Clinicians Hate NGS?

I recently attended a PacBio round table on human health in Tokyo. During which I was probably far too vocal, in particular about my pessimism with respect to the growth potential for clinical human genomes.

I’m going to summarize my thoughts here. But I thought I’d lead with something positive…

How Can We Drive Growth?

We need to drive every patient with a rare disease toward rare disease programs where they can at least potentially receive genome sequencing. Right now, I’d guess that <10% of patients are introduced to these programs (for reasons we’ll discuss below).

To do this you need to directly engage with clinicians and patients. And not the good clinicians, the shitty ones. The ones that have never even heard of whole human genome sequencing.

How? I don’t know, get a list. You need a list of doctors who will first encounter the rare disease and are able to refer patients to genetic counselling. For my son (who is profoundly intellectually disabled) this was a Head of Psychiatry.

Explain to them that there are hypothesis free genetics tests available through rare disease programs. Explain that while results may not be actionable (in terms of change of treatment), they can impact subsequent family planning choices and are valuable in themselves.

Explain that identifying genetic causes and in turn help us understand disease, and drive drug development.

As well as front line clinicians. Talk directly to patient advocacy groups. Try and get this information in front of patients and the public in general.

With enough patients asking for whole human sequencing, or at least enrolled in rare disease programs funding pressure to address these patients needs with whole genome sequencing will increase.

Make it a standard of care for rare diseases, and any disease with a suspected but unidentified genetic cause.

Why Doctors Don’t Like NGS

Doctors don’t like tests. Yes, the really good doctors you read about in Nature Genetics or whatever or ones working on a large research project. The ones you’ve talked to or read about do. The rest don’t. The ones at a prefectural university who are dealing with these rare disease patients. That is to say 99% of doctors.

I’m going to discuss how this goes in practice.

We first went to Chiba Children’s Hospital to meet the Head of Psychiatry for my son who is intellectually disabled. I asked what tests were available he offered no advice and said “You can’t fix disabled”. On the next visit, after some amount of shouting, I was introduced to a geneticist.

Not particular satisfied with the standard of care at the above institution we also went into Chiba University Hospital¹ to see the Neurologist. I was curious to understand what tests they would perform.

Part of our conversation went like this:

Me: What are the standard tests that he should have done.

Doctor: Um... Basically, in Japan, rather than thoroughly investigating the cause, the standard approach is to follow along and make it easier for this child to live.

Me: So you don’t do any tests?

Doctor: If something different that can be done...

Me: I understand there are no therapeutics for intellectual disability¹. If he has fragile X it effects my daughters children. So of course you do tests.

The basic standard as outlined by the American Academy for Pediatrics is fragile X, Microarray (CMA) and metabolic testing before moving on to brain imaging, gene panels, whole genome sequencing etc.

Their 2004 report elucidates the reasons for testing, even in the absence of therapeutics quite succinctly:

“Accurate etiologic determination, despite the fact that many disorders have no specific therapeutic interventions, has specific implications regarding treatment, prognosis, ongoing medical management of associated conditions, assessment of recurrence risk, counseling of families if there is a risk of recurrence, and implementation of prevention programs. Determining causality also empowers the affected family in planning for their child and limits further unnecessary testing.”

In the case of intellectual disability, there are a number of potential genetic causes (fragile X among others) which would be a consideration in family planning, both for parents and any other siblings. In these cases, even knowing what “it isn’t” is of value.

From my personal standpoint as a parent doing everything possible to understand my sons condition feels like it has value in itself.

Here’s another fragment of a conversion I had this time with a Neurologist at Chiba University Hospital:

Me: Fragile X is not tested for in Japan, but it is common in other countries. please explain.

Doctor: Well, if the ear has a major abnormality, you can do it.

American Society of Pediatrics write “Fragile X genetic testing should be performed in all.” (cases of intellectual disability).

Fragile X often results in other symptoms along side intellectual disability such as a “long and narrow face and large ears”. Which is perhaps why this doctor is suggesting testing only when the child has abnormal ears.

Why then is the American Society of Pediatrics in favor of testing in all cases?

Informally the American Society of Pediatrics writes about this on their blog citing one case in particular:

“His parents came into my clinic when Brian’s developmental pediatrician referred him for a genetic evaluation. Part of the genetic work-up we did was a Fragile X DNA test. When those results came back positive, his parents were surprised to hear that Brian had Fragile X syndrome. They thought that he was just a little slow with his language and that he might be autistic. They didn’t think he looked different enough to have a syndrome.

Not all children with Fragile X have distinctive features, which is why it’s important to test.”

I discussed this in more detail here, but the summary is facial features are associated with Fragile X, may not be in 30 to 50% of cases.

Some might say a bias against testing is peculiar to Japan. But in my opinion there’s enough evidence that it’s relatively pervasive… and not just in rare disease testing, you’ll find the same issues in infectious disease testing and elsewhere.

They don’t just dislike whole genome sequencing, they dislike all tests. If a treatment is available for a condition and it might improve patient outcomes, they often just want to try it. If a treatment isn’t available, what good is a test anyway? It’s not going to do any good is it?

That’s why the doctors above are suggesting no testing in a case of profound intellectual disability… their attitude can be summed up as “So What?”

It’s Not Cost

Multiple vendors offered to sequence my son for free (based on a post here). Of these in the majority of cases regulatory issue prevented them from doing this in Japan. One could go ahead and do it in Japan. We were already in the national rare disease program, so our samples were queued for sequencing.

It’s been a year and 3 months since we got the sign off. And I’ve still yet to hear anything. The hold up appears to be somewhere within the national program itself, rather than with the vendor…

The regular national program did a whole exome I believe. I received no report regarding the results.

I doubt very much if the cost of whole genome sequencing was zero it would make a huge impact on adoption of whole genome sequencing for rare disease testing.

This is in a case where I’ve been very vocal (i.e. shouting at doctors) regarding my desire to have genetic testing. In a country generally considered to have a high standard of healthcare (Japan).

The reason why clinical whole genomes are not preformed isn’t money… it’s that clinicians don’t like tests (described above).

Summary

• Doctors don’t like tests because they don’t think they directly change patient outcomes (which is often true).

• The cost impact of testing is likely a minimal consideration.

• Try and make grass roots clinicians aware of the benefits of whole genome sequencing.

• Try and make people in general aware of the benefits of whole genome sequencing.

• Hope this applies pressure from the bottom up.

1. For reference, you might consider these “poor” institutions. But be aware they are likely typical and not easy to get appointments at. From memory Chiba Children’s Hospital required ~100 phone calls to get a reservation during the monthly one hour reservation window. It look ~2 months. For Chiba University Hospital I had to build an automated call system which made ~1000 calls before someone picked up the phone. I suspect most “normal” people would not be able to get an appointment at all.