Copy Number and AOH Detection from NGS

High-quality detection of CNV from NGS data has been a challenge for many years. BioDiscovery has perfected algorithms for the detection of CNV and AOH from almost all NGS assays.

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Algorithms for CNV and AOH Detection

BioDiscovery has developed two algorithms for the detection of CNV and AOH events from NGS using its decades-long expertise in the area. One algorithm, the “Self-reference” algorithm, can be used for all WGS data regardless of sequencing depth. The second is the “Multi-Scale Reference” (MSR) algorithm that is applicable to all NGS data (WGS, WES, and Gene panels). The MSR algorithm is able to create “virtual” bins with sizes proportional to the expected number of reads offering high-resolution detection of events in areas of interest (e.g. exons) while also providing a nice genome-wide backbone.

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Whole Exome Sequencing

Getting CNV calls from Whole Exome Sequencing has been one of the most challenging efforts in the community. There have been numerous algorithms proposed but they suffer either from poor sensitivity or too many false-positive calls. The MSR algorithm has been able to offer the best balance of these competing measures, detecting small true-positives without generating many false-positives. The image below shows a small 12Kb deletion overlapping part of MECP2 gene resulting in only 2 virtual probes indicating a small copy number loss. At the same time, with such sensitivity, only four other CNVs were detected that passed the basic filtering stage demonstrating a very low false-positive rate.

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Whole Genome Sequencing

As described in Chaubey et al., Journal of Molecular Diagnostics, vol. 22, No. 6 June 2020, they used 10x WGS and validated that the N_xClinical algorithm detected all CNVs and AOH that were found by high-resolution SNP arrays. Figure 2. shows a small exonic deletion detected using 10x WGS with the MSR algorithm.

With higher depth NGS, smaller CNVs can be detected and integrated with sequence variants to provide a holistic view of the sample. In Figure 3., the ideogram shows regions of copy number gain (blue bars), loss (red bars), AOH (yellow shading), Allelic Imbalance (purple shading), as well as various types of Sequence Variants (e.g., SNV, In/Del, etc.) as colored “lollipops”.

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Figure 4. Shows the log R whole genome view of TSO-500 panel in NxClinical. By using a virtual probe strategy, NxClinical gives a much richer view of the whole genome than would be expected by a 500 gene panel. enlarge in a new tab »

Gene Panels

The MSR algorithm can be applied to any gene panel from single gene (e.g. DMD test) to large panels having thousands of gene. The image below is from the Illumina TruSight^TM Oncology 500 (TSO500) panel showing a somatic cancer profile. The cytogenetic complexity of the tumor sample is clearly evident with a large copy number gain of 8p and loss of a large section of 13q. Aberrations associated with genomic scarring, such as Loss of Heterozygosity (LOH), telomeric allelic imbalances (TAI), and large-scale state transitions (LST) can be visualized and manually called with confidence.

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Figure 5. A large duplication event affecting the q arm of chromosome 21. enlarge screen in new tab »

Shallow Sequencing

The MSR algorithm can also be applied to detect CNVs from shallow sequencing, including very low-level mosaic events seen in NIPS or ctDNA samples. The image below shows a sample with trisomy 21 detected using 1x WGS.

CNVs are an important contributor to disease and are required for accurate diagnosis. For clinical sequencing to be fully accepted as a replacement for microarrays and other widely used techniques, it must provide high-quality CNV information. NxClinical can easily and accurately provide that information from various approaches using NGS data.

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Detect, display, and decide—all from one place.

Detect.

You can’t diagnose what you can’t see. N_xClinical is the gold standard for calling CNVs from NGS data generated on any platform.

Display.

Context is everything! N_xClinical provides integrated analysis and raw data visualization of CNV, SNV, and AOH simultaneously on the same screen for each patient sample.

Decide.

Make the right call in record time. AI-driven tools and extensive automation enable rapid and accurate interpretation. Active links to the latest databases keep your knowledge base fresh and up-to-date.

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Get the software trusted by renowned academic and commercial clinical labs to stay on top of demanding, time-sensitive workloads.

Achieve the speed, confidence, and capability clinical labs need to make the right call—fast.

Analyze across different platforms.

N_xClinical enables combined analysis and interpretation of all genomic variants on a single, platform-agnostic system. It’s fully integrated and future-proof.

Analyze and interpret from a single screen.

N_xClinical presents all the important information for evaluation on a single screen for quick and confident interpretation of variants. The layout automatically adjusts to the type of variant (e.g. CNV vs. SeqVar) as well as test type (Oncology vs. Constitutional).

Store variant and genomic region data.

N_xClinical enables your lab to collect, organize, and use CNV and AOH events from its own constitutional or oncology case history to create consistent interpretations and reports.

Put your case history and genetic databases to work.

Stop leaving past data behind. N_xClinical’s automatic in-house case history and integrated genetic databases enable you to load and use all prior case data to continually enhance classifications.

Resolve cases faster and minimize TAT with automation, AI, and variant prioritization tools.

Automated workflows mirror your lab’s interpretation rules and/or regional guidelines. Automated processes reduce errors. Automatically pre-classify events and filter false-negative results. Phenotype-driven variant prioritization (SAP scoring) using standardized vocabulary (HPO) quickly ranks clinically relevant events.

Free webinar: Increasing the yield of whole exome sequencing (WES) with copy number variant (CNV) analysis »

Maximize clinical utility and diagnostic yield.

Simultaneous review of SNV, CNV, and AOH increases diagnostic yield. NxClinical is unique in that it stores NGS data in the same database, allowing you to review and interpret all events (CNV, AOH, and sequence variants) simultaneously for a single sample. Uncover synergistic events (e.g. a deletion of a recessive gene that also has a LOF mutation) which may not be easily revealed when using different software for each modality.

Dr. Sharon Mexal

Senior Director of Clinical Operations, Ambry Genetics

We were eager to be part of the Early Access program and try out N_xClinical. We have now been using N_xClinical for many years and each release has features that we find really useful. BioDiscovery has also been very receptive to feedback from us on feature requests and we are happy to see many of those implemented as they make our interpretation process even easier.

Todd Ackely

Manager, Michigan Molecular Genetics Laboratory (MMGL)

My CAP/CLIA clinical lab has used BioDiscovery CNV software since 2012. I have evaluated many CNV analysis software programs and the BioDiscovery software always has been the best choice for my lab. BioDiscovery listens to their customers and utilizes this information to improve and refine their software for clinical laboratories.

Liqiang Song

Be Creative Lab

N_xClinical software allows us to comprehensively analyze CNV,LOH and sequence variants together. The local database functionality has provided a lot of valuable experience for us. We can directly access up-to-date integrated database within N_xClinical software and add tracks to the genome browser for clinical analysis requirements.

Dr. Sarah Murray

Director of Genomics Technologies, UC San Diego

At the UCSD clinical genetics lab, we are tasked with providing a complete and clinically actionable genomic profile of a patient’s tumor. N_xClinical allows us to do this rapidly and comprehensively by allowing us to consider CNV, LOH, and sequence variants together within a single software.

Let’s talk.

Book a free personalized demo to assess fit and see N_xClinical in action.

Seeing is believing! Let us know you’re interested and we’ll connect on an initial consultation to answer questions and dive a little deeper before demonstrating N_XClinical—either with example data or your own.

Submit the request form and we’ll follow up to schedule a session at your convenience.

Copy Number and AOH Detection from NGS

Algorithms for CNV and AOH Detection

Whole Exome Sequencing

Whole Genome Sequencing

Gene Panels

Shallow Sequencing

Detect, display, and decide—all from one place.

Detect.

Display.

Decide.

Get the software trusted by renowned academic and commercial clinical labs to stay on top of demanding, time-sensitive workloads.

Achieve the speed, confidence, and capability clinical labs need to make the right call—fast.

Analyze across different platforms.

Analyze and interpret from a single screen.

Store variant and genomic region data.

Put your case history and genetic databases to work.

Resolve cases faster and minimize TAT with automation, AI, and variant prioritization tools.

Maximize clinical utility and diagnostic yield.

Dr. Sharon Mexal

Todd Ackely

Liqiang Song

Dr. Sarah Murray

Let’s talk.

Book a free personalized demo to assess fit and see NxClinical in action.

Book a free personalized demo to assess fit and see N_xClinical in action.