Unit of Biostatistics

Santa Maria Imbaro, Italy

Unit of Biostatistics

Santa Maria Imbaro, Italy

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Fontana A.,Unit of Biostatistics | Copetti M.,Unit of Biostatistics | Kypraios T.,University of Nottingham | Pellegrini F.,Unit of Biostatistics
Statistics in Medicine | Year: 2013

The assessment and comparison of multiple biological rhythms represent an important challenge in chronobiology. They allow the investigation of whether a well-defined time-qualified relationship between biorhythms of the same frequency range is maintained in the presence of functional alterations, which may lead to chronodisruption or internal desynchronization. We propose a multivariate linear mixed model approach where functions of several biorhythms are jointly modeled in a multivariate longitudinal fashion, handling both the correlation between biorhythms of multiple outcomes and the correlation between measurements collected over time within the same biological entity. Furthermore, between-subject heterogeneity is also taken into account with the inclusion of random effects. Pairwise comparisons between biorhythms are performed by means of proper contrasts. As an example, we define contrasts which allow us testing whether or not two biorhythms are identical or opposing, providing additional support in clinical practice. Moreover, we illustrate the proposed method using both simulated and biological real data, concerning the comparison of three specific lymphocytes profiles which modulate the function of immune system between healthy subjects and non-small lung cancer patients. Finally, the corresponding SAS syntax is provided. © 2012 John Wiley & Sons, Ltd.


Buchner A.M.,University of Pennsylvania | Heckman M.G.,Unit of Biostatistics
American Journal of Gastroenterology | Year: 2012

Objectives: Probe-based confocal laser endomicroscopy (pCLE) allows real-time in-vivo microscopic imaging of tissue. Narrow band imaging (NBI) can also classify colorectal lesions. Both systems may allow accurate optical diagnosis of small (6-9 mm) and diminutive (1-5 mm) polyps without histopathology. This study assesses the accuracy of pCLE and NBI for prediction of histology. Methods: Participants underwent high-definition colonoscopy. The surface pit pattern of all polyps (1-9 mm) was determined in vivo using NBI. Confocal videos were obtained after administration of IV fluorescein. Recorded videos were subsequently analyzed offline, blinded to endoscopic characteristics, and histopathology. Confocal images were classified as neoplastic and non-neoplastic according to the Miami classification system. Results: A total of 130 polyps (58 neoplastic, 72 non-neoplastic, mean size 4.6 mm) from 65 patients were assessed. Assuming histopathology as gold standard, pCLE had higher sensitivity than NBI (86% vs. 64%, P=0.008), with lower specificity (78% vs. 92%, p=0.027) and similar overall accuracy (82% vs. 79%, P=0.59). When 65 high-confidence cases were analyzed (polyps diagnosed identically with pCLE and NBI and with high-quality confocal videos), sensitivity and specificity were 94 and 97%. Conclusions: pCLE demonstrated higher sensitivity in predicting histology of small polyps compared with NBI, whereas NBI had higher specificity. When used in combination, the accuracy of pCLE and NBI was extremely high, approaching the accuracy of histopathology. Together, they may reduce the need for histological examination. However, further studies are warranted to evaluate the role of these techniques, especially in the population-based colon cancer screening. © 2012 by the American College of Gastroenterology.


Touil Y.,French Institute of Health and Medical Research | Igoudjil W.,Lille University Hospital Center | Corvaisier M.,Lille University Hospital Center | Dessein A.-F.,Lille University Hospital Center | And 18 more authors.
Clinical Cancer Research | Year: 2014

Purpose: Metastasis and drug resistance are the major limitations in the survival and management of patients with cancer. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of patients with colon cancer with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. Results: We show that a clonal 5F31 cell population, resistant to 1 mmol/L 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0 state upon reexposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, YES1 silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FUfreemedium. Importantly, YES1 and YAP transcript levels were higher in livermetastases of patients with colon cancer after 5FU-based neoadjuvant chemotherapy. Moreover, the YES1 and YAP transcript levels positively correlated with colon cancer relapse and shorter patient survival (P < 0.05 and P < 0.025, respectively). Conclusions: We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer. © 2014 American Association for Cancer Research.


Rizza S.,University of Rome Tor Vergata | Copetti M.,Unit of Biostatistics | Rossi C.,University of Chieti Pescara | Cianfarani M.A.,University of Rome Tor Vergata | And 9 more authors.
Atherosclerosis | Year: 2014

Aims: Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors. Methods and results: Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n=67, mean age=85±3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models.At follow-up (median=3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence=7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR=1.77 (95%CI=1.11-2.81, p=0.016) and HR=2.18 (95%CI=1.17-4.07, p=0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring. Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement=7%, p=0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI=0.79 (p=0.005). Conclusions: Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors. © 2013 Elsevier Ireland Ltd.


Knoebl P.,Medical University of Vienna | Marco P.,Hospital General Universitario | Baudo F.,Niguarda Hospital | Collins P.,University of Cardiff | And 5 more authors.
Journal of Thrombosis and Haemostasis | Year: 2012

Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by autoantibodies against coagulation factor VIII and characterized by spontaneous hemorrhage in patients with no previous family or personal history of bleeding. Although data on several AHA cohorts have been collected, limited information is available on the optimal management of AHA. Objectives: The European Acquired Hemophilia Registry (EACH2) was established to generate a prospective, large-scale, pan-European database on demographics, diagnosis, underlying disorders, bleeding characteristics, treatment and outcome of AHA patients. Results: Five hundred and one (266 male, 235 female) patients from 117 centers and 13 European countries were included in the registry between 2003 and 2008. In 467 cases, hemostasis investigations and AHA diagnosis were triggered by a bleeding event. At diagnosis, patients were a median of 73.9years. AHA was idiopathic in 51.9%; malignancy or autoimmune diseases were associated with 11.8% and 11.6% of cases. Fifty-seven per cent of the non-pregnancy-related cases were male. Four hundred and seventy-four bleeding episodes were reported at presentation, and hemostatic therapy initiated in 70.5% of patients. Delayed diagnosis significantly impacted treatment initiation in 33.5%. Four hundred and seventy-seven patients underwent immunosuppression, and 72.6% achieved complete remission. Conclusions: Representing the largest collection of consecutive AHA cases to date, EACH2 facilitates the analysis of a variety of open questions in AHA. © 2012 International Society on Thrombosis and Haemostasis.


Fontana L.,University of Salerno | Fontana L.,Washington University in St. Louis | Addante F.,Gerontology Geriatric Research Laboratory | Copetti M.,Unit of Biostatistics | And 7 more authors.
Aging Cell | Year: 2013

A combination of several metabolic and hormonal adaptations has been proposed to control aging. Little is known regarding the effects of multiple deregulations of these metabolic and hormonal systems in modulating frailty and mortality in hospitalized elderly patients. We measured 17 biological serum parameters from different metabolic/hormonal pathways in 594 hospitalized elderly patients followed up to 1 year who were stratified into three groups according to their multidimensional impairment, evaluated by a Comprehensive Geriatric Assessment (CGA)-based Multidimensional Prognostic Index (MPI). The mortality incidence rates were 7% at 1 month and 21% at 1 year. Our data show that frailty and mortality rate were positively associated with chronic inflammation and with a down-regulation of multiple endocrine factors. Of the 17 biomarkers examined, blood levels of IGF-1, triiodothyronine, C-reactive protein, erythrocyte sedimentation rate, white blood cell and lymphocyte counts, iron, albumin, total cholesterol, and LDL-c were significantly associated with both MPI severity grade and mortality. In multivariate Cox proportional hazard model, the following biomarkers most strongly predicted the risk of mortality (adjusted hazard ratio (HR) per 1 quintile increment in predictor distribution): IGF-1 HR = 0.71 (95% CI: 0.63-0.80), CRP HR = 1.48 (95% CI: 1.32-1.65), hemoglobin HR = 0.82 (95% CI: 0.73-0.92), and glucose HR = 1.17 (95% CI: 1.04-1.30). Multidimensional impairment assessed by MPI is associated with a distinctive metabolic 'signature'. The concomitant elevation of markers of inflammation, associated with a simultaneous reduction in multiple metabolic and hormonal factors, predicts mortality in hospitalized elderly patients. © 2013 John Wiley & Sons Ltd and the Anatomical Society.


Tengborn L.,Skåne University Hospital | Baudo F.,Niguarda Hospital | Huth-Kuhne A.,Kurpfalzkrankenhaus Heidelberg GmbH and Haemophilia Center | Knoebl P.,Medical University of Vienna | And 5 more authors.
BJOG: An International Journal of Obstetrics and Gynaecology | Year: 2012

Objective The European Acquired Haemophilia registry (EACH2) collected data on the demographics, diagnosis, underlying disorders, bleeding characteristics, treatment, and outcome of women with acquired haemophilia A (AHA), a rare and often severe bleeding disorder caused by autoantibodies directed against coagulation factor VIII. Design Prospective, multi-centre, large-scale, pan-European registry. Setting A total of 117 haemophilia centres in 13 European countries. Population Pregnancy-associated AHA. Methods Data were reported using a web-based electronic case report form. Diagnosis was based on the presence of a prolonged activated partial thromboplastin time, reduced coagulation Factor VIII level and positive inhibitor assay. Main outcome measures Presenting characteristics, time to diagnosis, haemostatic treatment and outcome, immunosuppressive treatment and outcome. Results The EACH2 registry (n = 501) documented 42 (8.4%) cases of AHA associated with the peripartum period, a median Factor VIII level at diagnosis of 2.5 (range 0-25) IU/dl and inhibitor titre of 7.8 (range 0.7-348) BU/ml. Antepartum inhibitors were evident in eight women. Time to diagnosis of AHA after delivery was 89 (range 21-120) days. First-line haemostatic treatment was successful in 20/23 (87%) women treated. Bleeding episodes resolved in 17/18 (94%) women treated with a bypassing agent and 29/39 (74%) women achieved complete remission with first-line immunosuppressive treatment. Two babies experienced postnatal bleeding, suggesting transplacental transfer of the antibody. All women were alive at last follow-up. Conclusions Although rare, pregnancy-associated AHA may cause severe bleeding-related morbidity. Once diagnosed, women respond well to haemostatic treatment with bypassing agents and immunosuppression. Awareness of peripartum AHA requires improvement to facilitate rapid and appropriate management. © 2012 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2012 RCOG.


Collins P.,University of Cardiff | Baudo F.,Centro Emofilia | Knoebl P.,Medical University of Vienna | Levesque H.,University of Rouen | And 5 more authors.
Blood | Year: 2012

Acquired hemophilia A (AHA) is an auto-immune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level. © 2012 by The American Society of Hematology.


Baudo F.,Thrombosis and Hemostasis Unit | Collins P.,University of Cardiff | Huth-Kuhne A.,SRH Kurpfalzkrankenhaus Heidelberg GmbH | Levesque H.,University of Rouen | And 5 more authors.
Blood | Year: 2012

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%). © 2012 by The American Society of Hematology.


Wessel M.,Karolinska Institutet | Helgesson G.,Karolinska Institutet | Olsson D.,Unit of Biostatistics | Juth N.,Karolinska Institutet | And 2 more authors.
European Journal of Public Health | Year: 2013

Background: The way in which patients experience encounters with healthcare professionals seems to affect care outcome, but very little is known about reactions evoked by experiences of negative encounters. Aims: To examine how patients perceive healthcare encounters, with a special focus on negative encounters and feeling wronged. Methods: A questionnaire was sent to 10 042 long-term sickness absentees (response rate 58%). Attributable risk (AR) with 95% confidence intervals (CIs) was calculated regarding relations between experiences of different types of negative encounters with healthcare staff and of feeling wronged. To test the consistency of our results, we also analysed the AR for positive experiences and feeling respected. Results: Of 5802 participants, 1628 reported having experienced negative encounters, and 1036 of them also reported having felt wronged. The types of negative encounters with the highest AR for feeling wronged were 'nonchalant behaviour': AR 71.1 (95% CI 66.3-75.8) and 'treated me with disrespect': AR 54.8 (95% CI 49.8-59.8). Males in general tended to have higher ARs for feeling wronged than females, as had respondents with psychiatric diagnoses in comparison to other patients. Conclusion: The present study indicates high ARs of feeling wronged among long-term sickness absentees if exposed to negative encounters in healthcare. Nonchalance and disrespect were the most important factors in this regard, but the different types of negative encounters were very much intertwined. Feeling wronged seems to be an outcome based on several experiences of negative encounters, either in a series of events or bundled together in a single event. © 2012 Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.

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