Clinical Metagenomic Sequencing Roadmap

SARS-CoV-2 circulated in human populations as an unknown respiratory disease for an estimated 4-8 weeks, undiagnosed by traditional methods like culture and PCR. Imagine if, instead, we lived in a world where the first severe cases are linked to a yet unknown novel coronavirus, and public health authorities get a chance to contain the outbreak before it develops into a devastating pandemic.

We could live in such a world if clinical metagenomic sequencing (MGS) was widely used to diagnose acute respiratory disease. However, sequencing workflows are currently prohibitively costly and labor-intensive, and MGS therefore remained confined to centralized laboratories and a few clinical pilot programs, with many hurdles to surpass before wide-scale use in a clinical setting.

However, sequencing technologies are diverse and nobody has given a focused shot at optimizing them as infectious disease diagnostics. In collaboration with Open Philanthropy, we partnered with experts on sequencing hardware to scan the technology landscape and answer what it would take for sequencing to become competitive with PCR as a diagnostic tool, focusing on sensitivity, time-to-answer and cost. You can read the results in our technology roadmap.

Abstract

This technology roadmap proposes target specifications for a MGS diagnostic device to enable routine use: sensitivity comparable to polymerase chain reaction, time-to-answer under 1 hour, cost per test under $10, and a portable, affordable instrument. We estimate that throughput of 1-10 million reads per hour with modest read lengths >25 base pairs and accuracy >95% could robustly detect most pathogens in human respiratory samples. Existing sequencing platforms do not meet this combination of targets, so focused technology development is needed. Nanopore and single-molecule optical sequencing are highlighted as promising approaches if optimized for the proposed specifications rather than long reads and maximum accuracy. Realizing ubiquitous MGS may require push and pull incentives for innovation. A low-cost, rapid MGS diagnostic appears technically feasible and could greatly enhance pandemic preparedness.