Large-Scale Discovery of Disease-Disease and Disease-Gene Associations
Electronic Health Records
Genetic Diseases, Inborn
Genetic Predisposition to Disease
Genome-Wide Association Study
Permanent link to this recordhttp://hdl.handle.net/20.500.12613/5028
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Abstract© 2016 The Author(s). Data-driven phenotype analyses on Electronic Health Record (EHR) data have recently drawn benefits across many areas of clinical practice, uncovering new links in the medical sciences that can potentially affect the well-being of millions of patients. In this paper, EHR data is used to discover novel relationships between diseases by studying their comorbidities (co-occurrences in patients). A novel embedding model is designed to extract knowledge from disease comorbidities by learning from a large-scale EHR database comprising more than 35 million inpatient cases spanning nearly a decade, revealing significant improvements on disease phenotyping over current computational approaches. In addition, the use of the proposed methodology is extended to discover novel disease-gene associations by including valuable domain knowledge from genome-wide association studies. To evaluate our approach, its effectiveness is compared against a held-out set where, again, it revealed very compelling results. For selected diseases, we further identify candidate gene lists for which disease-gene associations were not studied previously. Thus, our approach provides biomedical researchers with new tools to filter genes of interest, thus, reducing costly lab studies.
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Continuing trastuzumab beyond disease progression: Outcomes analysis in patients with metastatic breast cancerCancello, G; Montagna, E; D'Agostino, D; Giuliano, M; Giordano, A; Di Lorenzo, G; Plaitano, M; De Placido, S; De Laurentiis, M; Giordano, Antonio|0000-0002-5959-016X (2008-07-16)Introduction: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD.Methods: We identified 101 patients treated between July 2000 and January 2007. Nineteen were still receiving the first-line trastuzumab-based treatment without evidence of PD and were not included in this analysis. Of the remaining 82 patients, 59 retained trastuzumab for one or more additional lines of chemotherapy after PD, according to our institution policy. Twenty-three patients who changed treating institution and stopped trastuzumab at first progression were used as a control group.Results: For patients retaining trastuzumab, the median follow-up was 39.6 months. Clinical outcomes showed the typical degradation between first and second lines of therapy which we would expect by halting trastuzumab at first progression. Response rates were 35% and 16% and median times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy, respectively. The median overall survival (OS) rates were 70 months for patients who retained trastuzumab and 56 months for patients who halted the drug (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.51 to 1.18; P = 0.52). If we consider OS from the start of trastuzumab therapy, the figures are 53.9 and 34.8 months, respectively (HR 0.78, 95% CI 0.58 to 1.32; P = 0.2).Conclusion: A nonstatistically significant trend of improved survival for patients retaining trastuzumab is observed. This is in line with most retrospective analyses and recent randomized data. Retaining trastuzumab after progression is a reasonable option, but further randomized data are warranted to better define its role in comparison with other available options. © 2008 Cancello et al.; licensee BioMed Central Ltd.
CD40 monocyte differentiation mediates tissue inflammation in chronic kidney diseaseWang, Hong, 1956 September 19-; Yang, Xiao-Feng; Ashby, Barrie; Gallucci, Stefania; Merali, Salim; Susztak, Katalin (Temple University. Libraries, 2015)Patients with chronic kidney disease (CKD) develop hyperhomocysteinemia (HHcy), have increased inflammatory monocytes (MC) and 10-times higher cardiovascular mortality than the general population. Here, we investigated HHcy-related MC differentiation in CKD. Twenty seven CKD and CVD, and 14 healthy subjects were recruited. CD40 was selected as a CKD-induced MC activation marker by mining for CKD-MC-mRNA screen database. We found that CD14++CD16+ MC, often denoted as inflammatory subset, soluble CD40 ligand (sCD40L), and TNFα/IL-6 levels were augmented in CVD and CKD subjects. CD40hiCD14++CD16+ MC, plasma homocysteine (Hcy) and S-adenosylhomocysteine (SAH) levels were increased in CVD and further elevated in CKD subjects. In cultured human peripheral blood mononuclear cells, CKD patient serum, Hcy, CD40L and TNFα/IL-6 induced CD40hiCD14++CD16+ MC differentiation, which was prevented by Hcy-lowering folic acid and neutralizing antibodies against TNFα and IL-6. Interestingly, CD14++CD16+ and CD40hiCD14++CD16+ MCs were negatively correlated with plasma S-adenosylmethionine/SAH (SAM/SAH) ratios, an indicator of methylation status, in CKD and CVD subjects. In white blood cells (WBC) isolated from CKD and CVD subjects with lower SAM/SAH ratios, hypomethylation was identified on the CG pair of NFκB consensus element in the core promoter located at the CpG island of CD40 gene by DNA methylation mapping using bisulfite converting pyrosequencing. Moreover, Hcy inhibited DNA methyltransferase-1 activity in cultured human blood MC. In conclusion, HHcy induces CD14++CD16+ and CD40hiCD14++CD16+ MC differentiation, at least in part, via sCD40L induction and CD40 DNA hypomethylation in CKD and CVD subjects. To study the role of CD40 in the development of kidney pathology and vascular disease, we then established mouse model of CKD-induced CVD (5/6 nephrectomy CKD model plus left carotid artery ligation) in CD40-/- mice. Bone marrow (BM)-derived cells were traced by the transplantation of BM cells from enhanced green fluorescent protein (EGFP) transgenic CD40+/+ mice after sublethal irradiation of the recipient CD40-/- mice. We demonstrated here that CKD accelerated carotid artery atherosclerosis, exacerbated metabolism, increased spleen weight and circulating CD40+ inflammatory MC, and further increased differentiation of mononuclear phagocytic cells (MPC); CD11b+F4/80- MC, CD11b+F4/80+ macrophage (Mϕ) and CD11c+CD11b+F4/80+ bone marrow-derived dendritic cell in the kidney and aorta, which were abolished by CD40-/- mice. We also found that CKD kidney elevated CD40 expression and induced MC chemotactic signals; CCL2, CCL12, and CCL5 chemokines, which were abolished in CD40-/- mice. In conclusion, our results suggest that CD40 induction in the chronic kidney disease mediates kidney chemokine production, which in turn contributes to acceleration of myeloid cell infiltration, MPC differentiation, and carotid artery atherosclerosis.