Inaccurate direct-to-consumer raw genetic data can harm patients, new research suggests

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Whether or not you’ve ever had genetic testing, you probably know someone that has. Millions of people each year have their DNA analyzed by companies like 23andMe and Ancestry.com, seeking out personalized information about their heritage, health and other traits.

“The general public is excited about genetics because it can tell us a lot about our past ancestry and, if the right technology is used, about our future­­ ­— such as the likelihood of developing certain health problems,” said Tia Moscarello, a genetic counselor with Stanford’s Center for Inherited Cardiovascular Disease. “These tests are popular for good reason: many people want to be proactive about their health without spending a lot of money or making a trip to the doctor’s office to do it.”

Typically, these direct-to-consumer (DTC) genetic tests are less expensive than more comprehensive, clinical-grade genetic tests obtained through a health care provider.

However, the Food and Drug Administration limits what these companies can say about a consumer’s health. So many people download their raw genetic data obtained from the company, and then upload it to another company’s website for additional interpretation. But their raw data come with a disclaimer stating the information is not validated for accuracy nor intended for medical use.

“To our understanding, raw genetic data doesn’t go through quality control. We and the DTC labs know that raw data may not be accurate,” Moscarello said. For instance, a small study recently showed that 40 percent of genetic variants identified in direct-to-consumer raw data and sent for clinical confirmation were false positives — meaning that the genetic variants weren’t really present.

Moscarello has personally witnessed the impact of these false positives on patients and their families. In a recent commentary in Genetics in Medicine, she and her colleagues describe two cases of false positives seen at Stanford and two more seen at other institutions. These patients received raw data with genetic variants known to be associated with inherited heart conditions that would predispose them to sudden death, she said. Fortunately, a clinical lab determined that the results were incorrect.

Moscarello said she and her co-authors wrote the commentary to call attention to the potential harms of direct-to-consumer raw data interpretation, which extend beyond the potential for inaccurate results. She explained:

“Finding out that you or a family member are at risk for an inherited heart condition can be a very emotional, life-changing event. To go through that without an expert to talk to, or perhaps without support systems nearby, was challenging for our patients. They had to wait for an appointment with a genetic counselor who could explain the test and its limitations, and to provide support. That is usually provided prior to genetic testing, so patients can decide if they would like to proceed.”

The commentary also discussed the impact that DTC testing is having on the health care system.  For the four cases, this burden included the time and expense of four clinical-grade genetic tests, several echocardiograms and electrocardiograms for each patient, multiple visits with physician specialists, an MRI, and the implant and subsequent explant of an implantable cardioverter defibrillator, Moscarello said.

So what can be done?  The authors call for more research to determine the frequency and impact of people being affected by false positives in their raw genetic data interpretations. When a result with potential clinical significance is found, they recommend that it be sent for confirmation to a clinical-grade lab. This should occur before the consumer has to undergo costly clinical evaluations and tests, she said, concluding:

“It is clear that DTC genetic testing is here to stay, and for good reason. So it’s important to focus on maximizing the benefits of such large-scale, clinician-free testing, while minimizing the harms to consumers.

Collaboration between clinicians, consumers and the DTC genetic testing companies is a priority. I hope that DTC genetic testing companies will work with clinical genetics experts to create educational resources — so that consumers and non-specialist physicians know the data may be inaccurate, and what to do next if something is found.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

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Stanford data analyst’s childhood inspires his research: A Q&A

Photo, of Jonathan Altamarino and collaborators in front of an Asili clinic, by Valery Namuto

Data analysts are critical to medical research — particularly to epidemiology studies that look at the incidence, distribution and determinants of health conditions in specific populations. So I was happy to have the opportunity to speak with Jonathan Altamirano, a research data analyst in Stanford’s Global Child Health Program.

How did you get involved in global health research?

“Growing up, I spent summers with family in Nicaragua in a very poor, rural coastal village called Puerto Cabezas. We would often lose water around noon and power by sunset. Personally,  I was lucky. I had food on the table every night. But I saw kids who didn’t — and that was my biggest impetus for getting into global health. I also got dengue and malaria one summer, which got me interested in science and epidemiology. It’s a weird thing to say: a mosquito almost killed me, so I wanted to go into medicine.

I knew I wanted to help less fortunate populations, but I wasn’t sure how I’d fit into that landscape. As a biology undergraduate at Stanford, I then took an epidemiology class taught by Bonnie Maldonado, MD and I fell in love with it. It looked at how best to approach problems: If you have an intervention, is it effective or not? And how can you tell? That got me interested in statistics and ways to model diseases.

When I was getting my masters in biology at Stanford, I took another class with Dr. Maldonado just after she started her polio project in Mexico, which is investigating vaccine-derived poliovirus transmission. And I was hired as a research data analyst for the project.”

You’re now working on a project in the Democratic Republic of the Congo. What exactly are you studying?

“We’re acting as external evaluators for Asili, a poverty-reduction program launched by the American Refugee Committee and IDEO.org aimed at improving child survival and reducing poverty in South Kivu. They’re bringing clean water and small-format health clinics to help these communities recover from years of civil conflict. I’m working with a team including Rasika Behl, Clea Sarnquist and Bonnie Maldonado to collect and analyze on-site data to measure the impact of these interventions.

We’re looking at household demographics — such as what their house is made of , whether they have land and other indicators of wealth. We’re also collecting various health information on the children — such as the incidence of stunting, wasting, diarrhea, fever and cough. And we’re collecting data on the mothers, looking at women empowerment metrics and views on gender relations.

We collect this data in the field with tablets, which I program and setup. After we provide training, local data collectors go out into the community and survey the households. We collected all the baseline data in 2016 and 2017. We’re now collecting the same data after the interventions to evaluate the effectiveness of Asili’s clean water and health clinic programs. We’re also interested in characterizing this understudied population.”

Why did you recently travel to DRC? What was that like?

“In April, I went to South Kivu to help train Asili data collectors to take the end-line data. It was really great to get to know the American Refugee Committee team.

This was my first time in DRC, and I was struck by similarities with my family’s village in Nicaragua. The colors of the houses were the same and the roofs were made of the same kind of corrugated metal. I saw households with a lot of kids in the same space, and I was like ‘yeah, everyone had that in Nicaragua.’ Also, an older woman was running a small restaurant — consisting of plastic lawn chairs and a giant cooking pot. And I immediately pictured our neighbor lady in Nicaragua who made carne asada every night. Of course, the villages in DRC weren’t exactly the same, but they brought up childhood memories.”

What’s next for you?

“We hope to continue working with American Refugee Committee to evaluate Asili as they roll out the program in new parts of Bukavu over the next several years.

Our team is also completing a randomized clinical trial on a gender-based violence intervention, which was rolled out in schools in Kenyan informal settlements to reduce rates of sexual assault in adolescents. We also recently secured funding to collect pilot data on gender-based violence prevention in Fiji and other Pacific islands, in collaboration with the RISE program and Monash University.

However, I’m hoping to apply to medical school next year, once I have time to study for the MCATs.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Virtual reality helps train emergency physicians

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Imagine you are an emergency medicine resident, trying to focus on your patient with abdominal pain — asking about his medical history and symptoms as you give him a physical — but you keep getting interrupted. A technician stops by to hand you another patient’s EKG. A staff member asks about an order for pain medication for a different patient. And then you are called to see a psychiatric patient who is agitated. You return ready to focus and then an attending physician breaks in to redirect your attention to a new patient with a high heart rate.

All told, you’re interrupted 12 times during the patient exam. How can you possibly maintain your train of thought? How can you build trust with the patient, when all these disruptions are stressing him out?

The above narrative was inspired by the script of a new training simulation, which was filmed at Stanford’s emergency department as a virtual reality video.

This is a typical scenario faced by emergency physicians, who are interrupted on average every six minutes. These interruptions increase the likelihood of errors, so it is critical for emergency doctors to practice how to multitask in this fast-paced, high-risk and disruptive environment.

The script was written by Henry Curtis, MD, a Stanford clinical instructor in emergency medicine, and Cameron Mozayan, MD, a Stanford emergency medicine resident.

“A problem with many current learning modalities is that they don’t engage modern participants in an active, immersive learning environment, so it’s difficult to sustain their attention,” Curtis said. “Virtual reality-based education presents an innovative solution to address this problem. Distractions are minimized as the learner excitedly engages in the VR world. The perception of the experience also triggers strong memories, which connect them to the educational content. So participants allot their full attention as they contemplate important medical decisions.”

Over 30 health care educators and providers at the 2018 International Health Humanities Consortium Conference at Stanford tried the training simulation recently. While viewing, the participants were asked to choose which interruptions were more important than the patient-physician consultation. The participants then viewed the video again with expert pro and con discussions — interactively testing to see if the others’ viewpoints swayed their opinions on the importance of the interruptions.

“Training is more powerful if the participants are seeing it in 360 virtual reality and they are being engaged in an interactive experience,” Curtis told me.

Participants said the VR training realistically conveyed what it was like to work in an emergency department. One health care worker declared, “This experience makes me feel like I’m in the emergency department. I feel like I’ve seen all of these things happen at work.” Another said, “Sometimes emergency medicine feels like a warzone.” A third participant added, “I was feeling so tense in there with all of the interruptions.”

The users also provided insights. For instance, one person was struck by how often technology caused the interruptions.

Curtis worked with Jason Lowe, MD, and Anne Merritt, MD, members of Stanford’s medical humanities team and with Stanford’s Education Technology team to create the first video. Now, they are analyzing the data from the conference, and are planning a series of VR training simulations.

For his next project, Curtis is also working with Aussama Nassar, MD, to film a trauma simulation with an agitated patient who deteriorates into neurogenic shock after a bicycle accident.

Curtis said he hopes the virtual reality series will enhance the quality of the lessons learned during the training simulations, in addition to extending their reach to a larger audience. He added:

“VR education can be transported globally to allow learners across the world to immerse themselves in the intricacies of innumerable clinical encounters, as well as receive structured debriefing in the virtual world by renowned experts from Stanford University and the like.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Citizen science research investigates neighborhoods’ effects on well-being

Image courtesy of Ben Chrisinger

When walking through different parts of a neighborhood, how do you feel? Comfortable and relaxed, or stressed and on-alert? And how do these different environments — over days or even years — impact your well-being?

A new Stanford study explores how to answer these kinds of questions using citizen scientists, as recently reported in International Journal of Health Geographics. To learn more, I spoke with lead author Ben Chrisinger, PhD, a postdoctoral research fellow at the Stanford Prevention Research Center.

What inspired you to study the built environment and health?

“I’ve always been fascinated by how and why we perceive different neighborhoods as safe or unsafe, welcoming or unwelcoming, and attractive or unattractive. If we can develop a more granular understanding of where we feel certain ways, and why, it’s possible that we can improve urban design.

Chronic stress contributes to a number of negative health outcomes, ranging from decreased immune function to cardiovascular disease.

Understanding what exactly contributes to stress in different places can be valuable information for individuals. But we also think there’s great potential in pooling these stress data across many individuals to see if common themes exist. Urban planners, policymakers and developers could learn from these themes to better promote health in their communities.”

How did you conduct your recent citizen scientist study?  

“We partnered with an urban design and planning non-profit, Place Lab, in San Francisco. They recruited eight women and six men in their 20s and 30s who lived locally. We had all the volunteers do the same 20-minute walk in a Hayes Valley neighborhood.

We used a citizen-science method called Our Voice, developed by the Healthy Aging Research and Technology Solutions Stanford research group led by Abby King, PhD. Individuals use a smartphone app to take pictures and record audio narratives of their neighborhoods.

We asked people to document things along the walk that they thought were contributing or detracting from their well-being. Their phone app recorded where they took their pictures and audio narratives. Everyone also wore a sensor on their wrist that measured time-stamped biometric data — including blood volume pressure, heart rate, skin temperature and electrodermal activity as a proxy for stress — to show how their bodies responded to different environments.

We then created a web platform to share back the participants’ photos, transcribed audio and biometric data superimposed on a map.”

What did you find?

“The phone app data showed that participants often talked about traffic, noise and whether they felt safe as a pedestrian. Even in high volume areas, people also talked about the aesthetic qualities of streets and historic buildings. It appears that it’s not just parks that are stress reducing — quiet areas might also be important. We need to do more research to understand the elements that provide a break from the urban environment.

Our exploratory statistical analyses revealed that, on average at the group level, there were significant associations between participants’ electrodermal activity and the built-environment characteristics. However, it’s clear that these models explain some participants’ data much better than others. One possible explanation is that we’re leaving out some influential neighborhood variables.”

 What’s next?

“We want to do this again with more people all walking a smaller section — like one alley or a pair of streets — so we can dig deeper into what explains the differences between people’s perceptions of specific places.

We also want more diversity in the age, race and ethnicity of our participants. We know this is important from earlier citizen scientist projects. For example, a previous study showed that kids take pictures of graffiti and see it as a good thing, as art, whereas older adults see it as vandalism.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

New study observes Tuberculosis bacteria attacking antibiotics

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Tuberculosis was one of the deadliest known diseases, until antibiotics were discovered and used to dramatically reduce its incidence throughout the world. Unfortunately, before the infectious disease could be eradicated, drug-resistant forms emerged as a major public health threat — one quarter of the world’s population is currently infected with TB and 600,000 people develop drug-resistant TB annually.

New research at SLAC National Accelerator Laboratory is seeking to better understand how this antibiotic resistance develops, as recently reported in BMC Biology.

TB is caused by Mycobacterium tuberculosis bacteria, which attack the lungs and then spread to other parts of the body. The bacteria are transmitted to other people through the air, when an infected person speaks, coughs or sneezes.

These bacteria survive antimicrobial drugs by mutating. Their resilience is enhanced by the lengthy and complex nature of standard treatment, which requires patients to take four drugs every day for six to nine months. Patients often don’t complete this full course of TB treatment, causing the bacteria to evolve to survive the antibiotics.

Now, a team of international researchers has investigated an enzyme, called beta-lactamase, that is produced by the Mycobacterium tuberculosis bacteria. They wanted to understand the critical role this enzyme plays in TB drug resistance.

Specifically, the researchers made tiny crystals of beta-lactamase and mixed them with the antibiotic ceftriaxone. A fraction of a second later, they hit the enzyme-antibiotic mixture with ultrafast, intense X-ray pulses from SLAC’s Linac Coherent Light Source — taking millions of X-ray snapshots of the chemical reaction in real time for two seconds.

Putting these snapshots together, the researchers mapped out the 3D structure of the antibiotic as it interacted with the enzyme. They watched the bacterial enzyme bind to the antibiotic and then break open one of its key chemical bonds, making the antibiotic ineffective.

“For structural biologists, this is how we learn exactly how biology functions,” said Mark Hunter, PhD, staff scientist at SLAC and co-author on the study, in a recent news release. “We decipher a molecule’s structure at a certain point in time, and it gives us a better idea of how the molecule works.”

The research team plans to use their method to study additional antibiotics, observing in real time the rapid molecular processes that occur as the bacteria’s enzymes breakdown the drugs. Ultimately, they hope this knowledge can be used to design better antibiotics that can fight off these attacks.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Assessing our nation’s control of blood pressure: A Q&A

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Whenever you see a physician, an assistant probably takes your blood pressure. But does she tell you what the numbers mean?

The top number, called the systolic blood pressure (SBP), measures the maximum pressure your heart exerts while beating. The bottom number, called the diastolic blood pressure (DBP), measures the amount of pressure in your arteries between beats. Both are important. High systolic and diastolic blood pressure are associated with a higher risk of heart attacks, heart failure, stroke and kidney disease.

But what is considered high enough to treat? I was recently surprised to learn that physicians are still debating the national blood pressure clinical guidelines. To learn more, I spoke with Shreya Shah, MD, a clinical instructor of primary care and population health at Stanford.”

Why have clinical guidelines for blood pressure been controversial?

“Recommendations regarding optimal blood pressure control have shifted over the past decade. In 2003, the recommendations were to target a systolic blood pressure less than 140 for most patients and less than 130 for patients with certain risk factors. In 2014, new recommendations relaxed the blood pressure goals to a SBP less than 140 for most patients and less than 150 for those 60 and above. This was a big change in recommendations and thus sparked controversy.

Newer studies, especially the SPRINT trial, point towards the increased benefits of more intensive blood pressure control. This led to the recent set of guidelines in 2017.

At Stanford, we’re working to bring blood pressures down as close to normal as possible. We are targeting a SBP less than 140 and DBP less than 90 in all patients. But for those with certain risk factors, especially increased risk for heart disease, we may recommend lowering the goal to a SBP less than 130 and DBP less than 80.”

Are these goals being met? What did your latest study find?

“Using a national database, Randall Stafford, MD, and I analyzed patterns of blood pressure control for millions of patients who were treated for hypertension in 2016.

Our study, which appears in the Journal of General Internal Medicine, found that we’re not doing a great job with blood pressure control: 43 percent of hypertension patients had a SBP of 140 or higher and 24 percent of patients had a SBP of 150 or higher.

There were also higher rates of uncontrolled blood pressure among certain demographic groups — blacks, Hispanics and patients with Medicaid. These groups may have had less intensive attention to their high blood pressure for a number of reasons, including less access to high quality care and an inability to afford some medications.”

What can be done?

“Studies have demonstrated that team-based care leads to better improvements in blood pressure when compared to traditional models of primary care. Team-based care for hypertension involves the patient and their primary care physician, as well as other health professionals such as pharmacists, nurses, dieticians, case managers and social workers. Especially for treatment strategies involving health behavior change, physicians may not be as effective as other people whose training focused on these skills.

Stanford has already implemented this team-based care model in our primary-care clinics. And we are looking at other strategies, including helping our patients to be more involved in managing their high blood pressure. For instance, I encourage patients to regularly measure their blood pressure at home. The American Heart Association has resources available with information about choosing a home blood pressure monitor and using the correct home blood pressure technique.

I also encourage my patients to adopt a largely plant-based diet, lose weight and become more physically active. These non-medication strategies can be helpful for preventing high blood pressure, but are also as an integral part of treating high blood pressure.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

New understanding of cellular signaling could help design better drugs, Stanford study finds

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An effective drug with minimal side effects — the dream of all drug companies, physicians and patients. But is it an impossible dream?

Perhaps not, in light of new research led by Ron Dror, PhD, an associate professor of computer science at Stanford. IN collaboration with other researchers, Dror used computer simulations and lab experiments to better understand G-protein-coupled receptors, which are critical to drug development.

G-protein-coupled receptors (GPCRs) are involved in an incredible array of physiological processes in the human body, including vision, taste, smell, mood regulation and pain, to name just a few. As a result, GPCRs are the primary target for drugs — about 34 percent of all prescription pharmaceuticals currently on the market target them. Unfortunately, despite all of this drug research, many of the underlying mechanisms of how GPCRs function are still unclear.

We do know that GPCRs act like an inbox for biochemical messages, which alert the cells that nutrients are nearby or communicate information sent by other cells. These messages symbolize a variety of signaling or pharmaceutical molecules. When one of these molecules binds to a GPCR, the GPCR changes shape — triggering many molecular changes within the cell.

Dror’s team investigated the relationship between these GPCRs and a key family of molecules inside cells called arrestins, which can be activated by GPCRs and can lead to unanticipated side effects from medications. Specifically, they sought to understand how GPCRs activate arrestin, so they can use this knowledge in the future to design drugs with fewer side effects.

“We want the good without the bad — more effective drugs with fewer dangerous side effects,” Dror said in a recent Stanford news release. “For GPCRs, that often boils down to whether or not the drug causes the GPCR to stimulate arrestin.”

Researchers know that GPCR is composed of a long tail and a rounder core, which bind to distinct locations on the arrestin molecule. Based on past studies, it was believed that only the receptor’s tail activated the arrestin — causing it to change shape and begin signaling other molecules on its own.

However, Dror’s new study demonstrated that either the tail or core can activate arrestin, as recently reported in Nature. And the core and tail together can activate the arrestin even more, Dror said.

Using this new understanding, the researchers hope in the future to design drugs that activate arrestin in a more selective way to reduce drug side effects.

Dror concluded in the release:

“These behaviors are critical to drug effects, and this should help us in the next phase of our research as we try to learn more about the interplay of GPCRs and arrestins, and potentially, new drugs.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.