The processes in the lab are what it is related to. In clinical research, sample tubes labeled with bar code are double checked in multiple places so that we can be certain that the genetic result belongs to the patient. Research studies don't pay for that process because it's more expensive and may involve running smaller batches.
There is a difference. Even with clinical standards, there is always an element of imperfection in understanding genetic results.
What do you mean?
Maybe you are certain that there is a genetic change in a patient. Every human has a bunch of genetic changes that are specific to them. The hard part of being a geneticist is figuring out which variant causes disease or increases the risk of it.
What was it that you needed to show that the pathogenic variant was linked to the dissection?
We let other researchers evaluate the significance of the genetic variants we found. We contracted with other laboratories to see if the variants were causing disease. A leading physician-scientists studying aortic dissection made the call for us to look at the data from both the variant and control cases to see if the variant was a problem.
They sent us a list of only 26 that they thought were likely to cause disease. The 26 people carrying the pathogenic variant were all found to have aortic dissection cases. The healthy controls did not carry these genetic changes. The conclusions were correct, that reassured us.
We had to think about whether people would feel like they were being set up to get a disease.
What are some of the ethical considerations that went into notifying the patients?
There was a lot of discussion about the risks and benefits. If the information about the variant means they can get more timely treatment or head off a repeat of the problem, there is a clear benefit. The doctors could perform the surgery sooner if they wanted to. They might be more attentive to the diameter. They could suggest more specific counseling for reducing behavioral or lifestyle risk factors.
We wanted to make sure that the patient could act on this information to reduce their risk and improve their care.
We had to consider whether returning this result would cause patients a lot of stress and whether this news would affect their ability to have health care insurance, long-term disability or life insurance. We had to think about whether people would feel like they were being set up to get a disease. We wanted to reduce the risks as much as possible.
It is relevant to the research participant's family members since some of them may be carrying the same variant. How might the news change their treatment?
Some of the research participants already knew that a family member died suddenly in their 30s or 40s from a heart condition, but they didn't know the details. It's more likely that person died of a dissection because of the new genetic information. It is possible to screen the participant's children or grandchild to see if they carry a specific genetic change associated with that problem. Those individuals can have surgery earlier in life to repair their aorta, and be followed more closely in the clinic.
What did you do when you knew you had to give the biobank participants critical information?
The University of Michigan's ethics board worked with us to develop a procedure for notifying participants that we found a genetic change that causes this disease.
You told the participants.
We did not reveal the specific genetic change in the letter. We found some information that will be important to your medical care. Please make an appointment with this genetic counselor to learn more.
Why did you not communicate electronically?
Many of our patients are older and prefer letters over emails, and the results of previous surveys show that. We sent the letter by certified mail, so we knew when it was delivered.
Why was it important to keep the findings vague?
We didn't want recipients to be getting a letter in the mail with some potentially scary medical information in it and then searching the internet for the gene while not knowing that it was a research result, not a clinical test.
As you study other genetic variations, are you considering options for giving patients a choice in advance about what type of information they would like to receive in the letters mailed to them if they are found?
Absolutely. I think it's better for patients to have a say in how they receive information.
The letter may have been the end of your team's involvement with the biobank participants.
We followed up with a phone call from a genetic counselor, asking if you had any questions after we sent you the letter. We are happy to schedule the appointment for genetic counseling.
We followed up with the phone call and appointment in order to reduce the risk of stress on the research participant. After the letters went out, the genetic counselor blocked off appointments in her calendar for a week or two. We didn't think it was fair to send a letter and say, "Come and meet our genetic counselor." We don't have appointments. The research program covered the costs for genetic counseling and clinical testing that came out of this.
I think it's better for patients to have a say in how they receive information.
How is your protocol evolving?
We ask every participant if they would like to be informed if we find something in their genes that will affect their care. We only talk to people who said yes.
Have researchers at other universities or research centers gone through the same process?
Several institutions are sharing genetic information. One of the leaders is the Geisinger Health System. Patients in certain cases are being returned results from the Mount Sinai medical school. Most institutions are returning results from a clinical test. If you have genetic information on a patient, but it is only at a research level of accuracy, it is more difficult to ethically.
Do you think the approach you use might be a starting point for other researchers who want to decide what to do with similar information?
Our goal was to get that. The letters that we sent in our scientific manuscripts were provided by us.
Why is the Michigan Racial Equality and Community Health project important to you?
If we are only helping a certain group, it is very uncomfortable because we are motivated to help other people. Science and research taking advantage of people participating in studies have a history of unfairness. As we move forward, we wanted to make sure our research was conducted ethically.
One way I could make a difference was to make sure that different groups are represented in our research studies, because we can't understand how different genetic variants might predispose different groups of people to disease if we're not studying those people. If we don't have enough women with heart disease enroll in our studies, we can't understand the risk factors that predict heart attacks. We wanted to make sure we had representation of people with different genetic ancestry.
Black Americans are more hesitant to participate in research studies because of past harms. Unfortunately, the price we have to pay for this is that we can't predict and prevent diseases in those populations that areunderrepresented in our research. To ensure that our research benefits all people more equitably, I founded and direct MREACH, and pay for it from my faculty research funds.
How did you get people to buy in to the idea of creating a more diverse biobank?
To build trust, we had to be more transparent about our research and make sure that the people we are trying to help know about it. Having more dialogue and creating newsletters that go to participants helps.
Reducing the burden on people for joining a research study was important. Reducing the time required to participate and making the infrastructure as convenient as possible for participants who own blood sample information is what that is. Those kinds of obstacles can be used to screen out people who are historically marginalized.
What are some ways to do that?
Talking to people about the study while they wait to see their doctor is a better use of their time than trying to talk to them at the end of their appointment. Also, trying to get patients to come to the clinic. The consent team was put in place to meet the patients where they are, because we looked very carefully at the demographic of patients seen in our medical centers.
Kenneth Jamerson, a physician who has done a lot of research in this area and has a wonderful bedside manner, helped us design the research study to be as protective of patients confidentiality as possible. Every person in the study gets a research ID. People have to go through many approval processes to see any identifying information about a patient. The majority of our research is done with information that is not known who the patient is. I am the principal investigator of the study, and I don't see a lot of identifying information about patients.
