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Nam K.,Merck And Co. | Henderson N.C.,Johns Hopkins University | Rohan P.,Office of Biostatistics and Epidemiology | Woo E.J.,Office of Biostatistics and Epidemiology | Russek-Cohen E.,Office of Biostatistics and Epidemiology
Journal of Biopharmaceutical Statistics | Year: 2017

The Vaccine Adverse Event Reporting System (VAERS) and other product surveillance systems compile reports of product-associated adverse events (AEs), and these reports may include a wide range of information including age, gender, and concomitant vaccines. Controlling for possible confounding variables such as these is an important task when utilizing surveillance systems to monitor post-market product safety. A common method for handling possible confounders is to compare observed product–AE combinations with adjusted baseline frequencies where the adjustments are made by stratifying on observable characteristics. Though approaches such as these have proven to be useful, in this article we propose a more flexible logistic regression approach which allows for covariates of all types rather than relying solely on stratification. Indeed, a main advantage of our approach is that the general regression framework provides flexibility to incorporate additional information such as demographic factors and concomitant vaccines. As part of our covariate-adjusted method, we outline a procedure for signal detection that accounts for multiple comparisons and controls the overall Type 1 error rate. To demonstrate the effectiveness of our approach, we illustrate our method with an example involving febrile convulsion, and we further evaluate its performance in a series of simulation studies. © 2017, Taylor & Francis. All rights reserved.


PubMed | Office of Biostatistics and Epidemiology and CBER FDA
Type: Journal Article | Journal: Hepatology (Baltimore, Md.) | Year: 2015

Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003).These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins.


Kachko A.,CBER FDA | Frey S.E.,Saint Louis University | Sirota L.,Office of Biostatistics and Epidemiology | Ray R.,Saint Louis University | And 4 more authors.
Hepatology | Year: 2015

Hepatitis C virus (HCV) neutralization occurring at the E2 region 412-426 (EP-I) could be enhanced when antibodies directed specifically to the E2 region 434-446 (EP-II) were removed from serum samples of persistently infected patients and vaccinated chimpanzees, a phenomenon of so-called antibody interference. Here, we show that this type of interference can be observed in individuals after immunization with recombinant E1E2 proteins. One hundred twelve blinded serum samples from a phase I, placebo-controlled, dose escalation trial using recombinant HCV E1E2 with MF59C.1 adjuvant in healthy HCV-negative adults were tested in enzyme-linked immunosorbent assay for binding reactivity to peptides representing the E2 regions 412-426 (EP-I) and 434-446 (EP-II). All samples were subsequently tested for neutralizing activity using cell-culture HCV 1a(H77)/2a chimera, HCV pseudotype particles (HCVpp) H77, and HCVpp HCV-1 after treatment to remove EP-II-specific antibodies or mock treatment with a control peptide. Among the 112 serum samples, we found 22 double positive (EP-I and EP-II), 6 EP-II positive only, 14 EP-I positive only, and 70 double negative. Depleting EP-II antibodies from double-positive serum samples increased 50% inhibitory dose (ID50) neutralizing antibody titers (up to 4.9-fold) in up to 72% of samples (P ≤ 0.0005), contrasting with ID50 neutralization titer increases in 2 of 70 double-negative samples (2.9%; P > 0.5). In addition, EP-I-specific antibody levels in serum samples showed a significant correlation with ID50 neutralization titers when EP-II antibodies were removed (P < 0.0003). Conclusion: These data show that antibodies to the region 434-446 are induced during immunization of individuals with recombinant E1E2 proteins, and that these antibodies can mask effective neutralizing activity from EP-I-specific antibodies. Elicitation of EP-II-specific antibodies with interfering capacity should be avoided in producing an effective cross-neutralizing vaccine aimed at the HCV envelope proteins. © 2015 by the American Association for the Study of Liver Diseases.


Mallick T.K.,Office of Biostatistics and Epidemiology | Mosquera A.,Office of Biostatistics and Epidemiology | Zinderman C.E.,Office of Biostatistics and Epidemiology | Martin L.St.,Office of Cellular | Wise R.P.,Office of Biostatistics and Epidemiology
Cell and Tissue Banking | Year: 2012

Processors distributed about 1.5 million human tissue allografts in the U.S. in 2007. The potential for transmitting infections through allografts concerns clinicians and patients. In 2005, FDA implemented Current Good Tissue Practice (CGTP) rules requiring tissue establishments to report to FDA certain serious infections after allograft transplantations. We describe infection reports following tissue transplants received by FDA from 2005 through June, 2010, and compare reporting before and after implementation of CGTP rules. We identified reports received by FDA from January 2001 through June, 2010, for infections in human tissue recipients, examining the reports by tissue type, organism, time to onset, severity, and reporter characteristics. Among 562 reports, 83 (20.8/year) were received from 2001-2004, before the CGTP rules, 43 in the 2005 transition year, and 436 (96.9/year) from 2006 through June, 2010, after the rules. Tissue processors accounted for 84.2% of reports submitted after the rules, compared to 26.5% previously. Bacterial infections were the most commonly reported organisms before (64.6%) and after (62.2%) the new rules. Afterward, 2.5% (11) of reports described deaths, and 33.7% (147) involved hospitalizations. Before the rules, 13% (11) described deaths, and another 72% involved hospitalizations. Reports received by the FDA quadrupled since 2005, suggesting that CGTP regulations have contributed to increased reporting and improved tissue safety surveillance. However, these data do not confirm that the reported infections were caused by suspect tissues; most reports may represent routine postsurgical infections not actually due to allografts. © 2011 Springer Science+Business Media B.V. (outside the USA).


Ball R.,Office of Biostatistics and Epidemiology
Expert Review of Vaccines | Year: 2014

Strong, scientifically-based postmarket safety surveillance is critical to maintaining public confidence in vaccinations and reducing the burden from vaccine-preventable diseases. The infrastructure and scientific methods for postmarket safety surveillance have continuously improved over the last 30 years, with major enhancements in the last decade. Supporting and enhancing this system will continue to be important as the number of vaccines and people vaccinated expands globally. © 2014 Informa UK, Ltd.


PubMed | Office of Biostatistics and Epidemiology and Booz Allen Hamilton
Type: | Journal: Studies in health technology and informatics | Year: 2014

The medical review of adverse event reports for medical products requires the processing of big data stored in spontaneous reporting systems, such as the US Vaccine Adverse Event Reporting System (VAERS). VAERS data are not well suited to traditional statistical analyses so we developed the FDA Adverse Event Network Analyzer (AENA) and three novel network analysis approaches to extract information from these data. Our new approaches include a weighting scheme based on co-occurring triplets in reports, a visualization layout inspired by the islands algorithm, and a network growth methodology for the detection of outliers. We explored and verified these approaches by analysing the historical signal of Intussusception (IS) after the administration of RotaShield vaccine (RV) in 1999. We believe that our study supports the use of AENA for pattern recognition in medical product safety and other clinical data.

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