By Diagnostics World News Staff
September 2, 2025 | When it comes to disease diagnostics, every missed genetic variant represents a delay in diagnosis—and often in treatment. Researchers at Pacific Biosciences (PacBio) developed a new genomic benchmark that could help close those diagnostic gaps, offering more accurate detection of genetic variants.
The study, published in Nature Methods (DOI: 10.1038/s41592-025-02750-y), builds on a four-generation Utah family pedigree (CEPH-1463) using multiple leading sequencing technologies—PacBio’s HiFi sequencing, Illumina, and Oxford Nanopore. Other collaborators also include the University of Washington School of Medicine, Google, National Institute of Standards and Technology (NIST), and others. By sequencing parents and eight children, scientists created what they call the Platinum Pedigree, a dataset designed to capture how variants are inherited and, crucially, to distinguish true mutations from sequencing artifacts.
“What we really wanted to do was concentrate on the parents and their children to build up a dataset where we could say, is this variant correct or is it not correct?” says Mike Eberle, PacBio’s VP of Computational Biology and senior author on the paper.
Current genomic benchmarks, such as those developed by the Genome in a Bottle (GIAB) consortium at NIST, put focus on variants that can be called with near certainty. Though this allows for reliable benchmarks for clinical validation, it leaves out vast swaths of the genome, such as complex and repetitive regions where disease-causing mutations may hide.
“We tend to make sure that when you’re comparing against the benchmark, the vast majority of the false positives and false negatives that you identify should really be false positives and false negatives,” says Justin Zook, co-leader of Biomarker and Genomic Sciences Group at NIST and co-author of the paper, about GIAB’s conservative approach. “That causes us to exclude some of the more complex regions of the genome that can’t be benchmarked reliably right now.”
The Platinum Pedigree widens the net. By leveraging inheritance patterns, researchers can validate variants across challenging genomic terrain. Compared with GIAB’s v4.2.1 benchmark, the new dataset identified nearly 12% more single nucleotide variants and almost 40% more insertions and deletions in NA12878, one of the most sequenced individuals in genomics. For clinicians, that expanded coverage could reveal disease-linked mutations that would otherwise go undetected.
Artificial intelligence (AI) tools also gain benefits from the Platinum Pedigree. The researchers used the new benchmark to retrain Google’s DeepVariant. Error rates dropped in small variant calls by around 38% for single nucleotide variants (SNVs) and nearly 20% for indels when evaluated on the new benchmark. Even when measured against GIAB, improvements reflected about 18% for SNVs and around 5% for indels. These reduction rates mean, in practice, faster and more accurate test results for patients undergoing sequencing-based diagnostics.
It must be stressed that Platinum Pedigree is not a replacement for existing clinical standards. GIAB benchmarks remain indispensable for regulatory-grade validation, notes Zook, but there is value to having a variety of benchmarks.
The entire Platinum Pedigree dataset is publicly available, ensuring that its impact extends beyond PacBio’s commercial interests. Research groups, including Evan Eichler’s lab at the University of Washington, are already incorporating it into their work, and the benchmark itself will continue to evolve as sequencing technologies advance.