• KPATH Scientific, LLC

Why your doctor isn't using molecular methods to diagnose infectious diseases

Updated: Jul 10, 2018

Rapid and exciting advances have been made in molecular detection of infectious agents over the past decade, for PCR, array, and sequencing platforms. However, if you or a family member is ill and visits your doctor in the U.S., the odds are very high that your diagnosis will be accomplished with clinical chemistry and immunochemistry alone. These are at best indirect or later-stage indicators of the pathogens involved in infectious disease. Why, in 2018, is this still the case?

I can identify at least 7 obstacles that all need to be overcome before we will be able to fully exploit the benefits of precise pathogen diagnostics that are already technically possible:

1) The inertia of existing solutions. Decades of improvements in clinical (blood) chemistry and immunochemistry have led to the development of highly automated, low-cost and scalable systems such as the Roche COBAS line. Your HMO undoubtedly uses systems like these to process millions of samples per year at a low cost/sample. The price we pay as patients for this includes, in many cases, the inability to even be sure if the causative pathogen is bacterial or viral. This is just one factor that has contributed to the abuse of anti-microbial therapies and the rapid rise in anti-microbial resistance.

2) Cost and time-to-answer improvements are needed for molecular techniques. Until quite recently, the DNA sequencing industry was mono-focused on cancer and inherited diseases. This spawned the race to lower the cost of whole human genome/exome sequencing, which was accomplished with massive scaling of systems like the Illumina X10. However, human genomes are ~1,000 times larger than average bacterial genomes and ~100,000 times larger than RNA viral genomes, making the largest DNA sequencers impractical to use for routine sequencing of human clinical samples (most of the sequencing bandwidth would be wasted on the human "haystack" background while looking for the pathogen "needle".)

Recently we have seen the advent of "targeted sequencing" approaches, where a sample can be enriched for a large set of molecular targets of interest; regions of microbial pathogens that are known by bioinformatics analyses to be highly defining at the species level of resolution. Targeted sequencing can be accomplished via PCR amplification techniques or probe hybridization-based "sequence capture" techniques on liquid or planar (array-based) platforms. In any case, the result is a sequencing library that is enriched for the information-rich targets of interest for the panel in question. To date, NGS approaches have been cheap enough or rapid enough to displace existing medical diagnostic practices. These barriers are now beginning to fall, but more research and investment are required.

3) FDA approval issues. Highly-multiplexed PCR, microarrays, and NGS diagnostics are now in use in various non-US locations, where obtaining local approval for human diagnostic use is less difficult than through the US FDA. What we are seeing now is the eventual replacement of single-plex PCR as the gold standard diagnostic technology by NGS-based approaches. About 15 years ago we suffered through a similar delay as single-plex PCR painfully replaced culture as the gold standard, so we may have a while to go before NGS is fully crowned as the new gold standard. This doesn't mean that sequencing will become the sole technique used for pathogen diagnosis, but merely that it will be faster and cheaper to validate new diagnostics whether based on multiplex PCR, arrays, or NGS in many different combinations and price-points. In the meantime, your doctor will remain using indirect (blood chemistry) and delayed (immunochemistry) results, handing out antibiotics and hoping for the best.

4) Medial insurance issues. Medical insurance reimbursement has been based on a "one patient, one test, one result, one billing code" paradigm for decades. Clearly, modern molecular methods (multiplexed PCR, arrays, NGS, etc.) all want to blow up this paradigm. Imagine that NGS or a microarray was used on a blood sample submitted to check for sepsis, and the results showed not only bacterial sepsis but also HIV and one or more STDs. The current medical insurance reimbursement system isn’t set up to cope with broad-spectrum microbial diagnostics. Ultimately, data will be needed to convince the insurance companies that they will save money in the long run if they get accurate pathogen diagnostics at the initial patient point-of-contact. Until that happens, they will likely continue to stall the adequate reimbursement of modern highly-multiplexed molecular diagnostics.

5) Electronic medical system billing code issues. This follows from the prior point. Hospital billing systems have recently struggled to add new billing codes for what many of us would consider to be low-plex PCR test. I am not aware if any are now ready to handle broad-spectrum microbial diagnostics. Clearly, the evolution of insurance reimbursement and electronic medical billing systems must proceed in lock-step. This may well end up being the most difficult barrier to overcome on the path to wide-spread adoption of modern molecular diagnostics.

6) Medical training issues. The bulk of today's MDs were not trained in an era where precise diagnosis of microbial pathogens was possible. Frankly, the generation of MDs for which that will be commonplace might still be in medical school. Ground-breaking work is now being done by Charles Chiu at UCSF Med School and others like him, to demonstrate how NGS can be utilized to resolve cases that defied traditional diagnostics. We are watching the early stage of a huge shift in the practice of medicine; don't expect the Titanic to nimbly dodge all the icebergs ahead.

7) Intellectual property issues. I rank this factor as last, but not insignificant. The US Patent and Trademark Office (USPTO) has been struggling for many years with the issue of how (and indeed, whether) to patent molecular "signatures" for pathogens. This has been tough enough for the USPTO in terms of single-plex PCR signatures, but they have been totally unable to determine how to handle something like a broad-spectrum pathogen detection microarray. Note that a similar problem may face the use of NGS as a diagnostic, should anybody try to patent a microbial analysis technique that depends on defining a set of highly-discriminating pathogen genomic regions. This is a problem because without a clear Intellectual Property path many VC investors will be far less likely to invest in promising molecular diagnostic technologies.

Some topics are too complex to handle in a tweet... My point in writing this was to illustrate the linked complexities involved in what will eventually be a huge change for the better in how infectious diseases are diagnosed (and treated...) in the US. Fundamental and exciting improvements in diagnostic technologies are but the first step on a long, rocky, and poorly-marked road, but it is one that we need to travel.

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