M-CM stands for macrocephaly-capillary malformation. It is a rare genetic syndrome first identified by researchers in 1997.
Could you tell us a little about the M-CM Network and how it was formed?
When my daughter, Signe, who is now 2 and a half years old, was diagnosed with M-CM, there was already a strong patient support community online facilitated by a family in England. The Internet and social networking largely solved the problem of connecting patients to each other without the need for a formal organization or fundraising. Because peer support was taken care of, our own organization was founded to accelerate research and make it easier to get clear, reliable information about M-CM.
What were you told about M-CM when you first found that Signe was affected?
Signe got a formal diagnosis of M-CM when she was about eight months old from a local geneticist. He sent us on our way with only a few paragraphs of information and no follow-up appointment. The next month, we made a trip to Michigan to see a geneticist that had a particular interest in M-CM and had seen many cases. He gave us much more information, but there was still an awful lot of “we don’t know” and “every child is different”. One of the things that we discussed at that appointment was screening for cancers that have an elevated risk in syndromes with similarities to M-CM. The degree of risk for these cancers in M-CM was sort of unclear and it was largely left up to us if we pursued screening or not. We asked how a clearer idea of the risk would ever be known and we were told that a longitudinal registry would be the answer.
What’s a longitudinal registry?
A registry is an organized system for collecting, storing, retrieving and analysing information on people with a specific condition. “Longitudinal” just means that data is collected over time rather than just once.
You’re not just supporting families and research you are also actually working to build up your own resources. Why does it fall to a patient advocacy group to do these things?
Well, nobody else was doing it. When my daughter was born, she was very peculiar, and I was amazed that there was no entity keeping track of her as a child with birth defects, or then as a child without a diagnosis and later as a child with a particular rare diagnosis. I just assumed that there were government bodies that kept track of all of those things. I had no idea how much of this depended on the non-profit sector.
Right now, patient families collectively know more about M-CM than is scientifically documented. We find ourselves having to educate our children’s care providers, sometimes with anecdotal information that we have picked up on Facebook. As I’m sure you can imagine, this doesn’t always go over very well. Our organization wants to connect the knowledge that patients have with the medical and research community so that what we’ve learned can be verified and documented scientifically, and so that we can learn much more than can be gleaned from anecdote alone.
Our founding objective was to create a longitudinal registry. We’ve been inspired by efforts by the Genetic Alliance and some specific rare disease organizations to create advocacy-owned data and sample repositories, so that these research assets can’t be siloed in any one institution. This will make it easier for all interested researchers to study M-CM and it saves families from needing to submit the same data and samples to multiple studies.
We are exploring using Indivo X, an open source electronic health record, as a research platform. One benefit will be that once participants add their data, it exists in a format that will continue to be useful to them as an electronic health record. We can build custom apps that provide feedback to families based on how their data compares to that of other participating families. For example, our families are often asking about head circumference and how their child compares to other affected children at the same age. A custom app could clearly demonstrates that comparison for a parent. On the researcher end, we think that the platform would give researchers extremely rapid access to motivated participants and their data.
The genetic marker for M-CM was discovered recently and we are now in a situation where there are researchers considering starting their own longitudinal registry. We believe that patients will be better served with an advocacy-owned registry, and we are looking to engage and benefit patients in that effort in ways that we can’t expect researchers do.
What kinds of use do members of your group have for research literature? What forms of research information do you find most useful?
Unfortunately, we can’t depend on all of our doctors to consult the published research literature about M-CM. I know that many of my daughter’s specialists haven’t and it’s clear from the questions of parents of newly diagnosed children that they are sometimes not getting advice from well informed practitioners. It’s not practical for doctors to spend a lot of time learning about a syndrome that they may see only once in their careers, so they provide recommendations based on a typical patient rather than the syndrome. Many parents, however, will make the time to learn everything they can — and this is why the inaccessibility of medical papers to patient families is so very frustrating. Some of the people most motivated to do this research are unable to.
Most of the published literature about M-CM consists of case reports. A few papers look at larger cohorts of patients: often the data is pulled from previously published case reports in addition to a few patients seen at a particular institution. There is one published paper at this time that is a longitudinal neuroimaging study. This on its own is the most valuable piece of literature, but the rest of it has value as a whole — it’s just that it’s very time consuming to process all of it. And as I said, it’s inaccessible to many of the stakeholders most likely to devote time to it.
M-CM is a rare disease with a relatively small literature. Is access to this literature a problem for you? Or for the researchers you work with?
I haven’t encountered professional medical researchers for whom access was a problem. The ones that we communicate with work at institutions where they have broad subscription access. In my opinion, parents of patients constitute another type of researcher and it is definitely a problem for them.
Has the NIH mandate had any effect on your work?
The longitudinal neuroimaging study that I mentioned before was published right before the NIH public access policy went into effect, so that paper will likely never be freely available. Most future research published from the US will probably be NIH funded and subject to the access policy, including the new findings about the genetic marker for M-CM. For this I am grateful.
I have had an interesting experience with a paper in the New England Journal of Medicine announcing the discovery of the genetic marker for Proteus syndrome. This was exciting for our community because there is some symptom overlap with M-CM: both are overgrowth syndromes thought to be the result of a mosaic mutation. Kids with M-CM are sometimes misdiagnosed with Proteus syndrome.
This paper was the direct result of research at the NIH and I was glad to see that when the announcement was made, the paper was freely available online. About a month later, I went looking for it and it was paywalled. I couldn’t believe it, I was sure someone at the journal had made a mistake, so I had an email correspondence with them. It turned out it was not a mistake, and they told me that it would be open again after nine months had passed.
We recently had a new family introduce themselves in our online patient community with a child with a Proteus syndrome diagnosis, but this child has a lot of M-CM characteristics. Apparently they had been told that the Proteus diagnosis had been verified with a genetic test on a blood sample. The trouble with that is that the NIH paper stated that the marker didn’t show up in blood, they had to test tissue to find it. It seems like this family may not have been getting accurate information, but who would I be — some stranger on Facebook — to tell them that? Fortunately, now the paper was open, so I could refer to the statement about testing directly in the paper, which the family could then share with their doctors. Rare disease patients really need access to medical literature, because doctors aren’t perfect.
Patient advocacy and support groups are playing an increasing role in medical research as both sponsors and sources of trial participants and clinical data. What does the M-CM Network bring to the research process? What do you see as the role of rare disease foundations in the research process going forward?
We are a very young organization, only a little over a year old, so the most substantial thing that we have done so far is refer patient families to the study that has now identified the genetic marker. We have started a patient contact registry and we’are in the process right now of conducting an anonymous natural history survey. We hope to have data from both of those things online in the next year. Neither of these are research in the traditional sense, but they were simple things that we could do quickly that we knew would answer some basic questions for patient families.
Again, I am very new to this, but it seems like the current medical research paradigm of closed and proprietary data is extremely dysfunctional. Rare disease advocacy organizations, by virtue of their small scale and very personal relationship with the issues at stake, have an opportunity to cut through a lot of nonsense fundamental to typical institutional research. I tend to think that we can be powerful change agents, by demonstrating innovative, truly collaborative and efficient ways of accomplishing things at a small scale.
A lot of people think of advocacy organizations as strictly for patient support, fundraising and grantmaking. But there is a clear trend in rare disease advocacy toward a more direct relationship to research. The NIH has acknowledged the strength of this trend by launching a pilot program to fund and facilitate the creation of 12 registries to be owned by rare disease organizations. Genetic Alliance has been a leader in this area as well, by creating a cooperatively owned biobank and registry product for advocacy organizations. Sharon Terry, who heads Genetic Alliance as well as an organization for the genetic disease that her children have, authored an inspiring paper on this phenomenon in 2007, Advocacy Groups as Research Organizations: The PXE International Example.
So we are just at the beginning of this journey, but the choices we are making are influenced by others that have been pushing in this direction for many years.
I just want to add that those of us entering into this space from the outside and scratching our heads at the status quo, are really in debt to those of you working on change from the inside. It is such a relief every time I encounter the rare person within the medical or research establishment that acknowledges the problems with data/research/science that is not open. So, thank you all very very much.
Christy Collins is the president of the M-CM Network. She was interviewed for Who Needs Access? by Cameron Neylon.