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Q&A: Howard Jacob on Clinical Whole-Genome Sequencing to End Diagnostic Odysseys

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This story was originally published on Aug. 19.

JacobHoward.jpgName: Howard Jacob
Title: Director of the Human and Molecular Genetics Center, Warrant P. Knowles Chair of Genetics, Professor of physiology and pediatrics; Medical College of Wisconsin
Experience: Professor at Massachusetts General Hospital Cardiovascular Research Center, 1992-1996;
Faculty at Medical College of Wisconsin, 1996 – present, director of the Human Molecular Genetics Center since 1999
Education: PhD in pharmacology, University of Iowa

Howard Jacob is the director of the human and molecular genetics center at the Medical College of Wisconsin, which has instituted a clinical whole-genome sequencing program for children with very rare, undiagnosed diseases (CSN 3/29 2011).

The clinical sequencing program is perhaps best known for the case of Nicholas Volker, a 6-year-old boy with an extreme form of inflammatory bowel disease. The MCW team used exome sequencing to identify a mutation in the XIAP gene that indicated the boy would respond to a bone marrow transplant. The case was one of the first instances in which genome sequencing identified the causal mutation in a poorly understood disease and led to a successful treatment, but not all cases have seen such resounding success.

Recently, Jacob spoke with Clinical Sequencing News about the program, its plans to expand to adult cases, how the team deals with the thorny issues of a non-diagnosis or a result that doesn't point to an obvious treatment, the importance of sequencing in a CLIA-certified and CAP-accredited laboratory, and how he sees whole-genome sequencing moving more broadly into the clinic.

Can you describe the process for the clinical whole-genome sequencing program at Medical College of Wisconsin?

The clinical program is designed entirely around ending diagnostic odysseys — a patient who has a severe form of disease that we have not been able to identify the cause of using all standards of care. It's a severe enough disease and there is a need for actionability that would make whole-genome sequencing warranted. Step one is two physicians nominate the case to a committee, which is run by our chief of staff at the Children's Hospital. There is a committee of ethicists, physicians who are not involved in the case, geneticists, genetic counselors, and bioinformaticians or genomicists, who then assess the merits of an individual case.

Four things can happen in the case review. The committee [can] send it back to the physician for more information, which typically involves questioning whether some other tests should be done first. [The second thing] that can happen is the case is determined not to be warranted for clinical sequencing. Number three is approval, in which case it is viewed as worth doing and to the benefit of the patient if we can find the mutation. The fourth option is called the parking lot, which is [when whole-genome sequencing] is viewed as being of value, but in the schema of a cost/benefit analysis, it's just not quite high enough a priority to be done currently.

If a case is approved, it then goes to the genetic counseling team who is involved in counseling the parents. People often ask about the children, but so far the children we've been doing this for have been either too sick or not capable of understanding the sequencing. As part of that process, the parents are asked what they would like for data return. Data return [options include] — just by law what we have to tell them — findings related to the disease process to whatever they want.

After the consent process, a clinical order is made through our pathology department, and the sample is drawn. Currently, we're sending the DNA to Illumina's CAP/CLIA-certified sequencing program. They then return back to us a hard drive, again through our pathology department. At that point, it goes into analysis, and we use a slew of analysis strategies, but the dominant platform we use is an internally built software program called Carpe Novo, as in, 'seize the new.'

After we go through an initial list of candidate genes, we work through other genes predicted to have defective function, and it's just a whole series of cascading events until you hopefully find the mutation.

And the key is to say 'hopefully,' because we have to make sure that everybody recognizes that it's still very hard to find these variants that are causally related.

One question we often get asked is what good is it if you find a mutation and you can't treat it? In one of our cases, where it was not a positive outcome like what happened with Nic Volker, the family at least knew what the diagnosis was. They didn't have this nagging feeling anymore of, 'Should we look somewhere else? Have we done everything we can?' It provided the family with understanding of what the disease was and what the cause was instead of some unknown. I think it's a nightmare when no one knows what's wrong with your child.

What is the timeline for the whole process?

We don't really have a set timeline. If [the mutation] is in one of the candidate genes, it's quite fast. But we have a couple of cases now where we haven't been able to find the variant, and we're continuing to pore through the data. We are currently in the process of trying to define when we're done, when we say we can't take it any further. So that's still being determined.

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How many cases have you done?

We have nine cases in process. We've finished four. We have found in two of the four [the causal mutation] and the other two are the ones we are trying to decide [whether we have] turned over every rock we can think of. We're trying to decide, 'Are we done with these or not?'

You also have plans to expand the clinical whole-genome sequencing program to adults. What types of diseases will you be looking at in adults?

Hereditary cancers is where we're looking to move next. There are some other rare diseases that are adult forms that we're also considering. But we are looking to start with hereditary cancers, following the same rules we've set up on the children's side. It would be important to understand what the gene cause is and it would be relevant to be actionable for either that patient or family members.

What have been the major lessons learned of doing this whole process and what have been some of the challenges?

I think the lesson learned is that it is possible to use this technology and the growing resource of genomic sequence information to add value to the clinical process. The other lesson, which is often implied but not explicitly stated, is that from our perspective, genome sequencing is another lab value. It's not the end-all or be-all. It is a piece of the puzzle that helps the clinical care team make decisions. It's not something to be looked at without being in the context of everything else.

Another thing is that it is still very, very hard, and there is a tremendous need for more genomes to be sequenced and [a need for] more attachment of clinical information onto the genomes in order to really drive the value of this into medicine. Much of what's been done so far has been annotating variants without the affiliated clinical phenotypes.

If you're looking at very rare disease, which we are for these diagnostic odysseys, you wouldn't expect there to be another variant like that available out there because these diseases are so rare. But, as you start trying to move this into more common diseases, you must have knowledge of what a variant means for the clinical trait that you're looking at. So I think that's going to be the big challenge. How do you make that assessment? How do you determine that a variant is causally related to that phenotype?

Going forward, how do you see whole-genome sequencing for clinical diagnosis progressing from rare diseases to more common disease?

I don't have an easy answer. I think we need to be careful in how we do this. I think we need to not be over-promising what genetics and genomics can bring to the table. I think for clinical [whole-genome sequencing], using it in these severe cases as a final option is fine and appropriate right now. But, to deploy it in a broader context without more data, without more knowledge, without better decision processes, I think it's too early to do this clinically. I think genome sequencing is still in the realm of research for the common diseases.

What is the importance of doing whole-genome sequencing for clinical purposes in a CLIA-certified and CAP-accredited laboratory?

I think the number-one reason is quality control and quality assurance. For example, you would not send blood chemistries out to some random laboratory and just accept the results. You'd insist that they come back from a certified laboratory. So we believe, as do others, that genomic sequencing should follow the same guidelines.

[CLIA certification] is also required by Medicaid, Medicare, and most insurance companies to reimburse.

Do you think that insurance companies will reimburse for whole-genome sequencing? And at what point do you think that will happen?

We've had two insurance companies agree to reimburse. And it's an economical issue. Many of the individual gene tests are quite expensive, between $1,000 and several thousand dollars a piece. With Illumina now offering — I think they're in the $7,500 range for their clinical sequencing — it doesn’t take very many gene [tests] to make [whole-genome sequencing] cost effective.

Also, in some cases, these [single-gene] tests take weeks to months before the data comes back. So, if you had sequenced a person's whole genome, and now the physician asks for results on the first three genes, it's very fast to then, if he doesn't find what he's looking for, ask the question on genes 6, 7, 8, 9 and 10. There are two issues: the actual assay costs, and how much time it takes to get the information back.

Are there specifications as to when insurance companies will reimburse and when they won't? For instance, are these companies only reimbursing if multiple gene tests haven't already been done?

Yes there are some specifications, but I can't share them with you right now for confidentiality reasons. But there are some specifics.

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There have been cases where whole-genome sequencing is being done for research purposes, not in a CLIA setting, but clinically relevant variants are discovered. Do you see this as problematic?

It's difficult to make a generalized statement. If it's being used as information and that information is being validated in a clinical laboratory, and the care team thinks it's an essential piece, then I think it's a different situation.

At this point in time, we need to be looking at the specifics of what this means for the [particular] case. I can imagine instances where there is value in sequencing in a research arena and then validating in a clinical laboratory and using that information. That's certainly how we did our first case. We used exactly that strategy.

Should it be done all the time that way? No. I think ultimately the goal is to continue to move the research to a clinical delivery just like what we've always done in medicine. When it reaches a certain point, it becomes a clinical test and there are clinical rules around why we use it, how we use it, and what we're using it for.

I do think there's still significant research [needs], particularly around the more common diseases. [There are unanswered questions] about how to use this information, what's the right strategy, what does it mean, what's the evidence around it about how to deploy this.

But let's just imagine that in that process of doing that type of research, the investigative team discovers something that is of value to that patient. I think ethically then, there needs to be consideration around what to do with that information. That's where [institutional review boards] and oversight boards and clinical care teams and families and patients all have to be involved in this process. It can't really be something that's done in a vacuum.

Do you think that we're moving to a place where all human whole-genome sequencing will be done in a CLIA lab, because it is inevitable that mutations of clinical significance will be found?

Do I think all genomic sequence being generated will be in a CAP/CLIA lab? No. But, do I think it should move to a point where for clinical use it's all done in a CAP/CLIA certified laboratory? Yes. And, the distinction between those two is that each institution needs to make a decision about at what point do they use it for clinical purposes, and at what point are they just using it as a research purpose? If you're going to use it clinically, then I think you need to do it inside a CAP/CLIA certification process. Now, as we were discussing, that could be done in two steps. It could be done as a research piece initially and then validated in a clinical piece. But I think as you move into that, it becomes increasingly required to move it all to a CAP/CLIA certification.

Do you think that whole-genome sequencing will become standard for diagnosing disease? Will everyone eventually have their genomes sequenced?

There are a lot of different views on this. In my opinion, family history is a critical piece of information that physicians use to help in dealing with their patients. I think genomic sequence offers the ability to add more resolution to the value of family history. It will take time. We need to understand what the variants mean in that context. But I can't imagine how having more data around somebody's risk doesn't add more value to a tool that's very well accepted in medical practice, which is a family's history.

The question is, then, at what point does it become cost effective to add that in? And I think as the data generation gets cheaper and cheaper, that question is really going to come down to a question you asked me earlier: How long does it take to analyze the data to make a decision? I think we're reaching a point where data generation is getting cheap enough, and if we can do the same thing with data analysis, I think it's going to be very difficult to argue that there's not value in that piece of information. Does that mean it will be useful for everything? No, there's no one thing in medicine that is useful for everything. But does it provide another piece of the puzzle? I think in most cases, yes.

Do you plan to continue to do the sequencing through Illumina's CLIA lab or are you looking to establish your own CLIA lab?

We are also looking to establish our own CLIA lab. I think there's some value in having your own CLIA-certified laboratory. It gives you control over the entire process. It also means that if you have an emergency situation and you need to do [the sequencing] faster for some reason, you have the ability to have some control around that versus when you're sending it off to another company.

The other thing that I think is important is that by being involved in data generation, you also understand the limitations of the data, the limitations of the data generation. And I think that adds value to your ability to have confidence in the decisions that are being made around the data that's being generated. Right now, in the early days, the more you're involved [in the data generation], the better you understand it.

If you do establish your own CLIA lab, would you continue to use the Illumina platform or are you considering others?

At this point, Illumina is the one we're using clinically, but we're not opposed to looking at alternative platforms. We've recently installed a Pacific Biosciences machine. It's too early in the game to be able to know where that's going to go. Certainly, the third-generation technologies with longer reads offer another advantage.

We're going to keep exploring technologies because what I'd like to do is get to a point where we can sequence an individual and do a de novo assembly on that individual, [but] with the current technologies, we have a ways to go before that can be accomplished.

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