The Orthogonal Approach
The “orthogonal approach” maximizes the comprehensiveness and accuracy of the Claritas Clinical Exome and Regions of Interest tests. The result is the highest resolution interpretation and best confirmed results available today.
The DNA sample is processed using two independent DNA capture and sequencing methods, on the Illumina Next-Seq™ platform and then confirmed on LIFE Ion Torrent™ system. This translates into a combined total coverage of ~99% of the exome, higher than any one platform alone.
This also results in the immediate confirmation (see by both platforms, also called “orthogonal confirmation”) of ~90% of all variants, accelerating turnaround time and simplifying the process of variant confirmation. Of the ~10% variants that are not immediately orthogonally confirmed, most are lacking sufficient coverage on the second platform. These variants are generally true positives and may require confirmation by leveraging data from a patient’s parents in trio testing or using Sanger or another sequencing technology.
Only those variants that are both phenotypically-relevant and potentially pathogenic are analyzed. Once the analysis of all such variants is finished, a complete report is generated that provides an easy-to-understand summary with a clear interpretation of findings. The WuXi-NextCODE system, which powers our interpretation, provides an additional level of confidence through the unique ability to instantly visually confirm all findings in raw sequence reads. The data underlying the clinical exome and the filters used on the case can be accessed at any time by the ordering provider through the Claritas-WuXi-NextCODE instance.
Definition
The “Orthogonal Approach” maximizes the comprehensiveness and accuracy of Claritas Clinical Exomes and Regions of Interest.
Method Outline
The Region of Interest Approach
The Region of Interest (ROI) test approach is built on capturing the whole exome and reporting all relevant variants within a specific clinical region of interest. This allows for rapid and focused delivery of results back to ordering providers and avoids the challenges posed by secondary findings in areas not related to the phenotype. The platform on which the Claritas tests are built provides complete coverage of all genes and confirmation of nearly all variants. Therefore, virtually any set of genes can be chosen and effectively used for diagnosing patients. Gene lists can be updated with the latest science, or unusual combinations of phenotypes can be grouped together to provide the most flexible and personalized analysis of the exome. No other commercial offering provides this level of comprehensiveness or flexibility for patients needing rapid and personalized diagnoses for guiding medical decision-making.
The first iteration of this ROI approach is the Pediatric Neurology Region of Interest test which allows providers to select patient-specific disease groups to refine the aperture into a laser-focused view.
Rules-based clinical interpretation of variants
Scalable clinical reporting of exomes remains a challenge in the molecular diagnostic field. As such, clinical expertise and informaticians at Claritas, in partnership with clinical colleagues from Boston Children’s Hospital, have been developing the basic principles for scalable solutions and implementing the software systems to solve these challenges.
Our bioinformatics and software assets are a strategic differentiator for our business. We are optimizing best-in-class methods for clinical genomics interpretation of genomic variants that are reliable, repeatable, and scalable and support Claritas’ clinical testing, including assay development, report preparation, and revisable reporting.
Reporting mechanisms
The Rapid Report: Clinically-relevant results are returned within 3-4 weeks with our Rapid Report. This report provides the clinician, through rules-based interpretation, with phenotypically-relevant, high impact variants, with 90% of variants confirmed.
The Complete Report: Within 4-12 weeks, a complete report is delivered which includes additional confirmed variants, select gap-filling, and analysis of variants in regions of low coverage.
The Patient Resource: Patients rarely see their genetic results, which are typically not written with them in mind. Claritas is developing specialized reports with patients in mind with the goal that they will help providers explain test results during the clinical results-delivery process and enable patients to be active participants in their care.