September 15, 2022 | The greater New York metropolitan area is the epicenter of an ambitious human genome sequencing research project newly launched by Mount Sinai Health System and the Icahn School of Medicine at Mount Sinai in collaboration with the Regeneron Genetics Center (part of biotechnology company Regeneron). If the vision is realized, Mount Sinai will enroll a million patients into a study over the next five years that will sequence and analyze the DNA in their blood to tease out the role of genetics and environment on health, according to Alexander W. Charney, M.D., Ph.D., associate professor of psychiatry, and genetics and genomic sciences, as well as leader of the Mount Sinai Million Health Discoveries Program.
“Genetics is moving us into the future where every treatment is data-driven for a given patient,” says Charney, who is also director of The Charles Bronfman Institute for Personalized Medicine at Icahn Mount Sinai. Researchers already have a sizeable dataset available from Mount Sinai’s BioMe Biobank—a growing repository containing genomic information on tens of thousands of patients across the five boroughs of New York City—which Charney most recently tapped to find rare patient-specific genetic subtypes of schizophrenia.
But that’s still not enough data to confidently answer basic questions like whether genetics can help predict treatment outcomes, he notes. To solve those puzzles, mathematical models require an extremely large dataset to account for the multitude of variables that might explain a result.
In contrast to NIH’s All of Us program, the Mount Sinai initiative aims to recruit participants from within its existing patient pool. It’s a funding challenge. In academic medicine, it is not financially feasible to sequence the genomes of a million people using traditional mechanisms such as philanthropy and government grants, continues Charney. The Regeneron Genetics Center, on the other hand, had the will and wherewithal. The company is physically close to Mount Sinai, academically oriented, and has a proven track record of doing the sequencing work at scale and partnering with academic institutions.
The big challenge now is to execute on the vision, which includes overcoming logistical hurdles such as electronic systems that don’t talk to each other, educating busy clinicians and uninformed patients of the value of their participation, and simplifying the enrollment process, Charney says. All the information needed for the study is fortunately already embedded in the electronic health record (EHR), which effectively shortens the interview process with patients and should enhance their chances of enrolling.
“It is really an all-hands-on-deck situation,” he says of the study. “We want everyone who works in the Mount Sinai Health System to say this is something they are part of... and [see that] it’s worth doing.”
Co-leaders of the genome sequencing research project are Girish N. Nadkarni, M.D., Dara Meyer, and Rachelle Weisman, all at Icahn Mount Sinai. Nadkarni is also, along with Charney, the director of the Institute for Personalized Medicine, which is administering the Mount Sinai Million Health Discoveries Program.
The enrollment conundrum has been encountered in other studies conducted at Mount Sinai involving biospecimen collection from many human subjects, says Charney. He draws from personal experience on two particularly challenging studies. The first, the Living Brain Project, began a decade ago where researchers wanted to obtain samples from the brain of living people. What is known about the brain is based entirely on what could be learned from organs donated after death which, he says, is problematic because at the biological level brains after life are unlikely to be the same as those during life.
To test that theory, Charney and his colleagues did the seemingly impossible with a simple but creative solution: place a research coordinator next to neurosurgeons already planning to remove a bit of healthy brain tissue from patients for various clinical care purposes. Instead of throwing the healthy brain tissue in the garbage, the samples are conserved for research purposes, he explains.
Other than obtaining consent, neither the physician nor the patient has to do anything different. Mount Sinai consequently grew—and continues to grow—the biggest collection of brain tissue from living people in the world, says Charney.
Similarly, for 48 days early in the COVID pandemic, Mount Sinai investigators succeeded in enrolling patients into a study who had recently come in for a blood draw by storing those samples in a freezer and approaching them later for consent rather than while they were masked, sick, and terrified within hospitals under siege by the unknown virus (including at a tent hospital in the park), Charney says. This sensible approach resulted in 90% of patients agreeing to participation.
Charney says he believes that getting to the one-million goalpost with the new sequencing research project will also happen simply by thinking through the potential barriers. Every year, 300,000 individuals in the health system are getting their blood drawn for clinical purposes and, if those tubes were stored, the research team could theoretically get consent from most of them. How to best go about doing that is not a settled issue.
The more immediate challenge will be setting up an interoperable system for tracking blood samples, which will be collected at eight different hospitals and dozens of outpatient clinics comprising the Mount Sinai Health System but be sent via a courier service to one central storage location. Charney and his team need to create new systems to report when tubes of leftover blood are sent to the central lab and to know which freezers house which samples.
All those electronic systems will need to connect and communicate in a coordinated, effortless way, he says. Existing systems will need to be modified to enable the information exchange.
Roles And Responsibilities
Regeneron’s role with the Mount Sinai Million Health Discoveries Program is the same as it was for the BioMe Biobank—to do the exome sequencing, whole-genome genotyping on all the DNA samples, and whole-genome sequencing on a subset of those samples, Charney says. Mount Sinai is contracting with Vibrent Health, the technology platform for the National Institutes of Health’s million-person All of Us Research Program, to handle e-consenting, data collection, and participant engagement.
Vibrent’s user-friendly platform allows people to consent using a digital device, a streamlined approach consistent with studies at this scale, he continues. In lieu of reading through a huge packet of printed information in front of a research coordinator, individuals will be able to watch a video that summarizes the study and highlights the most important points. They’re then able to go through the consent form at their leisure and answer a few questions to verify their comprehension before choosing to enroll or not.
Beyond enrolling study participants, Mount Sinai will provide deidentified data on those patients from the EHR system. The EHR will be used in a few different ways, says Charney, including to understand who has had blood drawn and where those patients were being treated to guide recruitment efforts.
It will also be used to create a deidentified dataset—a limited set of patient information, like medications prescribed or diagnoses given, scrubbed of anything that might make people knowable—which researchers in and outside Mount Sinai might analyze along with the companion genetic data to get insights into the genetic basis for disease, Charney says. Researchers at Mount Sinai may additionally want the genetic data to be tied back to other patient information that isn’t captured in the EHR, such as imaging tests and EKGs.
Only the more limited deidentified dataset will be broadly available to other academic institutions, he adds. The particulars of the external data-sharing process haven’t yet been established.
The research team is taking a multifaceted approach to patient recruitment for the Mount Sinai Million Health Discoveries Program, Charney says, emphasizing that the focus is on informing people who are getting treatment at Mount Sinai anyway versus a citywide enrollment campaign. “This is a study on the patients we treat... so it is really a matter of engagement within our health system.”
An app specific to Mount Sinai will be used to interface with healthcare providers and spread awareness and information about the study, he continues. Outreach efforts will be sweeping and touch everyone, including doctors, nurses, social workers, patient care associates, and other staff and faculty throughout the Mount Sinai Health System as well as patients directly. “That’s how we’ll make sure patients coming to Mount Sinai will have heard about the study and be given the basics and then the opportunity to choose to participate or not through the informed consent process.”
Clinician engagement has been both an opportunity and a barrier, Charney says. Physicians, for example, are “always spread too thin” and recruiting patients into a study will at times fall to the bottom of their priority list.
Likewise, phlebotomists are probably not interested in the inconvenience—to themselves as well as patients—of doing additional blood draws for a study, he continues. Taking that piece out so they’re not doing anything extra for research purposes makes them feel considered and thus more interested in participating.
To appreciate the potential of one million sequenced human genomes, Charney points to scientific discoveries already made with the more limited BioMe dataset. He and his colleagues used it for a study of schizophrenia, for example, to look at 10 genes recently identified to harbor higher rates of rare damaging genetic variants in individuals with the disease compared to healthy controls (Nature, DOI: 10.1038/s41586-022-04556-w).
The new investigation looked at 30,000 patients in BioMe to identify individuals with these types of rare damaging genetic variants in the 10 genes. One person they identified didn’t have any severe mental illness, but schizophrenia affected four siblings and across many generations schizophrenia as well as intellectual disability was reported. With the family’s partnership, further studies might now be done to explore the suspected genetic cause and potential treatments of the disease in the affected family members.
Cancer researchers at Mount Sinai seem particularly enthusiastic about the Million Health Discoveries Program, says Charney. They view it as “an amazing resource for understanding how cancer occurs” by allowing a comparison of the regular genome of the patients they treat with information gleamed from the tumors they later develop.
Making sense of all the big data being generated by the Mount Sinai Million Health Discoveries Program requires multi-modal data science looking at genetics in the context of all the different levels of biology (proteins, RNA, lipids, and metabolites) that are “interacting in ways we don’t quite understand,” as well as data contained in the EHR, Charney says. “More data does not mean answers... we need tools to parse information out of all this data.”
The “last mile” in this discovery journey will be to rigorously test new treatments and interventions before they are incorporated into clinical care, he notes. Data and statistical techniques can be used to make sound predictions about health outcomes, which can then be built into the interface that clinicians use as they’re treating patients. But too often this has been done without first pragmatically testing whether the information is in fact helpful, or just creates more confusion among clinicians and patients in the real world.