The Value of Population Based Data to Study Rare Diseases: An Example Using the Department of Defense Healthcare System
Authors: Ulcickas Yood Marianne , Jick Susan , Vasilakis-Scaramozza Catherine , Donato Bonnie M.K. , Tomazos Ioannis , L'Italien Gilbert , Sicignano Nicholas , Feldman Brian L. 
Published: October 2019

Abstract
Background: For patients suffering from rare diseases, accurate and early diagnosis is critical and often lifesaving, whereas misdiagnosis can be fatal. While patient registries are useful and necessary, they may not provide reliable patient population denominators or sufficient longitudinal clinical follow-up. Access to complete and integrated patient records necessary to capture full clinical history can be challenging. Commonly, there is a lack of centralized and continuous care in the health care systems of many countries, including the United States (US). It is also challenging to identify a sufficient number of cases to provide robust results because of the rare nature of these diseases. We describe a healthcare system that can identify patients for research purposes, who have rare diseases, by accessing de-identified electronic clinical details. We used Paroxysmal Nocturnal Hemoglobinuria (PNH) as an example of a rare disease for this abstract.
Methods: The Department of Defense (DOD) healthcare system is a US-based, longitudinal electronic health record (EHR) and claims database with health information on approximately 10 million active beneficiaries across the country. We evaluated the feasibility to conduct studies of rare diseases in the DOD healthcare system by assessing the capability to identify patients with PNH and to describe their course of disease and treatment. We used ICD 9/10 diagnosis codes, NDC and HCPCS codes, laboratory data and PNH treatment codes to identify patients with a clinical course consistent with PNH. Patients were classified as definite/likely, probable/possible or unlikely PNH based on the available clinical evidence and then findings were validated against review of patient records by a clinical expert. Individuals classified as unlikely PNH were excluded from the study. The clinical information on these patients will be used to understand the course of PNH in patients with and without treatments and to describe their treatment adherence and disease activity over time.
Results: We identified 244 people with a diagnosis or treatment code that was indicative of PNH during years 2007-2017; 71% of the patients had electronic records that covered 10 or more years starting as early as 2003 and extending as far as 2017. From these 244 patients, we identified 73 patients with a definite/likely or probable/ possible PNH diagnosis. An ICD-10 code for PNH or a prescription for eculizumab (PNH treatment) were required, but not sufficient to confirm the presence of PNH. There is no ICD-9 code for PNH. Cases had no other indication for eculizumab use and had to have appropriate symptoms, comorbidities or lab results to be considered a case. Patients with only 1 code for PNH and no treatment were assumed to have unconfirmed disease and were excluded. 27 cases, including those with no eculizumab and a random sample of likely cases, were reviewed to validate the PNH diagnoses in collaboration with DOD treating physicians.
Conclusion: The DOD healthcare system is a valuable and cost effective resource for the study of rare diseases in a timely manner. We have demonstrated the ability to identify a validated series of PNH cases that will provide important clinical insights for identifying and treating new PNH cases. This healthcare system provides long patient follow-up, demographics similar to the US population, and access to records in an integrated inpatient, outpatient and ER system that encompasses all patient care.
Disclaimer Statement: Research data were derived from an approved Naval Medical Center, Portsmouth, VA IRB protocol (NMCP.2017.0080). The views expressed in this abstract are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense or the United States Government. Copyright Notice: CAPT Brian Feldman is a military service member. This work was prepared as part of his official duties. Title 17 U.S.C. 105 provides that 'Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person's official duties.

Disclosures
Ulcickas Yood: Alexion Pharmaceuticals, Inc.: Other: Employee of EpiSource, LLC, which was contracted by Alexion Pharmaceuticals, Inc. EpiSource had the final decision on content. . Jick:Alexion Pharmaceuticals, Inc.: Other: Employee of the Boston Collaborative Drug Surveillance Program, which was contracted and paid by Alexion Pharmaceuticals, Inc. to work on a study of PNH using DOD data. . Vasilakis-Scaramozza:Alexion Pharmaceuticals, Inc.: Other: Employee of the Boston Collaborative Drug Surveillance Program, which was contracted and paid by Alexion Pharmaceuticals, Inc. to work on a study of PNH using DOD data.. Donato:Alexion Pharmaceuticals Inc: Employment, Equity Ownership. Tomazos:Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. L'Italien:Alexion Pharmaceuticals, Inc.: Equity Ownership, Other: Former employee and current stockholder of Alexion Pharmaceuticals, Inc. . Sicignano:Alexion Pharmaceuticals, Inc.: Other: Employee of Health ResearchTx, which has a business relationship with Alexion Pharmaceuticals, Inc.. Feldman:Alexion Pharmaceuticals, Inc.: Other: Employee, Department of Navy, United States Government..