Development and Validation of an Algorithm for Thrombosis with Thrombocytopenia Syndrome (TTS) at Unusual Sites

Abstract

Introduction

Thrombosis with thrombocytopenia syndrome (TTS) has been reported following receipt of adenoviral vector-based COVID-19 vaccines. However, no validation studies evaluating the accuracy of International Classification of Diseases-10-Clinical Modification (ICD-10-CM)-based algorithm for unusual site TTS are available in the published literature.

Methods

The purpose of this study was to assess the performance of clinical coding to 1) leverage literature review and clinical input to develop an ICD-10-CM-based algorithm to identify unusual site TTS as a composite outcome and 2) validate the algorithm against the Brighton Collaboration’s interim case definition using laboratory, pathology, and imaging reports in an academic health network electronic health record (EHR) within the US Food and Drug Administration (FDA) Biologics Effectiveness and Safety (BEST) Initiative. Validation of up to 50 cases per thrombosis site was conducted, with positive predictive values (PPV) and 95% confidence intervals (95% CI) calculated using pathology or imaging results as the gold standard.

Results

The algorithm identified 278 unusual site TTS cases, of which 117 (42.1%) were selected for validation. In both the algorithm-identified and validation cohorts, over 60% of patients were 56 years or older. The positive predictive value (PPV) for unusual site TTS was 76.1% (95% CI 67.2–83.2%) and at least 80% for all but one individual thrombosis diagnosis code. PPV for thrombocytopenia was 98.3% (95% CI 92.1–99.5%).

Discussion

This study represents the first report of a validated ICD-10-CM-based algorithm for unusual site TTS. A validation effort found that the algorithm performed at an intermediate-to-high PPV, suggesting that the algorithm can be used in observational studies including active surveillance of COVID-19 vaccines and other medical products.

Keywords:

• thrombosis with thrombocytopenia syndrome
• TTS
• COVID-19
• validation
• electronic health records

Acknowledgments

This work was supported by the United States Food and Drug Administration (https://www.fda.gov/) Center for Biologics Evaluation and Research under the Biologics Effectiveness and Safety Initiative [contract number HHSF223201810022I/75F40120F19003]. The funding source participated in the study design, in analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Development and validation of the unusual site TTS algorithm benefitted from significant engagement with the FDA Center for Biologics Evaluation and Research team members and their partners. We thank them for their contributions and feedback.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.