To the Editors:
Loss to follow-up (LTFU) is a serious concern in longitudinal research studies. High LTFU rates can bias study results,1 particularly if the reasons for the losses are related to the outcomes under investigation. When the death of a study participant goes unrecognized or unreported, a crucial endpoint goes undocumented while research staff may continue efforts to pursue contact, leading to the unnecessary use of study resources.
The Pediatric HIV/AIDS Cohort Study (PHACS) is a multisite cohort study of the effects of HIV infection and antiretroviral medication use in youth and young adults born with HIV or uninfected but exposed to HIV at birth.2,3 PHACS opened to enrollment in 2007 at 24 study sites in the United States. In 2015, a search of the National Death Index (NDI) was implemented to identify previously unreported deaths among LTFU participants among the 4207 participants enrolled in 2 PHACS youth cohorts. Given that death is a primary outcome measure in PHACS, it is important to determine whether the reason that contact ceased is due to a participant's death.
The NDI is a centralized database of death record information on file in US state vital statistics offices. It is maintained by the National Center for Health Statistics for the purpose of research. It is widely used to obtain outcome data in mortality studies; the NDI webpage provides a reference list of 658 peer-reviewed articles from studies using NDI data.4
Permission to conduct an NDI search is obtained by completing a 23-page application. Confidentiality agreements, institutional signatures, Institutional Review Board approval letters, and other supporting documents must be provided on behalf of all individuals who will have access to the search results. PHACS is a collaboration between 9 NIH institutes and close to 30 academic and research institutions, including study sites, 2 leadership centers based at Harvard and Tulane Universities, a contract research organization (CRO), and a data management center (DMC). To reduce the effort required to complete the application, the submission process was delegated to the CRO. The handling of the output files produced by the search was limited to the CRO, the DMC, and the leadership center at Harvard. Nonetheless, the information and supporting documentation required for the application was substantially greater than for studies for which a single applicant could handle both the application and the output files produced from the search.
The compilation of the user records, which contain the identifying information necessary to conduct a search, required coordination among staff from all study sites. To facilitate the task of identifying LTFU participants, the DMC used information from the study database to create lists for review by sites of participants meeting the study's LTFU definition of “no contact for 2 consecutive study visit windows, or approximately 2.5 years.” Because participants are identified by randomly generated Participant Identifiers in the study database, once staff confirmed that a participant was indeed LTFU (versus missing 2 study visits but still in contact with the site), they needed to take the additional step of replacing the Participant Identifier with his/her name in order for CRO staff to create user records to submit for the search.
Across all sites, LTFU status was confirmed for 231 of 4218 participants (5.5%). User records were created pursuant to the NDI User's Guide for specific data coding and specifications, and included first and last names, sex, and dates and states of birth.
Possible matches were produced for 95 of the 231 user records. PHACS investigators reviewed the output and concluded that only one record was a true match, and a death certificate was obtained for confirmation. Using the NDI, PHACS was able to document one previously unidentified death among the 231 LTFU study participants (0.4%).
The process of completing the application to conduct the NDI search, collecting the required information from the clinical sites to create the user records, and handling and interpreting the output files proved complicated and time-consuming for a multisite research network like PHACS. The PHACS investigators concluded that the additional data gained from the search did not justify the resources invested to complete the application, compile the user submission records, and review the search results. Subsequent searches are unlikely to be pursued.
It is unclear whether the search produced only one true match because there were additional, actual deaths that were not identified or because there was indeed only one death among the LTFU participants. There are several factors that may support the conclusion that there may be actual deaths that the search did not identify. The likelihood of receiving a match increases according to the level of personal information that can be provided. In an HIV study, where confidentiality is of paramount importance, research staff are sensitive to the desire to limit the collection of personally identifying information. Published studies documenting the utility of the NDI in establishing deaths among study cohorts were typically able to provide social security numbers,5,6 which PHACS does not collect from study participants. Also, NDI records are limited to deaths occurring within the United States. PHACS study sites serve a diverse patient population. Although the large majority (>99%) of participants enrolled in the 2 youth cohorts for which the NDI search was conducted were born in the United States, 32% of caregivers of participants in the perinatally exposed, uninfected cohort and 28% of caregivers of participants in the perinatally HIV infected cohort were born outside the United States. Site staff report that it is not unusual for youth participants to move frequently between the area where the study site is located and their primary caregivers' country of birth, increasing the likelihood that a death may take place outside the country. Given these circumstances, an NDI search may be a more worthwhile investment of resources for studies that can provide more personally identifying information or have a less diverse, more geographically stable cohort.
There is also evidence to support the conclusion that the single, true match was indeed the only death occurring among the LTFU group. PHACS is a clinic-based study for which participants provide permission to access their medical records, and often the clinic is also a direct health care provider to the participants. As a result, study staff may be more likely to learn of participant deaths as they occur, reducing the likelihood that there are unidentified deaths. In addition, the average age of PHACS LTFU participants was 10 years. Although the NDI has been used with success to document mortality among HIV cohorts,7,8 the younger age of the PHACS cohort, advances in HIV care in the United States, and better engagement with care among youth versus adults may reduce the risk of mortality in this pediatric cohort.9,10 Among the 3986 participants not LTFU, there have been 27 participant deaths (<1%) since PHACS opened to enrollment 10 years before the initiation of the search. It may be reasonable to conclude that the observation of one death among the 241 LTFU participants is valid when considered within this context. Moreover, most PHACS participants were born to women infected with HIV but were not infected themselves and thus may not be subject to the same mortality risk as participants in other HIV cohort studies. An NDI search may be a more productive effort for studies of cohorts with a higher mean age or which anticipate higher mortality rates based on the health status of their study participants.
The NDI offered limited utility in identifying previously unrecognized participant deaths in this clinic-based, multisite pediatric study. Although it was a benefit to the study to be able to identify even one previously unknown death, given that death is the most serious outcome that can be documented, the resources required to conduct an NDI search led us to conclude that it may not be a time- or cost-effective approach to obtaining mortality data for studies with a design or cohort characteristics similar to PHACS. We recommend the application process be streamlined to reduce the time, effort, and resources required to complete an application to conduct an NDI search for a multi-institution study.
The authors thank the children and families for their participation in PHACS, and the individuals and institutions involved in the conduct of PHACS. The study was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with cofunding from the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, the Office of AIDS Research, the National Institute of Mental Health, the National Institute of Neurological Disorders and Stroke, the National Institute on Deafness and Other Communication Disorders, the National Institute of Dental and Craniofacial Research, and the National Institute on Alcohol Abuse and Alcoholism, through cooperative agreements with the Harvard T.H. Chan School of Public Health (HD052102) and the Tulane University School of Medicine (HD052104). Data management services were provided by Frontier Science and Technology Research Foundation, and regulatory services and logistical support were provided by Westat, Inc.
The following institutions, clinical site investigators, and staff participated in conducting PHACS SMARTT in 2017, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ellen Chadwick, Margaret Ann Sanders, Kathleen Malee, Scott Hunter; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Emma Stuard, Mahboobullah Mirza Baig, Alma Villegas; Children's Diagnostic & Treatment Center: Ana Puga, Dia Cooley, Patricia A. Garvie, James Blood; New York University School of Medicine: William Borkowsky, Sandra Deygoo, Marsha Vasserman; Rutgers New Jersey Medical School: Arry Dieudonne, Linda Bettica, Juliette Johnson; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins, Jamie Russell-Bell; San Juan Hospital/Department of Pediatrics: Nicolas Rosario, Lourdes Angeli-Nieves, Vivian Olivera; SUNY Downstate Medical Center: Stephan Kohlhoff, Ava Dennie, Ady Ben-Israel, Jean Kaye; Tulane University School of Medicine: Russell Van Dyke, Karen Craig, Patricia Sirois; University of Alabama, Birmingham: Marilyn Crain, Paige Hickman, Dan Marullo; University of California, San Diego: Stephen A. Spector, Kim Norris, Sharon Nichols; University of Colorado, Denver: Elizabeth McFarland, Emily Barr, Christine Kwon, Carrie Chambers; University of Florida, Center for HIV/AIDS Research, Education and Service: Mobeen Rathore, Kristi Stowers, Saniyyah Mahmoudi, Nizar Maraqa, Laurie Kirkland; University of Illinois, Chicago: Karen Hayani, Lourdes Richardson, Renee Smith, Alina Miller; University of Miami: Gwendolyn Scott, Sady Dominguez, Jenniffer Jimenez, Anai Cuadra; Keck Medicine of the University of Southern California: Toni Frederick, Mariam Davtyan, Guadalupe Morales-Avendano, Janielle Jackson-Alvarez; and University of Puerto Rico School of Medicine, Medical Science Campus: Zoe M. Rodriguez, Ibet Heyer, Nydia Scalley Trifilio.
The following institutions, clinical site investigators, and staff participated in conducting PHACS AMP and AMP Up in 2017, in alphabetical order: Ann & Robert H. Lurie Children's Hospital of Chicago: Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Yoonsun Pyun; Baylor College of Medicine: William Shearer, Mary Paul, Norma Cooper, Lynnette Harris; Bronx Lebanon Hospital Center: Murli Purswani, Mahboobullah Mirza Baig, Alma Villegas; Children's Diagnostic & Treatment Center: Ana Puga, Sandra Navarro, Patricia A. Garvie, James Blood; Boston Children's Hospital: Sandra K. Burchett, Nancy Karthas, Betsy Kammerer; Jacobi Medical Center: Andrew Wiznia, Marlene Burey, Ray Shaw, Raphaelle Auguste; Rutgers—New Jersey Medical School: Arry Dieudonne, Linda Bettica, Juliette Johnson; St. Christopher's Hospital for Children: Janet S. Chen, Maria Garcia Bulkley, Taesha White, Mitzie Grant; St. Jude Children's Research Hospital: Katherine Knapp, Kim Allison, Megan Wilkins, Jamie Russell-Bell; San Juan Hospital/Department of Pediatrics: Midnela Acevedo-Flores, Heida Rios, Vivian Olivera; Tulane University School of Medicine: Margarita Silio, Medea Gabriel, Patricia Sirois; University of California, San Diego: Stephen A. Spector, Kim Norris, Sharon Nichols; University of Colorado Denver Health Sciences Center: Elizabeth McFarland, Emily Barr, Carrie Glenny, Jennifer Dunn; and University of Miami: Gwendolyn Scott, Grace Alvarez, Gabriel Fernandez, Anai Cuadra.
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