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Diagnostic yield of exome reanalysis over time: Contribution of reevaluation type, timing, and patient phenotype
Yi-Lee Ting1, Trevor J Williams1, Hillery Metz1
1Labcorp (formerly Invitae Corporation), San Francisco, CA.
Purpose:
Exome reanalysis increases diagnostic yield; yet, the optimal cadence remains unclear. We evaluated factors influencing molecular diagnosis (MolDx) during routine 6 month reanalyses.
Methods:
Exome data were reanalyzed biannually for 3 years after initial analysis. For each updated report, the timing, reason for update, and diagnostic results were examined. For clarity on clinical indications, we performed a cluster analysis using human phenotype ontology terms to define patient phenotypic clusters. Logistic regression was performed on factors influencing MolDx.
Results:
The overall MolDx rate increased from 18.3% to 20.4% by the end of the study. Diagnostic rate from reanalysis was 2.6% for nondiagnostic reports with the highest rate occurring approximately 2 years after the initial report. The 21 patient clusters demonstrated significant differences in mean age at testing and MolDx rates. Initial and reanalysis MolDx rates ranged from 3.9% to 37.7% and 0% to 7.3%, respectively. No one factor drove the increase in MolDx.
Conclusion:
Cluster analysis offered refined guidance on the diagnostic utility of reanalysis based on clinical indication and age, with pediatric clusters having higher MolDx rates at initial analysis and upon reanalysis than adults. Automated processes and tools enable more frequent reanalyses, reducing the wait time for patients to receive a MolDx.
Insights
Routine exome reanalysis improves molecular diagnosis (MolDx) rates over time. Patient characteristics, identified through cluster analysis, refine understanding of reanalysis utility, especially for pediatric cases.
Area of Science:
- Genomics
- Clinical Diagnostics
- Bioinformatics
Background:
- Exome reanalysis is crucial for increasing diagnostic yield in genetic disorders.
- The optimal frequency for exome reanalysis remains an area of active investigation.
Purpose of the Study:
- To evaluate factors influencing molecular diagnosis (MolDx) during routine, biannual exome reanalyses.
- To determine the diagnostic utility of exome reanalysis based on clinical indications and patient demographics.
Main Methods:
- Exome data were reanalyzed biannually for three years.
- Human Phenotype Ontology (HPO) terms were used for cluster analysis of patient phenotypes.
- Logistic regression analyzed factors impacting MolDx.
Main Results:
- The overall MolDx rate increased from 18.3% to 20.4% during the study.
- Reanalysis yielded a 2.6% diagnostic rate, peaking around two years post-initial analysis.
- Patient clusters showed significant variations in age and MolDx rates.
Conclusions:
- Cluster analysis provides guidance on reanalysis utility, with pediatric groups showing higher MolDx.
- Automated reanalysis processes can reduce patient wait times for molecular diagnoses.
