given a perturbation vector, a user can interpret it as an "action" for obtaining one's desired decision result. In practice, however, showing only a perturbation vector is often insufficient for users to execute the action. The reason is that if there is an asymmetric interaction among features, such as causality, the total cost of the action is expected to depend on the order of changing features. Therefore, practical CE methods are required to provide an appropriate order of changing features in addition to a perturbation vector. For this purpose, we propose a new framework called Ordered Counterfactual Explanation (OrdCE). We introduce a new objective function that evaluates a pair of an action and an order based on feature interaction. To extract an optimal pair, we propose a mixed-integer linear optimization approach with our objective function. Numerical experiments on real datasets demonstrated the effectiveness of our OrdCE in comparison with unordered CE methods.Comment: 20 pages, 5 figures, to appear in the 35th AAAI Conference on Artificial Intelligence (AAAI 2021

Histone variant H2A.B-H2B dimers are spontaneously exchanged with canonical H2A-H2B in the nucleosome

精子形成に重要なヒストンによるDNAの新たな折りたたみを解明. 京都大学プレスリリース. 2021-02-22.H2A.B is an evolutionarily distant histone H2A variant that accumulates on DNA repair sites, DNA replication sites, and actively transcribing regions in genomes. In cells, H2A.B exchanges rapidly in chromatin, but the mechanism has remained enigmatic. In the present study, we found that the H2A.B-H2B dimer incorporated within the nucleosome exchanges with the canonical H2A-H2B dimer without assistance from additional factors, such as histone chaperones and nucleosome remodelers. High-speed atomic force microscopy revealed that the H2A.B nucleosome, but not the canonical H2A nucleosome, transiently forms an intermediate “open conformation”, in which two H2A.B-H2B dimers may be detached from the H3-H4 tetramer and bind to the DNA regions near the entry/exit sites. Mutational analyses revealed that the H2A.B C-terminal region is responsible for the adoption of the open conformation and the H2A.B-H2B exchange in the nucleosome. These findings provide mechanistic insights into the histone exchange of the H2A.B nucleosome

Exploratory classification of clinical phenotypes in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis using cluster analysis

A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n=8) and proteinase 3-ANCA-positive (n=41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n=47); cutaneous (n=36); renal (n=256), non-renal (n=33); and both ENT and cutaneous symptoms (n=6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n=42), without s-Cr elevation (1.3 mg/dL) with high CRP (>10 mg/dL) (n=71), or s-Cr elevation (>= 1.3 mg/dL) without high CRP (<= 10 mg/dL) (n=157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis

Treatment-related damage in elderly-onset ANCA-associated vasculitis: safety outcome analysis of two nationwide prospective cohort studies

Background It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL  Results Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00–1.35) was a predictor for diabetes. Conclusion A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients

Prediction of response to remission induction therapy by gene expression profiling of peripheral blood in Japanese patients with microscopic polyangiitis

BackgroundMicroscopic polyangiitis (MPA), which is classified as an anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis, is one of the most frequent primary vasculitides in Japan. We earlier nominated 16 genes (IRF7, IFIT1, IFIT5, OASL, CLC, GBP-1, PSMB9, HERC5, CCR1, CD36, MS4A4A, BIRC4BP, PLSCR1, DEFA1/DEFA3, DEFA4, and COL9A2) as predictors of response to remission induction therapy against MPA. The aim of this study is to determine the accuracy of prediction using these 16 predictors.MethodsThirty-nine MPA patients were selected randomly and retrospectively from the Japanese nationwide RemIT-JAV-RPGN cohort and enrolled in this study. Remission induction therapy was conducted according to the Guidelines of Treatment for ANCA-Associated Vasculitis published by the Ministry of Health, Labour, and Welfare of Japan. Response to remission induction therapy was predicted by profiling the altered expressions of the 16 predictors between the period before and 1 week after the beginning of treatment. Remission is defined as the absence of clinical manifestations of active vasculitis (Birmingham Vasculitis Activity Score 2003: 0 or 1 point). Persistent remission for 18 months is regarded as a “good response,” whereas no remission or relapse after remission is regarded as a “poor response.”Results“Poor” and “good” responses were predicted in 7 and 32 patients, respectively. Five out of 7 patients with “poor” prediction and 1 out of 32 patients with “good” prediction experienced relapse after remission. One out of 7 patients with “poor” prediction was not conducted to remission. Accordingly, the sensitivity and specificity to predict poor response was 85.7% (6/7) and 96.9% (31/32), respectively.ConclusionsResponse to remission induction therapy can be predicted by monitoring the altered expressions of the 16 predictors in the peripheral blood at an early point of treatment in MPA patients

Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009

Comparison of severity classification in Japanese patients with antineutrophil cytoplasmic antibody-associated vasculitis in a nationwide, prospective, inception cohort study

OBJECTIVE: To compare disease severity classification systems for six-month outcome prediction in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV from 53 tertiary institutions were enrolled. Six-month remission, overall survival, and end-stage renal disease (ESRD)-free survival were evaluated. RESULTS: According to the European Vasculitis Study Group (EUVAS)-defined disease severity, the 321 enrolled patients were classified as follows: 14, localized; 71, early systemic; 170, generalized; and 66, severe disease. According to the rapidly progressive glomerulonephritis (RPGN) clinical grading system, the patients were divided as follows: 60, grade I; 178, grade II; 66, grade III; and 12, grade IV. According to the Five-Factor Score (FFS) 2009, 103, 109, and 109 patients had ≤1, 2, and ≥3 points, respectively. No significant difference in remission rates was found in any severity classification. The overall and ESRD-free survival rates significantly differed between grades I/II, III, and IV, regardless of renal involvement. Severe disease was a good predictor of six-month overall and ESRD-free survival. The FFS 2009 was useful to predict six-month ESRD-free survival but not overall survival. CONCLUSIONS: The RPGN grading system was more useful to predict six-month overall and ESRD-free survival than the EUVAS-defined severity or FFS 2009