Monday, March 2, 2015

When even well-posed questions are hard to answer

On Friday, in acknowledgement of Rare Disease Day, our daughter Ellen blogged about living with a rare disease.  She wrote eloquently about her wish to understand why she has this disease, including, if it's a single gene disorder, knowing the causal variant.  She wrote about the advantages of this when navigating a medical system that isn't always sensitive to rare diseases, but in which genetics has become the gold standard.  We fully support her wish to understand why she has this disease, and have tried to help as much as we can. We would do the DNA work ourselves if we could.

Even so, she mentioned that her parents, Ken and I, are skeptics about a lot of genetic research.  Yes, that's true, but another word for that is 'realist'.  We are alive at a time in history when more is known about genes and genomes than ever before, and for decades we've been hearing promises of what this new knowledge will mean for medicine, and the promises roll on.  Once we all have our genomes on a disk, we'll be able to predict and treat whatever it is our DNA foretells.

Lazuli Bunting; rare birds in Central Pennsylvania; Wikipedia, Leander Sylvester Keyser

Except, except, Ellen's genome is on a disk.  Or at least her exome, the protein-coding parts of her genome.  Her disease, hypokalemic periodic paralysis, is one of several forms of periodic paralysis, which have been found to be associated with three different ion channel genes.  At one time a researcher in Germany was offering free genotyping to anyone diagnosed with the disease.  Ellen sent  blood samples, but was told that she doesn't have any of the known causal variants in these genes. She was also involved in a large whole exome study of unexplained Mendelian disease, but all they were able to tell her was that she doesn't have any potentially causal de novo mutations, mutations that neither Ken nor I have.  She is the only family member with HKPP, and as such, the initial question in a search for the cause is whether she has a variant that we don't have, that might be responsible.

And, to her frustration, that is all she knows.  It has been suggested that she go the clinical genetics route, having her DNA tested for known causes of HKPP, but that seems unlikely to be helpful, given that she knows what disease she has, just doesn't know why, and clinical labs don't look for new causal genes or variants, but instead a battery of those that are known.

Ellen has classic symptoms and classic triggers, and her disease is pretty well controlled at the moment, so identifying the cause, as she wrote in her post, might not change her treatment, but it would ease her mind about future dealings with the medical system.  As importantly, it might help future patients avoid the lengthy, destructive diagnostic odyssey she herself experienced, which itself would be a very satisfying outcome.

Big Data advocates will say that the problem is that not enough people with HKPP have been sequenced, and once we've got a million genomes or more, that will facilitate identifying Ellen's and others' causal variants.  But only 1 in 200,000 people have HKPP, so one million is unlikely to help.  And, though the data are rather sparse, some estimates based on those data suggest that a fairly large minority, a third or so, won't have one of the known causal genetic variants.  As with most diseases, the phenotypes vary greatly, and again as with most diseases, this is likely to be because every genome is unique, and genetic background matters, along with exposure to other triggering factors.

Perhaps there's an as-yet unidentified gene that would explain many of the unidentified cases, or there are many unique pathways to the disease, or both, but given the rarity and the heterogeneity of the periodic paralyses, it would take a huge amount of luck for even a large database to answer Ellen's question.  We should perhaps call it dumb luck, because the investigators vacuum up generic data without specific regard to, say, the physiology of this particular disorder (and the same for countless other disorders).  Of course, collecting data on every possible physiological or environmental factor, mostly with weak individual effects, isn't possible and that is a dilemma for modern public health science.

In addition, it's known from affected families that penetrance of alleles related to the periodic paralyses is not 100% -- some people with a 'causal' variant never experience an attack, making associating genotype with phenotype even harder.  Again, genetic background may affect this but, as with many genetic disorders with variable penetrance, it's not at all clear.  Incomplete penetrance is a fact, but also a fudge factor, because it leaves the impression the trait really is 'genetic'; in fact, we often don't know how many people have such mutations but no symptoms at all, because they aren't screened (but some studies looking for such asymptomatic cases have easily found them, and they can be as common as the 'causal' mutations in affected patients).

Further, it's possible that there are non-ion channel related causes of these channelopathies.  That is, something upstream is going wrong.  In that case, it's unclear where to even begin to look for genetic causation.  Thus, hypothetically in this instance, ion channels respond to the ionic concentrations inside the cell and in its environs.  Factors that affect the ion concentrations themselves could lead to effects similar to ion channel defects per se.  Thus, again just surmising, there are known environmental stimuli for attacks but these may affect the ion concentrations themselves, not the channel protein function.  And, of course, both could be at work, which would be rather expected given the many precedents for disease complexity.

And, it's possible that Ellen's disease is polygenic, or not genetic at all, though given that many cases of periodic paralysis, including in families, seem to have a single genetic cause, this seems unlikely.

Genetics asks two basic questions: What causes disease X?  And, who will get it?  The promises of the past few decades are that answers to both these questions are just around the corner for most diseases.  The NIH Office of Rare Disease Research reports that there are 7000 known rare diseases (diseases that affect fewer than 1 in 200,000 people).  The cause of many of these diseases has been identified, and by some criteria over 6000 specific genes have been associated with some usually rare single-gene disorder.  In many cases, it's possible to predict who will get the disease, and that is where genetic counseling is so useful.  It is, in our view, also where our limited research resources should be directed.  

But, if you read MT at all regularly, you know what we think about the promise of predicting common, complex diseases with genes.  Current science is very far from answering the two simple questions, what causes common, complex disease X?, and who will get it?  And, you know that we think that's because these questions can't be answered in any way approximating the promise of, say, precision medicine.  

But single-gene disorders are a different kind of problem.  What causes Ellen's HKPP? That seems to be a well-posed question, and should be answerable.  But to date, it hasn't been.  Labs are reporting 25-30% success with identifying the cause of rare genetic diseases (some somewhat higher success rates), so she is not at all unique.   We commented last week on the problem of identifying specific at-risk subgroups more effectively than blanket epidemiological studies currently can.

Are we skeptics?  Or are we realists?  When even the 'easy' cases, like Ellen's, the low-hanging fruit, are hard, what does this mean about the promises for genomics?  


BenK said...

As a scientist with adequate background to discuss this, I agree with you and in overarching context, the scientific situation is as bad as you describe. Not only are complex genetic systems difficult to accurately describe and predict, so are complex social systems, complex ecological systems, and complex physical systems.

Genetics is presently frustrating and the path it is on will not yield the kinds of insights you need in the next decade. Microbiology for infectious disease is in a similar place. It's heresy against a particular faith, but climate science is also in the same bad place.

Realism is the only scientific stance available. I'm sorry that the news isn't more positive.

Ken Weiss said...

We have been trained to think of disease as discrete states, and causes as point or discrete causes (like infection or trauma). We are not good at the kind of complexity the real world presents. I haven't read much Hippocrates, but I wonder if he (and, later, Galen) had such a falsely discretized worldview. Or, perhaps, better, were as seduced by those cases that are reasonably viewed as due to discrete cause as we are, where we also carelessly meld issues of public health with issues of patient-specific medicine.

In any case, physics deals with complex causation, but they have at least rigorous universal principles to help them make sense, and to have ideas about what sort of sense makes sense to make, that are far more utile than what we have.

But at the fringes of physics, they face similar unresolved complexities. In a sense, life sciences' fringes are too close to the immediate concerns. And when sociopolitical and economic sorts of issues become dominant, the science itself becomes entangled in inapt ways, and we enter the current world of 'disconnect'

Peter said...

...all they were able to tell her was that she doesn't have any potentially causal de novo mutations...the initial question in a search for the cause is whether she has a variant that we don't have...

Did they not also check out the possibility that you and Ken are both carriers for a null mutation of some kind, and Ellen is a compound heterozygote?

Obviously they won't be able to look at all variants of every gene, but they should be able to spot mutations predicted to be of large effect such as deletions, frame shifts or premature translation termination.

Given the lack of other cases among family members, the alternatives (if it's a single gene) are either de novo mutation or recessive inheritance, so I'm surprised they didn't look at both possiblities.

I'm fully in agreement with the general principle that sequencing data has not yielded the level of information touted of it. However, I think the one area where it is likely to be useful is in looking at rare diseases with severe phenotypes, where there may well be as-yet-unidentified genes of large effect that will be detected by a comprehensive enough search strategy.

(Full disclosure: I too have a dog in this fight, with cleft lip and palate segregating apparently dominantly in my father's family and an unusual form of diabetes also running very strongly in my mother's family. I will certainly be trawling my own DNA for clues when I get a chance, however with much less likelihood of success as both parents are now unavailable to give samples...)

Where the sequencing approach seems doomed to failure is in the common disease / common variant arena, where contributing alleles can be identified but the effect of each is so small and confounded by epistatic effects as to be useless as a guide for diagnosis, prediction or treatment.

James Goetz said...

This is interesting. I'll share my perspective starting with current personal experience:

In my case, I have a common disease called "impaired glucose tolerance." This is a type of pre-diabetes and diabetes runs in my family. I couldn't care less if science identifies the gene or genes that gave me this disposition because I doubt that would help my treatment. But I definitely want science to give me better information on how my blood sugar interacts with the following:
1. sugar alcohols that are carbohydrates that include artificial sweeteners
2. dietary fiber that is also a carbohydrate
3. chromium that evidently can help blood sugar but is hyper advertised to work miracles in everybody's metabolism
4. magnesium that sometimes can help to lower blood sugar but is also hyper advertised
5. any other supplement that could actually help my condition

I know that many congenital dispositions have a genetic factor, but that genetic factor could have stopped expressing before birth while an organ is malformed. (Sorry that I do not have an example off the top of my head in the presence of researchers who know much more about this than me.) In any case, I doubt that knowing more about the original genetic problem will help me to lower my blood sugar and occasionally enjoy a sweet dessert.

By the way, cinnamon could also help me, but unfortunately cinnamon buns probably won't help :-)

Anne Buchanan said...


As far as we know, they looked at the known related genes, and they looked for de novo mutations, but what they did beyond that we don't know in detail. Your suggestions are good ones, and I certainly agree with you about when sequencing is most likely to be useful.

Anne Buchanan said...


Well, you're pointing out the difference between preventable, late-onset chronic diseases, which lifestyle clearly affects, and genetically determined diseases, that are present at birth and can't be prevented. You are also pointing out how much is still not known about common conditions!

Ellen said...

Well written and illuminative even for me. You're realists.

Unknown said...

Great essay Anne,

To me it demonstrates clearly how we are (always?) mixing two things, science (observations, facts and theories) and medicine (an art helping sick people). Science provises us (sometimes) usefull indights into diseaease pathobiology but medicine is much more than applied science. Even if we were able to know precicely "causal factors" of a disease we might not be able to help or cure a disease because such knowledge is only a part of medical culture and patient's life.

Anne Buchanan said...

Thank you, Jari. I often think about what it must be like for a physician, trying to apply what we think we know to patients. And, even when we really do understand a cause, as you say, it's not always possible to make a difference in a patient's life.

Karen Carr (Biehl) said...

Hi I also have a type of hypokalemic periodic paralysis. I have been reaching out to others and have been researching my family tree and have made some pretty interesting discoveries. I am in a group where individuals are examining their raw data and we are finding multiple mutations in very interesting genes. Not only ion channel genes but also colagen genes, known genes for longqt malignant hyperthermia and much more. We are discovering multiple and complex mutations that may or may not be the reason we are all so different. I have been in contact with Dr. Lehman Horn now retired and he believes I have a variation on the Andersen Tawil syndrome. I am receiving treatment for the potassium issues but still have not been evaluated for suspected malignant hyperthermia or ehler danlos or other collagen disorders. I am not descended from Elizabeth Barrett Browning directly but share much of her ancestry. I would love to talk to you and invite you to my page Andersen Tawil Syndrome and Anderson Tawil Syndrome+. I also share proven ancestry with many others with the diagnosis.

Anne Buchanan said...

Good to hear from you, Karen. I hope you have success with your search for the genetic cause of your version of ATS. We weren't aware that collagen genes were being explored for association with this, and will be interested in the results. The diagnostic odyssey that so many people with PP experience now becomes a gene variant identity odyssey...

While yours does sound like it's familial, do keep in mind that many cases, as I believe Barrett Browning's probably was, are sporadic, meaning they are due to a novel mutation that the affected person's parents didn't have and didn't pass down. EBB's only child had no (known) children, so it seems unlikely, at least to me, that distant relationship to her explains the origin of this disease in people alive today. But, that's just my guess.