Whole-genome sequencing when it isn't cancer
Volume 7, Issue 14 | April 12, 2023
In This Issue
What it would take to transform avian flu into a human pandemic
Ultrasound alone for focal breast problems? Probably yes
Eye exams for early Alzheimer’s? Probably no
mRNA vaccination outperforms prior infection - again
New and Noteworthy
How to Turn Bird Flu into the Big Bad
Wondering what it would take to transform the current global avian flu (subtype H5N1, clade 2.3.4.4b), which has infected mammals from house cats to raccoons to bears and more, into a human pandemic? Kai Kupferschmidt’s succinct article in Science answers this concerning question. The bullet-point list of necessary mutations:
The enzyme the virus uses to copy its RNA inside host cells would need to work better in mammals. A mutation in the PB2 subunit of that enzyme would do the trick - and has done so already in some of the cases in which the virus has infected foxes and seals.
Its hemagglutinin (one of the proteins it uses to attach to the surface of host cells) would need to change shape so that it can attach more effectively to mammal cells.
That hemagglutinin would need to be more stable in air - right now the disease can only be transmitted through water contaminated with infected fecal material.
So, big sigh of relief, right? Especially since one of these mutations (the hemagglutinin shape-shift) requires two genetic changes that are highly unlikely to occur together? Yeah, except that this virus continues to infect birds around the globe. That’s a lot of hosts in which mutations can happen. We’ll continue to keep watch.
For focal breast problems, you may not have to get flattened.
Some good news for those of us with boobs: If you have a localized problem with a breast (a lump, localized pain, nipple discharge, or the like), you may not have to undergo the added discomfort of mammography in order to get a diagnosis. A recent study in Radiology indicated that ultrasound alone had a sensitivity of 98.5% (specificity 90.8%) in diagnosing breast cancer. The technique was not perfect - of the 1961 patients in the study, 11 had malignancies that were missed by ultrasound and found by digital breast tomosynthesis (aka 3D mammography). (However, there was other good news: 80% of patients with focal breast problems didn’t have cancer. May the odds be ever in our favor.)
Food for Thought
Eye exams to screen for early Alzheimer’s? Not yet, at least.
There are two places in your body where a doctor can look at your brain without opening up your skull: Your eyes. Ganglion cells in your retinas are neurons, part of your brain tissue. And just like the rest of the brain, the retina is vulnerable to the formation of amyloid beta (Aβ) plaques, the historic hallmark of Alzheimer’s disease (AD).
That begs a question: Could eye exams be used to diagnose AD? A recent paper suggests that they could, confirming what many earlier studies have found: These plaques can be visible in the retina even in mild impairment cases, when they are just developing in the brain proper. In addition, eye exams are frequent (especially for seniors most susceptible to AD), non-invasive, inexpensive, and increasingly involve routine laser imaging, which aids plaque visualization.
Commentary: We have several concerns.
Aβ itself may not be specific to AD. It is also found in glaucoma and age-related macular degeneration, diseases that are limited to the eye.
This research was post-mortem and deduced progression by comparing individuals who had varying degrees of cognitive decline at death. That might not necessarily match what is seen in any one person over time.
Perhaps more importantly, are retinal Aβ plaques a reliable biomarker of AD at all? This small 2022 study of live patients found no difference in retinal Aβ between cases and controls, and (counterintuitively) reported Aβ in CSF to be twice as high in controls as compared to diagnosed AD patients. Phosphorylated tau correlates better with clinical AD.
This story is a continuation of our Alzheimer’s disease diagnostics focus of last week. We will continue to look for advances in the field and keep you up to date.
UHC covers whole-genome sequencing for some non-cancer indications
Health care giant UnitedHealthcare has announced that it will cover whole-genome sequencing (WGS) for some (very specific, because this is US health insurance) non-cancer indications. The result of the test must impact medical management and clinical outcomes, the patient’s clinical history must “strongly suggest a genetic cause,” and the patient must show at least one or two characteristics detailed on two different laundry lists of syndromes. (Whether the patient needs to show only one or needs two characteristics depends on which list is chosen, which is strangely reminiscent of Panera Bread’s “You Pick Two” menu rules.)
And there’s also a list of situations in which WGS won’t be covered, even if the above is met:
The patient can’t have received chromosome microarray analysis or whole-exome sequencing
Clinical features must be nonspecific, and can’t fit a syndrome for which there’s a more targeted genetic test
If the patient is on the company’s Individual Exchange, they can’t live in Colorado, Massachusetts, Nevada, or New York
Commentary: A significant step in the right direction in recognizing the power of appropriate testing. We don’t want to advocate for any and all tests to be covered without review, so we appreciate United’s initiative here. Is it enough? Probably not - but that’s ok for now. We see two critical follow-up actions:
Educate physicians on how and when these tests can be useful. Don’t assume that they know, and don’t leave it to the testing companies to conduct all of the necessary education.
Follow up with data / real-world evidence on how these tests were used (or not used) and the requisite impact on patient care and cost.
On a related note: In this opinion piece on the value of genome or exome sequencing in kids with challenging and unknown disorders, the author makes a strong case that a clear diagnosis is critical for these kids and their families - even without a treatment option. Clarity brings peace and acceptance that help people move forward. Without it, the time and money spent on a diagnostic odyssey continues in a non-productive way.
mRNA vaccination provides longer protection than prior natural infection.
There has been continuing discussion on how immunity conferred by prior COVID infection compares to that generated from vaccination. Research published this week in CellPress Immunity declares vaccination the winner.
Of course, natural infection as a strategy to build immunity has much higher risks compared to vaccination (natural infection causes ~1% death, ~20% Long COVID). But vaccination’s advantages go further. Long-term immunity depends on memory B and T cells – the cells that stand ready to regenerate immune response long after the initial encounter (whether from vaccination or infection). Researchers found that vaccination generates 10.6 times more of the all-important memory CD8+ (effector) T cells than natural infection (dropping to a 4.3x advantage after four months). Vaccination after a prior infection is less effective. This is a complex subject - expect more revelations to come.
Quick Hits
Coronavirus research got a $5 billion boost from the federal government with the creation of Project Next Gen. The goal is to speed development in three areas: vaccines that provide mucosal immunity, vaccines that work against all coronaviruses, and long-lasting monoclonal antibodies.
The COVID National Emergency has officially ended, with President Biden signing a congressional resolution to that effect this week. (See last week’s issue for details on how this emergency differed from the two public health emergencies.) Telehealth, however, was separately extended for two more years.