Autoantibodies

Sequential steps in causality assessment are outlined in Fig. 1. Complete clinical data, including serial laboratory test results together with the local ULN values, were extracted from the clinical records and entered into a 65-page case report form (CRF). To exclude conditions that can mimic drug-induced liver disease, the patients and their medical records were screened for previous liver disease, alcohol use, serological and virological evidence of hepatitis A, B, or C infection, autoantibodies, ceruloplasmin, alpha-1-antitrypsin, ferritin, and iron; additionally, results of imaging studies were reviewed. Patients who had not been fully evaluated when they were first identified underwent testing for any missing laboratory data at enrollment. Liver biopsy was not required for adjudication purposes, but if it was performed as part of routine clinical care, the results were collected and made available to reviewers. To facilitate adjudication, the extensive database was summarized in an abbreviated CRF that included such key elements as the date of onset of liver injury, complete information about all medications taken within 6 months of onset of the event, the presence of symptoms and signs of liver disease, pertinent past medical history, complete laboratory tests, imaging and liver biopsy results, and serial results for ALT, AST, AP, serum bilirubin, and the prothrombin time or INR.
In addition to the short CRF summary, a succinct case summary called the clinical narrative was completed by the study investigator who enrolled the subject. The narrative provided detailed information on the history and chronology of the illness with dates of drug initiation and liver disease onset, pertinent features of the liver disease, and the time to improvement or recovery. The narrative also included information on past use of the implicated agent and significant concomitant drugs, the past medical history, the extent of alcohol use, whether there had been an episode of hypotension, and information on the course of the illness, including hospitalization, a history of hepatic decompensation or organ failure, and death or liver transplantation. Finally, the investigator provided a rationale for ascribing the event to a specific medication or medications without offering a personal view on the estimated strength of the association.

TEDDY enrolled children younger than 4.5 months of age from December 2004 to July 2010 through newborn screening for high risk HLA-DR-DQ genotypes at six centers: three in the US at the Pacific Northwest Diabetes Research Institute, Seattle, Washington; the Barbara Davis Center, Denver, Colorado; a combined Georgia/Florida site at the Medical College of Georgia, Augusta, Georgia and the University of Florida, Gainesville, Florida; and three in Europe at University of Turku, (Turku, Oulu and Tampere, Finland); Lund University, Malmo, Sweden; and the Diabetes Research Institute, Munich, Germany. Detailed study design and methods have been previously published (11 (link), 12 ). Written informed consents were obtained for all study participants from a parent or primary caretaker, separately, for genetic screening and participation in prospective follow-up. The study was approved by local Institutional Review Boards and is monitored by External Evaluation Committee formed by the National Institutes of Health.
The first primary endpoint in TEDDY is the appearance of persistent confirmed islet autoimmunity (IA). Persistent confirmed IA is defined as the presence of one confirmed autoantibody (GAD65A, IA-2A, or IAA) on two or more consecutive samples. IAs are measured in two laboratories (Barbara Davis Center, Aurora, Colorado and the University of Bristol Laboratory, Bristol, UK) depending upon the location of the clinical site. All samples identified as positive in one TEDDY laboratory are sent to the other laboratory for confirmation (13 (link)). The second primary outcome is the clinical appearance of T1D as defined using the American Diabetes Association criteria (14 ).
The TEDDY study collects participants’ stool, plasma, serum, red blood cells, peripheral blood mononuclear cells (PBMCs), along with extensive questionnaire data. Blood sample collection begins at the 3 month study visit and continues at a 3 month interval up to 4 years of age. If a subject develops persistent IA, then they continue on the 3 month interval schedule up to age 15 years; otherwise, they switch to a 6 month interval schedule. In addition, the child’s parent collects at least 5g of the child’s stool each month (up until 48 months of age, then every 3 months until the age of 10 years, and then biannually thereafter) into the three plastic stool containers provided by the clinical center. All samples have been stored at a central TEDDY repository by following the centralized DCC instructions (15 )