MCHB EPI Atlanta Conference
December 5 - 7, 2006
Genetic Epidemiology, Genetics, and MCH
SONIA RASMUSSEN: Okay as Juan mentioned earlier, I’ll be talking about the challenges and opportunities of incorporating genetics and MCH studies. And I wanted to start with the information that really--the discussion that I’ll beginning today is really based on work that we’ve done with the National Birth Defects Prevention Study and many of you maybe heard this morning about the National Birth Defects Prevention Study. It’s an ongoing case control study of major birth defects to evaluate genetic and environmental risk factors that will eventually, we hope, lead to prevention of birth defects and enrollment began with births on or after October 1st, 1997. And you can see here the nine sites that are currently involved within the study. The components of the NBDPS include case ascertainment through birth defects surveillance systems and review, an hour-long maternal interview about a number of different environmental factors and DNA collection on infant, mother, and father. And I’m going to be focusing on issues related to that DNA collection. So why study genetic factors and gene environment interaction? And Cindy has discussed some of that and so as Juan so I’m just going to go through the opportunity part pretty quickly and then focus on some of the challenges. I think the biggest reason is that we hope that it will result in improved understanding of etiology that will lead to increased opportunities for prevention. And as Godfrey Oakley said earlier in the day, that’s why we’re all here, that’s what we are all here for, were trying to prevent disease. And we hope with birth defects that by looking at genetic risk factors that we can identify populations at high risk, susceptible genome types, possibly for increased screening or--and/or modifiable risk factors, environmental exposures that we can identify because we learned something more about a pathway that those genes are involved that people can avoid and then prevent birth defects.
So what are some of the--that’s the reason for doing it, what are the challenges? And that’s really what my talk will focus on. And it was pretty easy to come up with some of these challenges because I was able to sit down and think about the issues that we’ve discussed over the last eight years of working on this study. The study began in 1997, I started in CDC in 1998 and some of these issues we’ve discussed many, many times and other people who have worked on this studies can vouch for that. One of the issues is selecting source of specimens. Do you collect blood? Do you collect buccal samples? Do you collect newborn blood spots, etcetera? How do you maximize participation rates? And of course, that’s a problem in any sort of study, but it’s a particular problem when you’re asking people to give their DNA. Human subjects related issues, informed consent for studies of genes that haven’t even been identified yet, and disclosure of individual results. Do you give people their individual genetic results if they could potentially mean something about their health? And then, the last area that I’ll talk about is how do you choose what genes--Cindy has just told you there’s 25,000 genes that are predicted in the human genome. How do you decide which ones to look at?
So first of all, selecting source of specimens and I think there are three major types of specimens that have been used in different genetic epidemiologic genetics studies in the past. One is venous blood, another is buccal cells; and they can be collected by a soft swab, they can be collected by a cytobrush, they can be collected with the swab putting on to something called an FTA card where the saliva is absorbed into the card and the card can be mailed off, mouthwash samples and saliva samples. Another possibility is newborn blood spots, and as this audience is well aware, newborn blood spots are collected on almost every newborn that’s born in the United States, and those are--in about half the states are stored at least six months or longer and about quarter of the states have done some sort of epidemiologic studies with those blood spots. So that’s another opportunity and can potentially make it easier to collect, or to potentially make things more complicated.
So what are the issues to consider when you’re selecting source of specimens? One is the amount of DNA; another is the quality of the DNA; another is what are the other possible uses of the sample source. For example, if you’re looking at blood, you could look at chemicals in the blood like lead or cotinine, or other sort of things. If you have buccal cells, you can look at DNA. The cost and the ease of collection, obviously, if you have to have a phlebotomist, go to the person and draw their blood, either go to the person or have the person come to the phlebotomist, it’s a lot more expensive and it’s a lot more of a hassle. Another issue is age of participants, and that has two sorts of impacts one is that as a mother--many mothers are not that crazy about having their kid have their blood drawn and so is that--what kind potential impact is there going to have on participation rate if you have babies in your study and you're expecting blood to be drawn. Another issue is with mouthwash; babies aren’t very good with that swishing and spitting. And then finally, what's the impact on the participation rates? And clearly there have been studies that have shown that people are less likely to participate in studies when they have to have a needle stick.
So what was the decision made for the NBDPS? For our birth defects study we did decide on buccal cells and we collect them by cytobrush. It's a topic that we revisit nearly every year about this study that is there another set of samples? We do know that the quality of the DNA, and the amount of the DNA is not ideal for the large number of genes that we'd like to look at. On the other hand, we only have so much money and we know that if we were asking for blood, we think our participation rates would suffer.
So the next issue is participation rates. I'm not sure how well you can see, when I was in the back earlier today, I couldn’t see the slides at all, but hopefully you can see a little bit, but the green one--and how did you get this pointer to work, Cindy?
SONJA RASMUSSEN: Yeah. It doesn’t--okay, I'm just going to go without it. The green is interview participation rates, and these are data from Atlanta. From the Atlanta site of the National Birth Defects Prevention Study for the years 1999 to 2002, and these are data that were published in AJFE earlier this year, Krista Crider is the first author. And you can see that in the interview portion of the study, our participation rates aren’t too bad. Seventy-two percent overall, the farthest one on the right is overall, and they vary by race, but not as much as if you look at the light yellow color, that's the buccal cell collection and you can see that we have significant differences in percents of participation and participation rates by race ethnicity. We want to have at the end, results that are generalizable and to the general population and if people don’t participate, we're not going to be able to do that.
So what are the barriers to people participating? Krista looked at some of the factors associated with higher participation and buccal cell collection. Non-Hispanic, white race ethnicity was a factor associated with higher participation, English language versus Spanish language, receipt of a redesigned mailing packet and an additional $20 incentive when we saw that the participation rates were not as high as we'd like them to be, an additional $20 incentive was added and that has had an impact, a positive impact. And then finally we looked at some demographic and personal factors and consumption of folic acid was associated with better participation rates. And it was interesting that when she looked at within different race ethnic categories that the factors associated with higher participation were different.
And our group is planning a study that there will be focus groups trying to understand why the person who declined to participate, why they declined to participate, was it that they were too busy? Was it that they didn’t understand the instructions? Was it that they just really don’t want their DNA in a bank at CDC? So those are the issues that we hope to be able to better understand.
Another major issue are related to--set of issues is related to human subjects. And one of the things is informed consent. And how do you give informed consent for studies of genes that you haven’t even identified? And Wylie Burke and Dikama in this paper in 2006 talk about--you can either request people to give a blanket kind of consent where you ask them, you tell them we're going to be doing a bunch of genetics studies and please agree to that and you don’t go back and try to get additional consent. She talks also about periodic re-consent, and obviously that periodic re-consent is going to be hard. It's hard to find people a couple of years later and go back and try to explain again and once again that would limit participation in the studies and limit the usefulness of the information we're going to get from the study.
We were exactly in this situation when the study started in 1997; we had plans for these biologic specimens to be used for decades. We planned to study hundreds of--now we really think thousands of different genetic factors and we knew that some were not even discovered yet, and the methods of the study were likely to change. The informed consent states that--so we did sort of somewhat in between, we’re not going back for re-consent, but we did limit the studies that could be done to genes that have a role in birth defects causation. We have made a deal with the IRB. The interaction we have with the IRB is that every time we want to do a new gene, we put together what we affectionately call a gene one-pager. The investigator submits that gene one-pager to the CDC IRB for an expedited review as an amendment, and this really is asking about what gene is being studied, why are we wanting to study it, and is it of clinical significance? And if it is of clinical significance, what additional efforts that concern human subjects protection will be made by the investigators?
Another important issue is, are we going to give results back to people? And I think this is really a major area of interest right now on the ethics literature and in the genetics literature. And there really are two ends to the spectrum. One is sort of a research-focused approach thing. Well, these are research tests and we’re not going to give any results back. The other side of it is more of an autonomy focused approach that says results--these are those people’s results and they deserve to get it back. And I think most people are finding some place in the middle. There has been a recent National Heart, Lung, and Blood Institute working group that the results of that were published in 2006 and they’ve identified some key criteria that should be considered when you’re thinking about whether or not you should return results to people. The risk of the disease should be significant. It should have important health implications. And there should be proven therapeutic or preventive interventions that are available. And that the final decision, that it isn’t a blanket sort of decision, the final decision should be made with IRB approval after careful consideration of risks and benefits. There are some additional issues; the testing needs to be done in a CLIA-certified laboratory. There needs to be a qualified person to give the results. It shouldn’t be just a piece of paper handed to the person, but actually a counselor should discuss the results with the families. And then the information about what to do with those results should be given on a--preferably, on a single page.
And so these are similar to the decisions we’ve made with the NBDPS. The testing does--four genes of clinical significance, has to be on a CLIA-certified laboratory. The study participants are notified of aggregate results of genetic factors with clinical significance by an NBDPS newsletter that comes out annually. The participants can request results if desired. That was really to weigh between giving people results that they didn’t want, that they didn’t request and not giving results at all. And the informed consent form reflects this approach.
And there are some other issues that are really too complicated for that two-minute sign there that I’m getting, so I’ll just briefly go over this. But it’s important to remember that when you do genetic studies, you don’t just learn something about the patient that you’re looking at. You learn about the family. You can learn about non-paternity and in addition you can learn--there are additional issues related to reporting individual results on children; because who gives consent for those results to be given. Does a child’s parents give the consent? But then what if the child doesn’t want and when the child becomes 18 didn’t really want that information?
So finally, choosing genes for analysis, how do you choose out of those 25,000 genes which ones to analyze? And there’s really two main approaches. Do you pick genes that you know that might have something to do with the condition that you’re looking at? Or do you try to do some of the genome-wide studies that Cindy talked about. A candidate gene is one for which there is evidence of a possible role of the traitor disease that is under study. And it’s usually based on previously reported associations and epidemiologic or family studies, biologic plausibility, expression or linkage studies, or other factors. Where genome-wide studies, you’re really trying to do sort of a shotgun approach, a hypothesis generating type of approach trying to figure out what genes to--what genes might be associated. But you get a lot of false positives, you need huge numbers, you need a lot of money. And so there is this pull back and forth between--well, if I already knew that it was a problem, this other one I could find something knew. But it’s a lot more costly and I might get a lot of false positives.
So hopefully I’ve given you a quick run through of some of the challenges to incorporating genetics into MCH studies. I think it holds a lot of promise for better understanding, for disease ideology, and for possibly we hope for improved primary prevention but there are several considerations that need to be taken into account when designing a study that incorporates genetics. Thank you.