New Evidence of a Preventative Therapy for Gout

Among patients with cardiovascular disease, it’s a common complaint: a sudden, piercing pain, stiffness or tenderness in a joint that lasts for days at a time with all signs pointing to a gout attack. Gout and cardiovascular disease (CVD) appear to be intimately linked – they are frequently seen together although the underlying connection between the two remains unclear. When rheumatologist Daniel Solomon, MD, MPH, heard about a large, clinical study to determine if targeting inflammation among patients with a history of heart attacks could lower future risk of cardiovascular events, he immediately wondered if the new approach might help prevent gout attacks among these patients as well. Solomon and colleagues found a significant reduction in risk of gout attacks among patients who received the drug that targets a key inflammatory molecule, suggesting a new target for therapeutic strategies to prevent gout attacks. Their findings are published online today in Annals of Internal Medicine.

“By looking across diseases, we’re trying to put together a picture of the relationship between gout, cardiovascular disease and inflammation,” said Solomon. “There’s a long-held understanding that gout and cardiovascular disease travel together. We’re using data from the CANTOS trial to understand why.”

CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), sponsored by Novartis, was designed to test whether canakinumab, which targets interleukin-1β, could reduce risk of a future cardiovascular event. The study recruited people who had had a prior heart attack and who, despite aggressive care, had persistently elevated levels of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP).

CANTOS, which met its primary endpoints, also offers a treasure trove of data on 10,000 patients with a history of heart attacks. As part of the study, information on gout attacks and levels of baseline serum urate concentrations (a measure associated with the production of monosodium urate crystals that form in joints, tendons, kidneys and elsewhere) was collected.

Solomon et al. report that, over the course of the trial, 3 percent of participants taking the placebo had a gout attack. This percentage was reduced by half among participants taking the IL-1β blocker. Serum urate levels remained unchanged over time, suggesting that, importantly, the drug was acting on an independent mechanism to reduce risk of a gout attack.

“Our results suggest that targeting IL-1β could open up new therapeutic avenues for not only treating heart disease but also crystal diseases like gout,” said Solomon.

Canakinumab, manufactured by Novartis, has been shown in previous research studies to shorten the length of gout attacks but has not been approved by the FDA for gout treatment. Additional studies are ongoing to test the effectiveness of less expensive drugs, including generics, that target inflammation.

The CANTOS trial was funded by Novartis. Co-authors on the current study have received salary and/or research support from the following: AstraZeneca, Kowa, Pfizer, Novartis and the NHLBI. Additional details regarding funding and conflict of interest can be found in Annals of Internal Medicine.

Paper cited: Solomon, D et al. “Relationship of IL-1 Blockade With Incident Gout and Serum Urate Levels: Exploratory Analysis of a Randomized Controlled Trial” Annals of Internal Medicine DOI: 10.7326/M18-1167

Clinical Gene Discovery Program Solves 30 Medical Mysteries

A table in a recently published paper tells the story of 30 families who have, sometimes after years of searching, finally received an answer about the condition that has plagued one or more family members. The Brigham Genomic Medicine (BGM) program, an integrated, multi-disciplinary clinical and research program, brings together world-class experts from across Brigham and Women’s Hospital as well as the entire Harvard-affiliated community to help in the search for these answers, using the power of whole genome sequencing or whole exome sequencing, in combination with other genomic methods, to scour the genome for new genetic culprits. The results of this exhaustive search and analysis can yield not only a diagnosis for a patient or family that has been desperately searching for one but may also offer information that could help guide novel treatment or predict if other family members are at risk. In a recent paper published in Genomic Medicine, the BGM team describes its program, one the team hopes will serve as a model for other academic medical centers or institutions that are endeavoring to solve medical mysteries using genomic sequencing and the power of scientific crowdsourcing.

“Every patient can be an important subject for discovery,” said lead and corresponding author Alireza Haghighi, MD, DPhil, a faculty and scientist in the Department of Medicine, Brigham and Women’s Hospital, and Harvard Medical School, and the lead clinical molecular geneticist of Brigham Genomic Medicine. “One single patient or family may lead us to know more about the genes and what they do, and maybe ultimately uncover new therapeutic pathways.”

Researchers have been working for decades to unravel how genetics contributes to disease. Today, while studies of thousands of people have uncovered many disease associations, the function of much of the genome remains unknown. The BGM program’s approach takes advantage of state-of-the-art genomic technologies and access to genomic information from healthy individuals to filter out non-disease-causing genes and mutations and focus in on genetic alterations that might be driving an individual’s disease.

“We hope that some of the findings may ultimately inform drug discovery efforts,” said Haghighi.

The BGM program has developed new computational analysis pipeline – a workflow that uses computer programming for genomic analysis. “We have developed software, algorithms, and methodology optimized for the effective analysis of genome sequencing data and for the discovery of new disease-causing genes,” said Shamil Sunyaev, PhD, distinguished chair in Computational Genomics, a professor of medicine at BWH and a professor of biomedical informatics at Harvard Medical School.

The team also uses a crowdsourcing strategy. “While one analyst is responsible for each case, an interdisciplinary team that includes clinical experts from many different fields analyzes the data independently and interactively and discusses the findings. Our approach provides an opportunity for faculty across the Harvard community to look at both the genetic data and clinical information and contribute insights on these cases to help find a cause,” said Joel Krier, MD, clinical chief, and a faculty scientist in the Division of Genetics, Brigham and Women’s Hospital and Harvard Medical School.

Added Haghighi, “This approach reduces cost and time. Cases like these can be very expensive to solve when patients must go from one expert to another in search of answers, undergoing many different diagnostic procedures. We think that crowdsourcing provides an important opportunity to help these patients and the health care system.”

So far, the program has successfully identified culprit genes for 30 families. Patients are referred to it by their physician after their doctor has tested for known genetic causes of disease and been unable to find a cause. “After the BGM team performs genomic sequencing, analysis and crowdsourcing, we share their findings back with the patient’s physician and strategize together about a new or improved clinical management plan for the patient,” said Krier.

In some cases, findings can yield answers for an entire family. As reported in a paper published by the BGM team in The Proceedings of the National Academy of Sciences, one family has received critical information about the cause of a rare aortic disease, with implications for diagnostics and treatment going forward.

“Family members carrying the disease-causing mutation are now being monitored for aortic dilatation, which represents a significant therapeutic benefit to the family, enabling earlier interventions,” said Krier. Haghighi and colleagues hope that the findings from this family and others will lead to insights for therapeutic targets for the development of new treatments.

A distinctive feature of BGM is its focus on undiagnosed cases that are refractory to standard diagnostic approaches. In addition, the program provides an integrated and continuous pathway from case ascertainment to treatment. “While there are research programs that look for gene-disease associations, taking this approach in the practice of genomic medicine represents a new model,” said Richard Maas, MD, PhD, chief of the Division of Genetics at Brigham and Women’s Hospital, and a professor of medicine at Harvard Medical School. “By performing genome sequencing for gene discovery in a clinical setting with clinicians, we hope to improve individual treatment plans or therapeutics. Our model can be readily adapted by other academic medical centers around the world.”
Funding for this work was provided by a Brigham Research Institute Director’s Transformative Award, National Institutes of Health grants R01-GM078598-05, U01-DE024443-01 (NIDCR FaceBase Consortium), U01-HG007690-01 (NHGRI Undiagnosed Disease Network), P30-DK034854, a Crohn’s and Colitis Foundation RFA; the Helmsley Charitable Trust and the Wolpow Family Chair in IBD Treatment and Research.

Paper cited: Haghighi, A et al. “An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery” Genomic Medicine DOI: 10.1038/s41525-018-0060-9

Study Shows Importance of Personal Social Networks on Neurological Outcomes

Are healthy and unhealthy habits contagious? Can a person’s social network influence their risk of disease? It’s a contentious idea but one that researchers want to explore in the future and better understand. A new study by investigators from Brigham and Women’s Hospital helps lay important groundwork for such studies by developing and making accessible scalable tools to allow clinical researchers to assess social networks in a robust and quantifiable way. In addition, using data from a cohort of participants in the federally funded Genes and Environment in Multiple Sclerosis (GEMS) Project, the team reports finding an association between the habits of people connected to a participant and that person’s level of self-reported neurological disability. The team’s results are published online today in Nature Communications.

“We find that there’s a strong relationship between the health habits of people in a patient’s social network and outcomes that are of interest to physicians who specialize in multiple sclerosis. This relationship must not be ignored when considering an individual with neurological disabilities. We need to ask, ‘Is this person’s risk based solely on their biology, or is it influenced by the healthy or unhealthy lifestyles of those around them?’” said lead author Amar Dhand, MD, DPHIL, a neurologist in the Department of Neurology at BWH.

Dhand and colleagues have developed a social network assessment tool that can be applied to any patient population. To test it, they used the tool to measure the social networks of 1,493 people at risk of multiple sclerosis. Participants were asked to complete a brief questionnaire to assess neurological disability based on the person’s self-reporting of several abilities including walking, using arms and hands, vision, speaking clearly, swallowing, cognition, sensation and bowel and bladder function.

The team plotted a montage of each participant’s social network (see image), finding that the average network consisted of eight people who were densely linked. The team also plotted the milieu of health habits around each participant, including exercise, smoking and seeing a doctor. The researchers found that the health habits of the people in one’s social network were strongly associated with the participant’s self-reported neurological dysfunction, and the percent of network members who have a negative health influence had the strongest association with disability.

While it’s still early for the GEMS Project cohort – participants have been enrolled in the study for less than five years – Dhand and colleagues plan to continue assessing the relationship between participants’ social networks as well as genetic risk factors and other environmental factors in the development of symptoms of MS.

“We hypothesize that there is a link between social networks and neuro-immunological function, and, downstream, we plan to look at what social network features are related to disease susceptibility,” said Dhand.

Funding for this work was provided by National Institutes of Health grants K23HD083489, K08NS079493, and National Multiple Sclerosis Society RG-5003-A-2. The authors declare no competing interests.

Paper cited: Dhand, A et al. “A scalable online tool for quantitative social network assessment reveals potentially modifiable social environmental risks” Nature Communications DOI: 10.1038/s41467-018-06408-6

A New Model Takes Oxidative Stress to Heart

Using a novel approach called ‘chemogenetics,’ BWH investigators are shedding new light on a key molecular mechanism that can lead to heart failure

Oxidative stress – the molecular wear and tear that reactive oxygen species can exert on molecules and cells – has been linked to a range of human diseases, including heart failure and Alzheimer’s disease. But the results of many clinical trials that tested the effects of combatting oxidative stress with simple remedies – such as vitamin supplements or blueberries – have painted a more complicated picture.  For many years, researchers have been trying to tease out the nuances of the connections between oxidative stress and disease. But the diseases associated with oxidative stress typically involve multiple pathways in the body, and it has been challenging to define the specific roles of oxidative stress in disease progression at a molecular level. Investigators from Brigham and Women’s Hospital have developed a robust new method for examining oxidative stress in the hearts of rodents in vivo to better understand the development and treatment of heart failure. Results of their novel methodology, applying a cutting-edge approach known as “chemogenetics,” are published this week in Nature Communications.

“This is a new heart failure model that allows us to specifically study a critical player in heart disease: oxidative stress. This is the first time that we’ve been able to prove definitively that oxidative stress is a cause of heart failure,” said Thomas Michel, MD, PhD, senior physician in the Brigham and Women’s Hospital (BWH) Division of Cardiovascular Medicine and professor of medicine at Harvard Medical School.

Chemogenetics is an approach that allows researchers to activate or inactivate a recombinant protein in cells or tissues simply by providing or withdrawing the specific molecules that bind to the protein. The BWH researchers developed an in vivo method using this approach that allowed them to generate and measure a reactive oxygen species – hydrogen peroxide – specifically in the heart, and then monitor the onset of cardiac dysfunction. Michel’s team is using this approach to create a more tractable preclinical model of heart failure to help increase the speed and scope of drug development and testing.

“A lot of the models of heart failure that have been used for drug development have moved forward one animal at a time,” said Michel. “But with chemogenetics, a path is opening up for high-throughput screening of new heart failure drugs.”

To examine oxidative stress on the heart, the research team took advantage of a D-amino acid oxidase (DAAO) – an enzyme that was cloned from yeast. DAAO is known to generate hydrogen peroxide (H2O2) only in the presence of D-amino acids, leading to oxidative stress. But mammalian cells use L-amino acids, not D-amino acids: a subtle but important difference that allows the introduced yeast enzyme to remain quiescent until it’s provided with its D-amino acid substrate.  The team used a virus to deliver DAAO to the hearts of rats, and then the animals were provided with drinking water containing a D-amino acid in order to activate the DAAO. After 4-5 weeks, the team examined hearts using echocardiography to measure cardiac function and heart size. Additionally, the researchers measured markers of inflammatory and adaptive stress.

Compared to animals that received a control virus, the rats expressing DAAO showed signs of advanced heart failure, including increased heart size and decreased contractile function, which were specifically caused by oxidative stress in the heart.

“We anticipate that chemogenetic approaches will enable future studies not only in the heart, but also in the many other organ systems where the relationship between redox events and disease remains unclear,” said co-lead author Ben Steinhorn, a Harvard MD-PhD student who pursued his PhD in Michel’s lab.

“Heart failure can now be examined in a rapid, reliable, and reversible manner,” said co-lead author Andrea Sorrentino, a BWH postdoctoral research fellow. “Instead of doing surgery one animal at a time, we can deliver the virus to many animals at once, and then activate the DAAO enzyme just by providing its substrate in their drinking water to trigger specifically oxidative stress in the heart.”

With funding from the Brigham and Women’s Hospital Health and Technology Innovation Award, Michel’s lab is also developing a transgenic mouse – an animal model whose genome has been altered to encode DAAO, allowing researchers to skip the viral vector and more easily study oxidative stress.

Funding for this work was supported by NIH grants PO1-HL48743 and RO1-HL46457 (to TM); T32-GM007753 (to BS); American Diabetes Association grant 9-17-CMF-012 (to AS) NIH T32-HL007604 (to SB); Brigham and Women’s Hospital Health and Technology Innovation Award (to TM); and Russian Science Foundation grant 17-14-01086 and DFG IRTG 1816 (to VB).

Paper cited: Steinhorn, Benjamin et al., Chemogenetic generation of hydrogen peroxide (H2O2) in the heart induces severe cardiac dysfunction. Nature Communications. DOI: 10.1038/s41467-018-06533-2

Illustration depicting Transcribed Noncoding Elements (TNEs).

Genomic Dark Matter Activity Connects Parkinson’s and Psychiatric Diseases

Comprehensive study reveals an expanding universe of ‘darkest of the dark-matter’ RNAs in dopamine-producing cells in our brains

Dopamine neurons are located in the midbrain, but their tendril-like axons can branch far into the higher cortical areas, influencing how we move and how we feel. New genetic evidence has revealed that these specialized cells may also have far-reaching effects, implicating them in conditions that range from Parkinson’s disease to schizophrenia. Using a new technique known as laser-capture RNA seq, that involves cutting out dopamine neurons from a human brain section with a laser, investigators from Brigham and Women’s Hospital and Harvard Medical School have cataloged more than 70,000 novel elements active in these brain cells. Their results are published this week in Nature Neuroscience.

“We found that a whopping 64 percent of the human genome – the vast majority of which is ‘dark-matter’ DNA that does not code proteins – is expressed in dopamine neurons in the human brain,” said Clemens Scherzer, MD, a neurologist and genomicist who directs the APDA Center for Advanced Parkinson’s Disease Research and leads the Precision Neurology Program at BWH. “These are critical and specialized cells in the human brain, which are working sluggishly in Parkinson’s disease, but might be overactive in schizophrenia.”

Scherzer’s team developed laser-capture RNAseq to precisely dissect out dopamine neurons from the brain and perform ultradeep RNA sequencing on human brain cells. From 86 post-mortem brains, the team was able to extract more than 40,000 dopamine neurons. While other groups have focused on protein-producing messenger RNA, Scherzer and colleagues wanted to catalog the cells’ entire RNA content, which required taking a much deeper dive.

In total, they found 71,022 transcribed noncoding elements (so called TNEs). Many of these TNEs (pronounced “teenies”) are active enhancers – sites that act as regulatory “switches” for turning on specialized functions for billions of neurons in the brain. Many of the TNEs the team unearthed are novel and had never before been described in the brain. Working with collaborators in England, Scherzer and colleagues tested several of the TNEs in preclinical models, including zebrafish, finding evidence that many were active in brain development.

Scherzer and first-author Xianjun Dong, PhD, who are also Principal Investigators at the Ann Romney Center at BWH, originally set out to study dopamine neurons to gain insights into Parkinson’s but found that many of the genetic variants associated with schizophrenia, addiction and other neuropsychiatric diseases were also enriched in these elements.

“This work suggests that noncoding RNAs active in dopamine neurons are a surprising link between genetic risk, Parkinson’s and psychiatric disease,” said Scherzer. “Based on this connection we hypothesize that the risk variants might fiddle with the gene switches of dopamine-producing brain cells.”

The team has also made an encyclopedia of RNA content for dopamine neurons publicly available so that other investigators can look up any protein-coding or noncoding target for biomarkers and therapeutics for Parkinson’s and psychiatric diseases through the webportal

This study was funded by the National Institutes of Health (grants U01 NS082157, R01AG057331, NIA P30 AG028383, NIA P50 AG005134) and the US Department of Defense, the Michael J. Fox Foundation (MJFF, the Australia NHMRC GNT1067350, UK Wellcome Trust Investigator award, NINDS U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders. Scherzer has collaborated with Pfizer and Sanofi; has consulted for Sanofi; has served as Advisor to the Michael J. Fox Foundation, NIH, and Department of Defense; is on the Scientific Advisory Board of and has received funding from the American Parkinson Disease Association; and is named as co-inventor on two US patent applications on biomarkers for PD held in part by Brigham and Women’s Hospital. Additional disclosures can be found in the Nature Neuroscience paper.

Paper cited: Dong, X et al. “Enhancers active in dopamine neurons are a primary link between genetic variation and neuropsychiatric disease” Nature Neuroscience DOI: 10.1038/s41593-018-0223-0

Largest Study of ‘Post-Treatment Controllers’ Reveals Clues about HIV Remission

Some HIV patients maintain low viral loads after stopping treatment; early treatment and HIV reservoir size may be the keys

Most HIV patients need to take daily anti-retroviral therapy – if they suspend treatment, HIV will rebound within 3-4 weeks. But clinical trials have revealed that a small fraction of patients can stop taking medications yet keep the virus suppressed for 24 weeks or longer, maintaining viral control without the assistance of medication.

Much remains unknown about this unique group of individuals, known as HIV post-treatment controllers, including how rare this ability is. Two new studies – including the largest study of post-treatment controllers to date – explore the characteristics of this group as well as the biological mechanisms that may help explain this unique ability.

“Post-treatment controllers represent a natural model of sustained remission,” said Jonathan Li, MD, of Brigham and Women’s Hospital’s Infectious Disease Clinic and lead author on both studies. “Understanding these individuals can lead to new insights for HIV therapies.”

The researchers defined post-treatment controllers as having viral loads of 400 or fewer copies per milliliter of blood plasma for at least 24 weeks’ post-treatment interruption. The study characterized 67 post-treatment controllers, the largest cohort to date. They found these post-treatment controllers by sifting through data collected from over 700 participants in 14 clinical studies involving treatment interruption.

The CHAMP (Control of HIV after Antiretroviral Medication Pause) study, published in The Journal of Infectious Disease, examined what post-treatment control can tell us about HIV’s progression. The researchers observed that individuals treated early were significantly more likely to become post-treatment controllers. Previously published studies have found other benefits for early treatment, notably decreased risk of transmission to partners compared to treatment starting during chronic infection.

A second study published in The Journal of Clinical Investigation illuminated the biological mechanisms underlying post-treatment control. Li’s team sequenced viral DNA, which the HIV virus had woven into the patient’s DNA.

The team observed that post-treatment controllers had lower levels of intact viral DNA prior to treatment interruption. In other words, post-treatment controllers carried smaller viral reservoirs. Li believes that reservoir size could represent a useful biomarker to help predict which patients will become post-treatment controllers.

In addition to intact viral DNA, Li and his team found that reservoirs of defective viral DNA may offer novel insights for treating HIV. They observed that defective HIV DNA seemed to give rise to proteins that could interact with the immune system. They plan to study this further.

“Each year, there are millions of new HIV infections,” said Li. “The results of these studies may help inform the design of strategies and trials aimed at achieving HIV remission, which we hope will bend the curve of this epidemic.”

The CHAMP Study received funding from the Harvard University Center for AIDS Research (NIAID 5P30AI060354-08), National Institutes of Health (NIH) grants (AI125109, AI106039, UM1 AI068634, UM1 AI068636, UM1AI069419, UL1RR024996, subcontract from UM1 AI106701 to the Harvard Virology Support Laboratory, AI100665, AI036214, AI111806, AI125026, AI27757, AI127966, U01 AI41531) and Harvard University Center for AIDS Research (P30 AI060354, which is supported by the following NIH co-funding and participating Institutes and Centers: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, and OAR). Other partial supports were provided by the amfAR Institute for HIV Cure Research (amfAR 109301), Fonds de recherche en santé du Québec, SIDA Maladies infectieuses and Canadian Institute of Health Research (CIHR #385806).

The study published in JCI received funding from National Institutes of Health/National Institute of Allergy and Infectious Diseases grant AI125109, the Harvard University Center for AIDS Research (5P30AI060354-08 to JZL and RTG, 5P30AI060354-14, UM1AI068634 (Statistical and Data Management Center of the AIDS Clinical Trials Group), UM1AI068636 (AIDS Clinical Trials Group), a subcontract from UM1AI106701 to the Harvard Virology Support Laboratory, UM1AI126617 and UM1AI069423.

Studies Cited:

Namazi & Fajnzylber et al. The Control of HIV after Antiretroviral Medication Pause (CHAMP) study: post-treatment controllers identified from 14 clinical studies. The Journal of Infectious Disease. DOI: 10.1093/infdis/jiy479.

Sharaf et al. HIV-1 Proviral Landscapes Distinguish Posttreatment Controllers from Noncontrollers. The Journal of Clinical Investigation. DOI: 10.1172/JCI120549.

Barriers to Entry: Study Explores Why Parents Declined Genome Sequencing of Their Newborns

Imagine that you are in the hospital the day after your child is born. If a researcher approached you and asked if your family would like to enroll in a study in which your newborn’s genome might be sequenced, would you accept? Brigham and Women’s Hospital and Boston Children’s Hospital investigators for the NIH-funded BabySeq Project report that of the more than 3,800 families they approached, only 268 ultimately enrolled in their study to evaluate the medical, behavioral and economic outcomes of newborns provided an opportunity for free genomic sequencing prior to discharge from their birth hospital. In a paper published in Genetics in Medicine, the team reports on the reasons for the high rate of decline, many of which had less to do with genetics or privacy concerns than with a low interest in research in general as well as dealing with the logistical challenges of participating in a complex research study when offered immediately after the birth of a child.

“We found that families declined the opportunity to have their newborn sequenced for various reasons, many having nothing to do with genetics, but rather because of exhaustion, stress or simply not wanting to participate in any research,” said senior author Richard Parad, MD, MPH, director of the Newborn Genomic Medicine Program in Brigham’s Department of Pediatric Newborn Medicine. “To continue advancing evidence-based care of newborns, it is critical to be able to enroll families in research studies around the time of birth. Of course, we understand that we are approaching them at a very challenging and overwhelming time.”

The BabySeq Project is the first randomized, controlled clinical trial of sequencing in both healthy and sick newborns, with half of enrolled families receiving standard newborn screening (including the state-mandated “heel prick” test that screens for a limited set of genetic conditions) and half receiving whole-exome sequencing. For the latter group, the BabySeq team returns genetic results related to childhood onset conditions, both carrier status and disease risk.  A small group of actionable, adult onset conditions such as hereditary cancers that can be screened for early, are also assessed. Parents who enrolled had an additional blood sample drawn from their newborns, and agreed to return to the hospital to receive results as well as complete follow-up surveys over the first year of life.

“This study is the first of its kind to offer genomic sequencing to both healthy and sick newborns,” says Casie Genetti, MS, CGC, a genetic counselor in the Manton Center for Orphan Disease Research at Boston Children’s Hospital and first author on the paper. “In speaking with parents, we have learned a great deal about what motivates some families to participate, but also documented the concerns, like genetic discrimination and uncertainty around the results, that make many of them hesitate to join such research.”

Of the 3,860 families approached, only 402 agreed to attend an enrollment session to hear more about participating in the project. The team surveyed more than 1,700 declining families to explore their reasoning. More than 58 percent responded that they were “not interested in any research.” Of parents who provided reasons for specifically not participating in the BabySeq Project, over 40 percent cited logistical concerns, such as the inconvenience of returning for the research visit, 15 percent reported feeling too overwhelmed to make a decision, 15 percent had concerns about privacy and insurance discrimination issues and 12 percent anticipated feeling uncomfortable with receiving either uncertain or bad news results.

Of the 402 families who agreed to hear about the details of the study, 67 percent enrolled. The enrollment session provided an overview of the study logistics, genomic testing, results to be returned and stored in the baby’s medical record and described protections for genetic privacy and against genetic discrimination. Interestingly, families that declined to enroll after this session cited different reasons for decline than those who declined on initial approach, more commonly citing discomfort about the potential results they could receive as well as concerns about privacy and insurance discrimination.

“The BabySeq Project is one of the rare genomics studies to begin its recruitment opportunity with a truly representative population of new parents,” said Robert Green, MD, MPH, Professor of Medicine in the Division of Genetics at BWH and Harvard Medical School, and co-director of the study with Alan Beggs, PhD, Professor of Pediatrics at Boston Children’s Hospital. “These results remind us how difficult it is to enroll truly representative samples into any form of research, and how especially difficult it is to enroll new parents who are stressed and fatigued immediately after birth. But it also reassures us that families were fully capable of asserting their consent in this vulnerable moment, and reminds us that genomics research cannot fully flourish until we address societal considerations like protecting participants from future life insurance discrimination.”

Early results around the medical, behavioral and economic outcomes of the BabySeq Project will be presented at the upcoming American Society for Human Genetics Annual Meeting in October.

Funding for this work was provided by grants U19 HD077671 and R01 HD075802 from the National Institute of Child Health and Human Development and National Human Genome Research Institute of the National Institutes of Health, as well as by the Manton Center for Orphan Disease Research of Boston Children’s Hospital.

Paper cited: Genetti, C et al. “Parental interest in genomic sequencing of newborns: enrollment experience from the BabySeq Project.” Genetics in Medicine 10.1038/s41436-018-0105-6