Learning high-order interactions for polygenic risk prediction.

Within the framework of precision medicine, the stratification of individual genetic susceptibility based on inherited DNA variation has paramount relevance. However, one of the most relevant pitfalls of traditional Polygenic Risk Scores (PRS) approaches is their inability to model complex high-order non-linear SNP-SNP interactions and their effect on the phenotype (e.g.

Total embedding of spermatic cord and hilar soft tissue in orchiectomy for seminoma: does the extensive sampling improve pathologic risk factors?

Pure seminomas represent the majority of testicular germ cell tumors and accurate diagnosis and staging require an accurate sampling of radical orchiectomy specimens. The aim of our study is to find the most informative gross sampling method for orchiectomy specimens. We performed the extensive sampling of 88 radical orchiectomy specimens embedding in their entirety testicular hilum, rete testis, hilar soft tissue, and spermatic cord.

Stability over time of the "hospital effect" on 30-day unplanned readmissions: Evidence from administrative data.

Past studies showed that hospital characteristics affect hospital performance in terms of 30-day unplanned readmissions, proving the existence of a "hospital effect". However, the stability over time of this effect has been under-investigated. This study offers new evidence about the stability over time of the hospital effect on 30-day unplanned readmissions.

Development of a method for generating SNP interaction-aware polygenic risk scores for radiotherapy toxicity.

Aim: To identify the effect of single nucleotide polymorphism (SNP) interactions on the risk of toxicity following radiotherapy (RT) for prostate cancer (PCa) and propose a new method for polygenic risk score incorporating SNP-SNP interactions (PRSi).

Materials And Methods: Analysis included the REQUITE PCa cohort that received external beam RT and was followed for 2 years. Late toxicity endpoints were: rectal bleeding, urinary frequency, haematuria, nocturia, decreased urinary stream.

Treatment prescription, adherence, and persistence after the first hospitalization for heart failure: A population-based retrospective study on 100785 patients.

Background: This study evaluates, in a real-world setting, to what extent the recommended therapies by international guidelines, are prescribed after a first hospitalization for heart failure (HF), and to analyse adherence and persistence, and the effect of treatment adherence on mortality and re-hospitalization.

Methods: From the Lombardy healthcare administrative database, we analysed patients discharged after their incident HF, from 2000 to 2012. Adherence was defined as the proportion of days covered (PDC) ≥80% adjusted for hospitalizations and persistence as the absence of discontinuation of therapy for >30 days.

A Deep Learning Approach Validates Genetic Risk Factors for Late Toxicity After Prostate Cancer Radiotherapy in a REQUITE Multi-National Cohort.

REQUITE (validating pREdictive models and biomarkers of radiotherapy toxicity to reduce side effects and improve QUalITy of lifE in cancer survivors) is an international prospective cohort study. The purpose of this project was to analyse a cohort of patients recruited into REQUITE using a deep learning algorithm to identify patient-specific features associated with the development of toxicity, and test the approach by attempting to validate previously published genetic risk factors. The study involved REQUITE prostate cancer patients treated with external beam radiotherapy who had complete 2-year follow-up.

Evaluating the effect of healthcare providers on the clinical path of heart failure patients through a semi-Markov, multi-state model.

Background: Investigating similarities and differences among healthcare providers, on the basis of patient healthcare experience, is of interest for policy making. Availability of high quality, routine health databases allows a more detailed analysis of performance across multiple outcomes, but requires appropriate statistical methodology.

Methods: Motivated by analysis of a clinical administrative database of 42,871 Heart Failure patients, we develop a semi-Markov, illness-death, multi-state model of repeated admissions to hospital, subsequent discharge and death.

Impact of in-hospital cardiac rehabilitation on mortality and readmissions in heart failure: A population study in Lombardy, Italy, from 2005 to 2012.

Aims: The 2016 European guidelines for the diagnosis and treatment of heart failure classified cardiac rehabilitation as a mandatory class I intervention. We aimed to analyse in heart failure patients the impact of an in-hospital cardiac rehabilitation programme on all-cause mortality and readmissions.

Methods: From the Lombardy healthcare administrative database, we analysed in patients with incident heart failure, from 2005 to 2012, the number of all hospitalisations, cardiac rehabilitation admissions, post-discharge deaths, outpatient drug prescriptions and visits.

Immunomodulatory Drugs in the Context of Autologous Hematopoietic Stem Cell Transplantation Associate With Reduced Pro-tumor T Cell Subsets in Multiple Myeloma.

Immunomodulatory drugs (IMiDs) are effective therapeutics for multiple myeloma (MM), where in different clinical settings they exert their function both directly on MM cells and indirectly by modulating immune cell subsets, although with not completely defined mechanisms. Here we studied the role of IMiDs in the context of autologous hematopoietic stem cell transplantation on the T cell subset distribution in the bone marrow of newly diagnosed MM patients. We found that after transplantation pro-tumor Th17-Th1 and Th22 cells and their related cytokines were lower in patients treated with IMiDs during induction chemotherapy compared to untreated patients.

Non-parametric frailty Cox models for hierarchical time-to-event data.

We propose a novel model for hierarchical time-to-event data, for example, healthcare data in which patients are grouped by their healthcare provider. The most common model for this kind of data is the Cox proportional hazard model, with frailties that are common to patients in the same group and given a parametric distribution. We relax the parametric frailty assumption in this class of models by using a non-parametric discrete distribution.

Serum human epididymis protein 4 vs. carbohydrate antigen 125 in ovarian cancer follow-up.

Background: The addition of human epididymis protein 4 (HE4) to carbohydrate antigen 125 (CA125) in ovarian cancer (OC) assessment has been proposed. We compared the clinical value of biomarker changes in a prospective series of patients undergoing OC monitoring.

Methods: We studied 43 patients (79% post-menopausal), followed for 3.

Urn models for response-adaptive randomized designs: a simulation study based on a non-adaptive randomized trial.

Recently, response-adaptive designs have been proposed in randomized clinical trials to achieve ethical and/or cost advantages by using sequential accrual information collected during the trial to dynamically update the probabilities of treatment assignments. In this context, urn models-where the probability to assign patients to treatments is interpreted as the proportion of balls of different colors available in a virtual urn-have been used as response-adaptive randomization rules. We propose the use of Randomly Reinforced Urn (RRU) models in a simulation study based on a published randomized clinical trial on the efficacy of home enteral nutrition in cancer patients after major gastrointestinal surgery.

Laparoscopic Retroperitoneal Lymph Node Dissection for Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis: Safety and Efficacy Analyses at a High Volume Center.

Purpose: The prognosis of stage I nonseminomatous germ cell tumor of the testis is favorable. Early and late side effects of treatment may affect quality of life and survival. We determined the tolerability, safety and efficacy of laparoscopic retroperitoneal lymph node dissection in patients with stage I nonseminomatous germ cell tumor of the testis at a high volume center.

Regional variation in hospitalisation and mortality in heart failure: comparison of England and Lombardy using multistate modelling.

Heart failure (HF) is a common, serious chronic condition with high morbidity, hospitalisation and mortality. The healthcare systems of England and the northern Italian region of Lombardy share important similarities and have comprehensive hospital administrative databases linked to the death register. We used them to compare admission for HF and mortality for patients between 2006 and 2012 (n = 37,185 for Lombardy, 234,719 for England) with multistate models.

A multi-state approach to patients affected by chronic heart failure : The value added by administrative data.

Healthcare administrative databases are becoming more and more important and reliable sources of clinical and epidemiological information. They are able to track several interactions between a patient and the public healthcare system. In the present study, we make use of data extracted from the administrative data warehouse of Regione Lombardia, a region located in the northern part of Italy whose capital is Milan.

Trends in heart failure hospitalizations, patient characteristics, in-hospital and 1-year mortality: A population study, from 2000 to 2012 in Lombardy.

Background: This study was undertaken to evaluate trends in heat failure hospitalizations (HFHs) and 1-year mortality of HFH in Lombardy, the largest Italian region, from 2000 to 2012.

Methods: Hospital discharge forms with HF-related ICD-9 CM codes collected from 2000 to 2012 by the regional healthcare service (n=699797 in 370538 adult patients), were analyzed with respect to in-hospital and 1-year mortality; Group (G) 1 included most acute HF episodes with primary cardiac diagnosis (70%); G2 included cardiomyopathies without acute HF codes (17%); and G3 included non-cardiac conditions with HF as secondary diagnosis (13%). Patients experiencing their first HFH since 2005 were analyzed as incident cases (n=216782).

Non-invasive optical estimate of tissue composition to differentiate malignant from benign breast lesions: A pilot study.

Several techniques are being investigated as a complement to screening mammography, to reduce its false-positive rate, but results are still insufficient to draw conclusions. This initial study explores time domain diffuse optical imaging as an adjunct method to classify non-invasively malignant vs benign breast lesions. We estimated differences in tissue composition (oxy- and deoxyhemoglobin, lipid, water, collagen) and absorption properties between lesion and average healthy tissue in the same breast applying a perturbative approach to optical images collected at 7 red-near infrared wavelengths (635-1060 nm) from subjects bearing breast lesions.

Validation of the Italian Version of the Haemophilia Activities List.

Background: The aim of this study was to provide an Italian version of the Haemophilia Activities List (HAL) and check its reliability in Italian medical centers.

Methods: The Italian version of this assessment was administered to 80 patients (aged 18-65 years) affected by haemophilia A and B (moderate or severe). The validation was accomplished by comparing it to the revised and expanded Arthritis Impact Measurement Scales (AIMS2).

Methodological issues on the use of administrative data in healthcare research: the case of heart failure hospitalizations in Lombardy region, 2000 to 2012.

Background: Administrative data are increasingly used in healthcare research. However, in order to avoid biases, their use requires careful study planning. This paper describes the methodological principles and criteria used in a study on epidemiology, outcomes and process of care of patients hospitalized for heart failure (HF) in the largest Italian Region, from 2000 to 2012.

Basophil Recruitment into Tumor-Draining Lymph Nodes Correlates with Th2 Inflammation and Reduced Survival in Pancreatic Cancer Patients.

In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients.

Dynamic clustering of hazard functions: an application to disease progression in chronic heart failure.

We analyse data collected from the administrative datawarehouse of an Italian regional district (Lombardia) concerning patients affected by Chronic Heart Failure. The longitudinal data gathering for each patient hospital readmissions in time, as well as patient-specific covariates, is studied as a realization of non homogeneous Poisson process. Since the aim behind this study is to identify groups of patients behaving similarly in terms of disease progression and then healthcare consumption, we conjectured the time segments between two consecutive hospitalizations to be Weibull distributed in each hidden cluster.

A Combination of Cisplatin and 5-Fluorouracil With a Taxane in Patients Who Underwent Lymph Node Dissection for Nodal Metastases From Squamous Cell Carcinoma of the Penis: Treatment Outcome and Survival Analyses in Neoadjuvant and Adjuvant Settings.

Background: The role of chemotherapy in nodal metastases from penile squamous cell carcinoma is not defined. We evaluated the efficacy of a combination of T-PF (a taxane, cisplatin, and 5-fluorouracil) in neoadjuvant and adjuvant settings.

Patients And Methods: Since June of 2004, T-PF was administered to stage N2 to 3 patients.

Use of Depth Measure for Multivariate Functional Data in Disease Prediction: An Application to Electrocardiograph Signals.

In this paper we develop statistical methods to compare two independent samples of multivariate functional data that differ in terms of covariance operators. In particular we generalize the concept of depth measure to this kind of data, exploiting the role of the covariance operators in weighting the components that define the depth. Two simulation studies are carried out to validate the robustness of the proposed methods and to test their effectiveness in some settings of interest.

A semiparametric bivariate probit model for joint modeling of outcomes in STEMI patients.

In this work we analyse the relationship among in-hospital mortality and a treatment effectiveness outcome in patients affected by ST-Elevation myocardial infarction. The main idea is to carry out a joint modeling of the two outcomes applying a Semiparametric Bivariate Probit Model to data arising from a clinical registry called STEMI Archive. A realistic quantification of the relationship between outcomes can be problematic for several reasons.

Detecting and visualizing outliers in provider profiling via funnel plots and mixed effect models.

In this work we propose the use of a graphical diagnostic tool (the funnel plot) to detect outliers among hospitals that treat patients affected by Acute Myocardial Infarction (AMI). We consider an application to data on AMI hospitalizations recorded in the administrative databases of our regional district. The outcome of interest is the in-hospital mortality, a variable indicating if the patient has been discharged dead or alive.