Faculty Bibliography

Discrimination discovery from data is an important data mining task, whose goal is to identify patterns of illegal and unethical discriminatory activities against protected-by-law groups, e.g., ethnic minorities. While any legally valid proof of discrimination requires evidence of causality, the state-of-the-art methods are essentially correlation based, albeit, as it is well known, correlation does not imply causation. In this paper, we take a principled causal approach to discrimination detection following Suppes"™ probabilistic causation theory. In particular, we define a method to extract, from a dataset of historical decision records, the causal structures existing among the attributes in the data. The result is a type of constrained Bayesian network, which we dub Suppes-Bayes causal network (SBCN). Next, we develop a toolkit of methods based on random walks on top of the SBCN, addressing different anti-discrimination legal concepts, such as direct and indirect discrimination, group and individual discrimination, genuine requirement, and favoritism. Our experiments on real-world datasets confirm the inferential power of our approach in all these different tasks.

Atopic dermatitis is one of the most common complaints presenting to dermatologists, and patients typically inquire as to appropriate bathing recommendations. Although many dermatologists, allergists, and primary-care practitioners provide explicit bathing instructions, recommendations regarding frequency of bathing, duration of bathing, and timing related to emollient and medication application relative to bathing vary widely. Conflicting and vague guidelines stem from knowledge related to the disparate effects of water on skin, as well as a dearth of studies, especially randomized controlled trials, evaluating the effects of water and bathing on the skin of patients with atopic dermatitis. We critically review the literature related to bathing and associated atopic dermatitis treatments, such as wet wraps, bleach baths, bath additives, and balneotherapy. We aim to provide readers with a comprehensive understanding of the impact of water and related therapies on atopic dermatitis as well as recommendations based upon the published data.

MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122-treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30-1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03-1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population.

ATG16L1T300A, a major risk polymorphism in Crohn's disease (CD), causes impaired autophagy, but it has remained unclear how this predisposes to CD. In this study, we report that mice with Atg16l1 deletion in intestinal epithelial cells (IECs) spontaneously develop transmural ileitis phenocopying ileal CD in an age-dependent manner, driven by the endoplasmic reticulum (ER) stress sensor IRE1alpha. IRE1alpha accumulates in Paneth cells of Atg16l1DeltaIEC mice, and humans homozygous for ATG16L1T300A exhibit a corresponding increase of IRE1alpha in intestinal epithelial crypts. In contrast to a protective role of the IRE1beta isoform, hyperactivated IRE1alpha also drives a similar ileitis developing earlier in life in Atg16l1;Xbp1DeltaIEC mice, in which ER stress is induced by deletion of the unfolded protein response transcription factor XBP1. The selective autophagy receptor optineurin interacts with IRE1alpha, and optineurin deficiency amplifies IRE1alpha levels during ER stress. Furthermore, although dysbiosis of the ileal microbiota is present in Atg16l1;Xbp1DeltaIEC mice as predicted from impaired Paneth cell antimicrobial function, such structural alteration of the microbiota does not trigger ileitis but, rather, aggravates dextran sodium sulfate-induced colitis. Hence, we conclude that defective autophagy in IECs may predispose to CD ileitis via impaired clearance of IRE1alpha aggregates during ER stress at this site.

Developmental eye defects in X-linked Ocular Albinism type I (OA1) are caused by G-Protein Coupled Receptor 143 (GPR143) mutations. Mutations result in dysfunctional melanosome biogenesis and macromelanosome formation in pigment cells, including melanocytes and retinal pigment epithelium. GPR143, primarily expressed in pigment cells, localizes exclusively to endolysosomal and melanosomal membranes unlike most GPCRs, which localize to the plasma membrane. There is some debate regarding GPR143 function and elucidating the role of this receptor may be instrumental for understanding neurogenesis during eye development and for devising therapies for OA1. Many GPCRs require association with other proteins to function. These GPCR-interacting proteins also facilitate fine-tuning of receptor activity and tissue specificity. We therefore investigated potential GPR143 interaction partners, with a focus on the melanogenic enzyme tyrosinase. GPR143 co-immunoprecipitated with tyrosinase, while confocal microscopy demonstrated colocalization of the proteins. Furthermore, tyrosinase localized to the plasma membrane when co-expressed with a GPR143 trafficking mutant. The physical interaction between the proteins was confirmed using Fluorescence Resonance Energy Transfer. This interaction may be required in order for GPR143 to function as a monitor of melanosome maturation. Identifying tyrosinase as a potential GPR143 binding protein opens new avenues for investigating the mechanisms that regulate pigmentation and neurogenesis.

Increasing percentages of children are being born to older fathers. This has resulted in concerns about the potential adverse effects of advanced paternal age. To help clinicians counsel couples, a systemic review was performed to attempt to address questions that these couples may ask: Should routine sperm testing be performed in older males? Should preimplantation genetic diagnosis (PGD) be performed? How do providers counsel patients about risk? Should young males freeze sperm if they plan to delay paternity? Using the terms "advanced paternal age", "semen testing", "preimplantation genetic diagnosis/screening", and "cryopreservation", a comprehensive search was performed in PubMed and the Cochrane Library, and numerous international societal guidelines were reviewed. In total, 42 articles or guidelines were reviewed. There were no limits placed on the timing of the articles. Thirty articles were found to be relevant and beneficial to answering the above questions. Each question was answered separately by the supporting literature. While primary research exists to support the role of semen testing, PGD/preimplantation genetic screening, and sperm banking in males who may be affected by advancing age, comprehensive studies on the possible clinical benefit of these interventions have yet to be performed. As a result, societal guidelines have yet to incorporate distinct best-practice guidelines on advanced paternal age.

Objective: We sought to assess our experience between a private (TH) and a public hospital (BH), both staffed by faculty and trainees of the same major university medical center. Methods: Our gastric cancer database was used to identify patients undergoing curative intent resection. Descriptive statistics were used to compare demographic data. Kaplan-Meier survival analysis was used to examine recurrence (RFS) and overall survival (OS). Multivariate proportional hazards regression was used to identify factors associated with RFS and OS. Data were risk - and disease stage-stratified. Results: There were 100 patients in the BH group and 242 in the TH group, with a median age 55 and 70.5 years respectively (p<0.001). The majority of BH patients were Asians (60, 60%), and Caucasians (172, 72.3%) in the TH group. The median number of days from diagnosis to surgical intervention at BH was 47.5 vs. 30 days in the TH (p=0.01). BH group had a smaller BMI and more frequently received distal or subtotal gastrectomy. Perioperative morbidity and mortality was equally distributed, as was 30-day readmission rate. Pathologic staging was similarly distributed. By multivariate analysis, hospital of treatment was not associated with RFS (p=0.48) nor OS (p=0.56). Conclusions: Patients receiving care for gastric cancer at major public hospitals have equally good clinical outcomes when compared to patients treated at private hospitals, if cared for by physicians within the same institution dedicated to disease specific entities. Overall survival by treatment hospital

There are ~350 million chronic carriers of hepatitis B (HBV). While a prophylactic vaccine and drug regimens to suppress viremia are available, chronic HBV infection is rarely cured. HBV's limited host tropism leads to a scarcity of susceptible small animal models and is a hurdle to developing curative therapies. Mice that support engraftment with human hepatoctyes have traditionally been generated through crosses of murine liver injury models to immunodeficient backgrounds. Here, we describe the disruption of fumarylacetoacetate hydrolase directly in the NOD Rag1-/- IL2RgammaNULL (NRG) background using zinc finger nucleases. The resultant human liver chimeric mice sustain persistent HBV viremia for >90 days. When treated with standard of care therapy, HBV DNA levels decrease below detection but rebound when drug suppression is released, mimicking treatment response observed in patients. Our study highlights the utility of directed gene targeting approaches in zygotes to create new humanized mouse models for human diseases.