Invitae provides clinical genome interpretation services derived from high-throughput sequencing, producing detailed reports for up to 150 conditions within two weeks. Their system combines a curated database of pathogenic variants, rigorous sequencing protocols, and secure data management. The process emphasizes accuracy in variant interpretation while maintaining patient privacy through compliance with HIPAA standards.

1. Computational and informatics challenges in providing
clinically-relevant genome interpretation from
high-throughput sequencing data.
Reece Hart; InVitae Team, San Francisco, CA, 94107
InVitae provides sequencing and clinically-relevant genome interpretation services to Report Excerpts
physicians from patient blood samples. Our value is based on three essential InVitae reports findings only for requisitioned conditions. A
report for the 150 conditions currently offered is 250 pages.
components: a database of high-quality associations of variants and conditions, carefully Online reporting and organization make the report easily
designed targeted sequencing assays, and a sophisticated analysis pipeline for navigable. A few features of our reports are shown below.
condition groups sorted by
interpreting variants. The current process requires less than two weeks from the arrival risk level and evidence
of blood to the delivery of a clinical report covering over 10,000 curated variants in 250
genes for up to 150 conditions (subject to physician's requisition). This poster
summarizes the computational and informatics tools that enable this process.
Clinician's view of InVitae
one sample two weeks one report
one requisition one lab, one price up to 150 conditions
InVitae's process features online requisitioning and reporting, CLIA-certified
sequencing, and a HIPAA-compliant information management. similar conditions carriers of known
grouped together pathogenic variants
ancestry-dependent
intake sequencing interpretation director review quantitative risks
Requisitioning and Laboratory Information Management System
Sequence Analysis and Variant Interpretation
The InVitae pipeline is designed to provide at least 50x depth across all targeted regions for all covered genes/conditions.
known pathogenic variants have predicted frequency in 1000
Samples that do not meet stringent criteria for sequence depth, sequence coverage, and coverage of known pathogenic strongest evidence of association effect(s) Genomes Project
variants for requisitioned conditions are rerun or failed. Personal Health Information remains on premises; the rest of the
pipeline (reads through anonymized report) executes with the Amazon Web Services platform. supporting
☞ See also: 3692W, lab process (Session I) publications
known pathogenic, novel
pathogenic, and VUS
known variants appear in distinct
pathogenic sections of the report
inferred
blood reads alignments variants report
pathogenic
VUS
sample intake alignment variant calling variant annotation reporting
computing challenges
● online requisitioning ● bwa ● GATK ● classification ● overall pipeline
● barcoding ● base quality ● polyMNP caller ● variant effect/VUS versioning haplotype alleles, inferred
● information security recalibration ● variant phasing pipeline ● lab director haplotypes, and risk association
process
● automated ● haplotype calling ● quantitative risk oversight
sequencing assay ● coverage
● assay design
modeling absence of known pathogenic variants
(covered regions and qualities shown at end of report)
● PCR fill-in
analysis
● multiplexing
Curation Database
● automation
● LIMS
The heart of InVitae is the curation database, a manually curated compendium of
pathogenic variants inferred from condition-specific
associations of genomic variants and clinical conditions derived from literature and rules for the interpretation of novel variants
public sources. The curation database informs assay design and variant
interpretation.
☞ See also: variants of unknown significance,
Curated genomic variants and with and without prior observations
curation 1766W curation process
clinical findings derived from 
database 1771W variant classification
literature and public databases.
(both Session I)
ancestry-aware inference
of risk from combination
of odds ratios
The Trouble with Transcripts Variant Simulation and Report Testing
A consistent definition of a transcript's exon structure is Curators and developers may easily generate reports for
essential to reliably mapping and interpreting variants. simulated samples with arbitrary collections of curated and
Inconsistencies lead to incorrect translations of research novel variants across multiple conditions. Tests may be
findings to clinical settings. We account for the following saved for future execution and regression testing.
challenges:
simulate variants for specified simulate new variants
exon structure changes for disagreement between reference suboptimal alignments to genders and ancestry for VUS analysis
a single RefSeq accession genome and transcript the reference genome
e.g., NM_001035.2 (RYR2) (3514/33165 transcripts) e.g., ALMS1
NM_012345.6
NM_012345.6
ENST987654
NM_123456.7
select curated variants create homozygous,
heterozygous, and no-data loci regions where transcript sequences differ from
structure and CDS equivalence of transcript records with atypical record formats the reference genome are not interpretable
RefSeq and Ensembl transcripts (all 18 DMD transcripts)