Predicting inhibitor development using a random peptide phage-display library approach in the SIPPET cohort

Blood Advances, vol. 8, pp. 2880–2889

Abstract

ABSTRACT: Inhibitor development is the most severe complication of hemophilia A (HA) care and is associated with increased morbidity and mortality. This study aimed to use a novel immunoglobulin G epitope mapping method to explore the factor VIII (FVIII)-specific epitope profile in the SIPPET cohort population and to develop an epitope mapping-based inhibitor prediction model. The population consisted of 122 previously untreated patients with severe HA who were followed up for 50 days of exposure to FVIII or 3 years, whichever occurred first. Sampling was performed before FVIII treatment and at the end of the follow-up. The outcome was inhibitor development. The FVIII epitope repertoire was assessed by means of a novel random peptide phage-display assay. A least absolute shrinkage and selection operator (LASSO) regression model and a random forest model were fitted on posttreatment sample data and validated in pretreatment sample data. The predictive performance of these models was assessed by the C-statistic and a calibration plot. We identified 27 775 peptides putatively directed against FVIII, which were used as input for the statistical models. The C-statistic of the LASSO and random forest models were good at 0.78 (95% confidence interval [CI], 0.69-0.86) and 0.80 (95% CI, 0.72-0.89). Model calibration of both models was moderately good. Two statistical models, developed on data from a novel random peptide phage display assay, were used to predict inhibitor development before exposure to exogenous FVIII. These models can be used to set up diagnostic tests that predict the risk of inhibitor development before starting treatment with FVIII.

Authors 11

1. Shermarke Hassan Aachen 2Department of Clinical Epidemiology

   University of Milan · Leiden University Medical Center

   Affiliation as printed

   1Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

   2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

2. Guido Baselli

   Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

   Affiliation as printed

   3Department of Transfusion Medicine and Hematology, Translational Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy

3. Riccardo Lorenzo Rossi

   Istituto Nazionale Genetica Molecolare

   Affiliation as printed

   5Bioinformatics, Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi,” Milan, Italy

4. Amal M. El-Beshlawy

   Cairo University · Cairo University hospitals

   Affiliation as printed

   6Pediatric Hematology Department, Cairo University Pediatric Hospital, Cairo, Egypt

5. Mohsen Saleh Elalfy

   Ain Shams University

   Affiliation as printed

   7Faculty of Medicine, Ain Shams University, Department of Pediatrics, Cairo, Egypt

6. Vijay Ramanan

   Jehangir Hospital · Jehangir Clinical development Centre

   Affiliation as printed

   8Department of Hematology, Jehangir Clinical Development Centre, Jehangir Hospital Premises, Pune, India

7. Peyman Eshghi

   Shahid Beheshti University · Shahid Beheshti University of Medical Sciences

   Affiliation as printed

   9Congenital Pediatric Hematologic Disorders Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran

8. Mehran Karimi
   Affiliation as printed

   10Pediatric Hematology-Oncology Department, American Hospital Dubai, Dubai, United Arab Emirates

9. Roberta Palla

   University of Milan

   Affiliation as printed

   1Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy

10. Frits Richard Rosendaal Aachen 2Department of Clinical Epidemiology

    Leiden University Medical Center

    Affiliation as printed

    2Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands

11. Flora Peyvandi corresponding

    University of Milan · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

    Affiliation as printed

    11Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy

    1Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy