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Big data, Clinical Trials, Events, Research

At TEDMED 2015: Benign drugs? Not under the lens of big data

At TEDMED 2015: Benign drugs? Not under the lens of big data

This year’s TEDMED was held Nov. 18-20 in Palm Springs, Calif. Stanford Medicine is a medical research institution partner of TEDMED, and a group of MD and PhD students who represented Stanford at the conference will be sharing their experiences here.

xCUEHR0MrJlqiC9phSMFFEjCxjrDDo54Bv0Hc18sYdkPicture this: you go to the doctor and find out that your cholesterol is high. Your doctor prescribes you a medication taken by millions of Americans for lowering cholesterol – Pravastatin. A few months later, you see your doctor again because of persistent depression, and again, you are given a commonly prescribed medication – Paxil.

Russ Altman, MD, PhD, opened his 2015 TEDMED talk with this seemingly innocuous scenario. But through the course of his talk, Altman demonstrated how his lab leveraged big data to reveal the adverse side effects of supposedly benign pharmacological interventions.

When choosing medications for my patients during my clinical rotations, I would often cite evidence from randomized controlled trials about the clinical benefits versus the risks of that particular drug. However, this evidence-based medicine has one major limitation: In clinical studies, patients are usually only on one drug.

My patients, on the other hand, would often come in with bags full of prescription bottles in order to show me which drugs they took, since there were too many medication names to memorize. Often, I found myself wondering quietly, “Is there any way to know if combining these drugs could lead to an adverse event?”

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Chronic Disease, Clinical Trials, Mental Health, Research, Stanford News

Treating insulin resistance may speed recovery from major depression

Treating insulin resistance may speed recovery from major depression

depressionIn a randomized, placebo-controlled clinical trial detailed in this study in Psychiatry Research, pioglitazone – a generically available drug that’s approved for type 2 diabetes – helped to relieve symptoms of major depression in patients whose blues had withstood an assault by standard therapeutic regimens for six months or longer.

But this beneficial effect was seen only in depressed patients who were also insulin-resistant.

Depression is remarkably common. Stanford psychiatric researcher Natalie Rasgon, MD, PhD, the study’s senior author, told me that close to one in five Americans are diagnosed with depressive illness at some point in their lives.

Insulin resistance, a stepping stone on the path to type 2 diabetes (not to mention cardiovascular disease and probably Alzheimer’s), is even more common: About one in three otherwise healthy Americans – and an even greater share of people with depression – are insulin-resistant. Especially prevalent among overweight people, insulin resistance also occurs more often than one might expect even among thinner folks, a lot of whom don’t have the faintest idea that’s the case.

Insulin, released by the pancreas in response to food intake, alerts cells throughout the body to the presence of glucose, the body’s primary energy source, in the blood. Insulin-resistant people’s cells fail to take up glucose adequately, leaving high residual blood levels of the sugar to wreak havoc on the body’s tissues. Because the brain is a glucose glutton – it soaks up about 20 percent of all glucose consumption in a healthy, active person – it’s easy to imagine that lousy glucose uptake in the brain would have all kinds of deleterious effects, including effects on mood. Food for thought, anyway.

Here’s how my news release described the study:

[R]esearchers were blinded as to which patients were receiving pioglitazone versus a placebo. The patients didn’t know which they were getting, either. … All the patients had been experiencing episodes of depression lasting, on average, more than one year. Their symptoms had failed to remit under standard treatment regimens. They remained on these regimens for the duration of the Stanford study and, in addition, were given either pioglitazone or a placebo. … The patients were tested for depression severity and insulin resistance at the study’s outset and then roughly every two weeks from the beginning of the trial to the end.

A total of 37 patients – 29 women and eight men – completed the 12-week study. The insulin-sensitive subjects did about as well on the drug as they did on placebo. But among the insulin-resistant group, those given pioglitazone showed a much greater improvement than those who got a placebo. They also showed more improvement than insulin-sensitive patients did.

The more insulin-resistant a participant was at the beginning of the study, the better the drug’s antidepressant effect. Possible, but not proven, explanation: It could be that for some patients standard antidepressant therapies can kick into gear only once these patients’ insulin resistance is reduced. Hungry brains gotta eat.

Previously: Survey shows nearly a quarter of U.S. workers have been diagnosed with depression in their lifetime, Revealed: the brain’s molecular mechanism behind why we get the blues, and International led by Stanford researchers identifies gene linked to insulin resistance
Photo by S.Hart Photography

Clinical Trials, Ethics, Health Policy, Public Health, Stanford News

Using social media in clinical research: Case studies address ethical gray areas

Using social media in clinical research: Case studies address ethical gray areas


If a public-health researcher is reviewing Facebook profiles of 14-year-old males for firearm references and discovers photos or words referencing a potentially threatening situation, should the researcher intervene? What levels of privacy should these children expect in the online world?

These are the kinds of difficult questions that ethics consultants are faced with as they attempt to provide moral and legal guidance to researchers gathering health-related data from the Internet.

To help researchers with these nascent ethics issues, the Clinical Research Ethics Consultation Collaborative, a group of almost 50 bioethicists who provide free or low-cost ethics consultations across the United States, has begun publishing case studies on its most ethically challenging cases. Thus far they’ve posted 40 case studies in the categories of behavioral/social science research, clinical trials, genetics, pediatrics, research misconduct and surrogate decision making. The site also includes information on how to participate in educational webinars and collaborative case discussions.

This effort is being led by Benjamin Wilfond, MD, at Seattle Children’s Research Institute and University of Washington, and Mildred Cho, PhD, at the Stanford Center for Biomedical Ethics.

“Our bioethics consortium has learned a great deal from the complex ethics consultations that we’ve been providing since 2005,” said Cho. “Now we have a strategy for sharing these best practices with others, to provide moral and legal guidance to researchers across the country and to better inform policymakers on evolving ethical gray areas.”

More information on the collaborative or to request a consult can be found on this website.

Previously: The challenge – and opportunity – of regulating new ideas in science and technologySocial media brings up questions, ethical unknowns for doctorsBuild it (an easy way to join research studies) and the volunteers will come
Photo by NLshop/Shutterstock

Clinical Trials, Pain, Research, Stanford News

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

Pain-in-the-neck, begone! Better way to relieve chronic neck and shoulder pain?

shoulderHundreds of millions of people worldwide (115 million in the United States alone) suffer from chronic pain. Stanford diagnostic radiologist Sandip Biswal, MD, calls this group “one of the largest populations in the world for medical need of any kind.” But current treatments either aren’t all that great or – in the case of opioids, which are highly effective – put patients at risk for addiction.

A pair of randomized, double-blinded clinical trials, described in a study co-authored by Biswal, former Stanford visiting scholar Charlie Koo, PhD, and several colleagues and published in Nature Scientific Reports, may point to a potential path toward more pain-free lives. In the trials, patients with chronic neck or shoulder pain were treated with three to six 90-minute sessions of either standard physical therapy – so-called transcutaneous electrical nerve stimulation,  or TENS, along with exercise and both manual and heat treatments – or a protocol designed by Koo, who now runs a facility called the Pain Cure Center in Palo Alto, California.

The new method, which Koo calls Noxipoint therapy, also employs electrical stimulation of painful areas, but in a carefully defined way: electrodes are placed precisely at both of the two attachment points for each muscle in pain, and the electrical-current jolt is brief and just enough to cause local soreness and dull, but not sharp, pain. Patients receiving the novel therapy are also told to take it easy for several days after each treatment.

In both trials, Noxipoint therapy proved superior to conventional physical therapy using TENS by close to an order of magnitude. Four weeks after their last treatment, patients given Noxipoint therapy reported substantial pain reduction, restoration of function (for example, regained range of motion) and improved quality of life, without significant side effects. Those given standard treatment reported no significant lasting improvement.

These trials are preliminary and call for confirmation in larger studies, Biswal told me. Given the pressing need for safe, lasting relief from chronic pain and the apparent success of this new method, it would be nice to see those expanded trials take place.

Previously: “People are looking for better answers”: A conversation about chronic painNational survey reveals extent of Americans living with pain and Stanford researchers address the complexities of chronic pain
Photo by Jason Trbovich

Big data, Clinical Trials, Health Policy, Precision health, Research

Push-button personalized treatment guidance for patients not covered by clinical-trial results

green buttonA pediatrician, a cardiologist and a biomedical informaticist walk into a pharmacy. They all look as if they could use some strong medicine. “We want a Green Button,” they tell the pharmacist in unison.

“Green Button? Hmmm. I can’t say I know how to compound that prescription,” the puzzled pharmacist replies. “But if all three of you are ordering it, maybe I should. Can you tell me what, specifically, goes into a Green Button?”

“A lot of patients,” reply the three thirsty health experts.

“OK, I’ll play along,” says the pharmacist, beginning to lose his patience. “What comes out?”

“If we knew the answer to that, we wouldn’t need a Green Button.”

Actually, that punch line is no joke. The “Green Button” signifies a profound, potentially pervasive approach that could revolutionize medical practice. In a just-published feature in Inside Stanford Medicine, I report on a futuristic (but not too futuristic) vision of a “learning health-care system” outlined in a 2014 Health Affairs paper by three Stanford experts: pediatric specialist Chris Longhurst, MD, cardiologist Bob Harrington, MD, and biomedical informaticist Nigam Shah, MBBS, PhD.

As I noted in that feature:

The randomized clinical trial is considered the gold standard of medical research. In a randomized clinical trial… participants are randomly assigned to one of two – or sometimes more – groups. One group gets the drug or the procedure being tested; the other is given a placebo or undergoes a sham procedure. … Once the trial’s active phase ends, rigorous statistical analysis determines whether the hypothesis, spelled out in advance of the trial, was fulfilled.

There’s one problem: Clinical trials select only a small, artificial subset of the real population. The rest of us are kind of out of luck.

“Clinical trials are designed to prove one thing,” Shah told me. “And you’re testing it on people with just one thing: type 2 diabetes, eczema, whatever. But most real-life people don’t have just one thing. They have three or four or five things.”

Enter the Green Button. Suppose you’re a clinician facing a patient for whom no clear clinical guidelines exist. Instead, according to the scheme depicted by Longhurst, Harrington and Shah, you press a virtual “green button” on a computer screen displaying your patient’s electronic medical record. This triggers a real-time search of millions, or tens or millions, of other electronic records. In a matter of minutes, up pops a succinct composite summary of the outcomes of 25 or 100 or perhaps 1,000 patients very similar to the one in front of you – same race, same height, same age, same symptoms, similar medical histories, lookalike lab-test results – who were given various medications or procedures for the condition you’re hoping to treat. Those “lookalikes,” it turns out, respond much better to one treatment than to the others – something you’d have been hard put to guess on your own.

That’s all very nice, you say. Now I get your “artisanal faux-joke” lead. But, you ask, why does the button have to be green? And I answer: It doesn’t. But the other good colors were already taken.

Previously: Widely prescribed heartburn drugs may heighten heart-attack risk, New research scrutinizes off-label drug use and A new view of patient data: Using electronic medical records to guide treatment
Photo by Green Mamba :)–<

Clinical Trials, Mental Health, Parenting, Pediatrics, Research, Stanford News

Parents can help their teens recover from bulimia, say Stanford researchers

Parents can help their teens recover from bulimia, say Stanford researchers

Mom&teenTeenagers with bulimia nervosa benefit from their parents’ help in stopping their eating disorder. In fact, a therapy that involves parents works better for teens than one that does not, according to the first large head-to-head comparison in adolescents of two well-known bulimia treatments.

The findings are described in a study of 130 young people with bulimia that was published last week in the Journal of the American Academy of Child and Adolescent Psychiatry.

The research, which was jointly led by Stanford’s James Lock, MD, PhD, and a longtime collaborator, Daniel Le Grange, PhD, compared an approach tailored to teens with one commonly used in adults. In family-based therapy, the bulimia patient and a parent work together to stop the disordered eating behavior. In contrast, in cognitive behavioral therapy, which is widely recognized as the best approach for bulimic adults, there is more focus on changing abnormal thoughts about food and less emphasis on behavior change.

At the end of six months of treatment, 39 percent of patients in family-based therapy had abstained from the binge-and-purge cycle of bulimia for at least four weeks. Only 20 percent of those in the cognitive behavioral therapy group had done the same. The gap persisted six months after treatment ended, though it seemed to have closed by a year after the end of treatment.

Lock, who directs the Comprehensive Eating Disorders Program at Lucile Packard Children’s Hospital Stanford, said the findings are not surprising, given that teens are at a different stage of the illness and have different cognitive capabilities than adults with bulimia. But they are very important, since they suggest that the family-based approach is a faster way for young patients to recover from bulimia. From our press release about the study:

“The strategy for cognitive behavioral therapy requires a fair amount of abstract reasoning, motivation and persistence that often has not reached full capacity in teens,” [Lock] said, adding that doctors may need to decide on a case-by-case basis whether a teen would benefit from one treatment versus the other. “The cognitive and developmental context is very different for teens than for adult patients,” he said.

And it’s normal for teenagers to need their parents’ assistance in navigating difficult situations, he added. “The big take-home message is that families can really help their kids with bulimia nervosa.”

Previously: Family therapy an effective way to treat anorexic teens, Incorporating the family to help teens overcome eating disorders and Families can help their teens recover from anorexia, new study shows
Photo by J.K. Califf

Clinical Trials, Health Disparities, Mental Health, Research, Stanford News

How people with mental illness get left out of medical research studies

How people with mental illness get left out of medical research studies

One of the enduring challenges of evidence-based medicine is that the characteristics of people who participate in clinical trials can differ markedly from those of patients who ultimately access the treatment which the trial evaluates. One of the many reasons this occurs is that researchers often exclude patients with certain characteristics from participating in clinical trials.  In a new study in Journal of Psychiatric Research, my colleagues Laura Roberts, MD; Janet Blodgett, and I examine a particular population to whom this occurs: People with mental health and/or substance use disorders.

If scientists are to live up to their laudable commitment to sharing the benefits of health research with all citizens, they’ll have to more consistently include people with psychiatric problems in studies

In a sample of 400 highly-cited randomized trials across 20 common chronic disorders, we found that half had eligibility rules that prevented people with psychiatric problems from enrolling.   Those disease research areas with high rates of reported psychiatric exclusion criteria in clinical trials included low back pain (75 percent), osteoarthritis (57 percent), COPD (55 percent), and diabetes (55 percent).  People with conditions such as depression, anxiety disorders, alcohol problems and schizophrenia thus may face some added risk when they seek health care: People like them were often left out of the research that tells doctors what medical treatments work.

The study also raises questions about whether some clinical trials make much of a contribution to knowledge. For example, now that psychiatric and other substance use problems are virtually normative among smokers, what is the point of smoking cessation studies that continue to exclude the very populations that do most of the smoking?

Including people with psychiatric problems in medical research may require extra resources for researchers (e.g., people with serious mental illness may be harder to follow up) or pose other challenges in completing clinical trials. But if scientists are to live up to their laudable commitment to sharing the benefits of health research with all citizens, they’ll have to meet these challenges and more consistently include people with psychiatric problems in medical research studies.

Addiction expert Keith Humphreys, PhD, is a professor of psychiatry and behavioral sciences at Stanford and a career research scientist at the Palo Alto VA. He has served in the past as a senior advisor in the Office of National Drug Control Policy in Washington, DC. He can be followed on Twitter at @KeithNHumphreys.

Clinical Trials, Ethics, Research, Stanford News

Should patients pay their way into clinical trials?

Should patients pay their way into clinical trials?

Photo of U.S. currency and a pharmaceutical capsuleIn a time of shrinking federal research budgets, here’s one idea for a solution: charge patients to participate in clinical trials.

Patients’ payment could fund studies that would not otherwise be conducted, said a group of medical ethicists led by Ezekiel J. Emanuel, MD, PhD, the former White House health-policy adviser who now chairs the Department of Medical Ethics and Health Policy at the University of Pennsylvania. Emanuel was asked by a group of academic investigators to review the legality and ethics of charging for enrollment in an early-phase clinical trial; he and his co-authors examine the pros and cons.

No laws or regulations prohibit pay-to-play, said the authors, and it has some upsides. By putting their money where their mouth is, patients could be demonstrating deep engagement with the research protocol, and affirming their informed consent. Their payment could be seen as a direct, Kickstarter-style version of a charitable contribution to medical research, or as an analogue to permissible payment for experimental treatments outside the confines of a clinical trial. Last but not least, there is a liberty argument, that “people should have the freedom to do whatever they want with their own money as long as they are not harming others or diminishing their rights and opportunities,” said the authors, whose perspective essay (subscription required) appears today in Science Translational Medicine.

But before going full libertarian, the authors put on the brakes. Let’s be honest, they said, this is less about a collaborative partnership than a potentially desperate need to save one’s own life; less about a charitable impulse than purchasing a service. It will skew research toward the health needs of the wealthy and could interfere with research integrity: A paying participant may be less willing to accept randomization to a control group or more reluctant to disclose symptoms and side effects. For their part, investigators might feel pressure to bend inclusion or removal criteria, or not to terminate a study. Ultimately, the authors conclude that pay-to-play is generally unethical, and warrants legislative and regulatory attention.

Co-author Govind Persad, JD, a Stanford graduate student in philosophy, told me he’s particularly concerned about participants feeling pressure to pay: “There is this real psychological pressure, if you or your kid are sick or in this desperate position, to do something that not only you wouldn’t have done, but that you see as having this direct, imminent benefit to yourself out of proportion to the benefit it’s likely to have.”

Persad hopes the essay will ignite an “educated debate” among researchers, policy makers, potential donors to medical research and people who stand to benefit from interventions to be studied in clinical trials. “An issue for people to think about going forward is: If we need more research into Condition X but pay-to-play is not the way, what would be some other good ways to try to expand the universe of trials?”

Related: A look at crowdfunding clinical trials, Can crowdfunding boost public support and financing for scientific research, Stanford forum on the future of health care in America posted online and When it comes to health-care spending, U.S. is “on a different planet”
Photo by David Goehring

Cancer, Clinical Trials, Dermatology, Genetics, Pain, Pediatrics, Research, Stanford News

The worst disease you’ve never heard of: Stanford researchers and patients battle EB

The worst disease you've never heard of: Stanford researchers and patients battle EB

EB patient and docsI’m often humbled by my job. Well, not the job, exactly, but the physicians, researchers, and especially patients who take the time to speak with me about their goals and passions, their triumphs and fears. Their insight helps me as I struggle to interpret what goes on here at the Stanford University School of Medicine for others across the university and even around the world.

But every once in a while, an article comes along that brings me to my (emotional) knees. My article “The Butterfly Effect” in the latest issue of Stanford Medicine magazine describes the toll of a devastating skin disease called epidermoloysis bullosa on two young men and their families, as well as the determined efforts of a dedicated team of doctors and scientists to find a treatment. As a result, Stanford recently launched the world’s first stem-cell based trial aimed at correcting the faulty gene in the skin cells of patients with a severe form of the condition, which is often called EB.

I trace the path of one family as they learn, mere hours after his birth, that their son, Garrett Spaulding, has EB, which compromises the ability of the outer layers of the to stick together during friction or pressure. Patients develop large blisters and open wounds over much of their bodies. It’s incurable, fatal, and nearly indescribably painful. Paul Khavari, MD, PhD, now the chair of Stanford’s Department of Dermatology, was a young doctor at the time newborn Garrett was admitted to Lucile Packard Children’s Hospital Stanford in 1997.

“His whole body, his skin was blistered and falling off everywhere someone had touched him,” Khavari recalls in the article. “His parents were devastated, of course, at a time that was supposed to be one of the most joyful of their lives.”

Garrett’s now 18 years old, but the disease is taking its toll.

You’ll also meet Paul Martinez, one of the first participants in Stanford’s new clinical trial. He’s 32, which makes him an old man in the EB community. Unlike many EB patients, he has finished high school and completed a college degree in business marketing with a dogged determination that makes me ashamed of my petty complaints about my minor life trials. And he’s done it without relying on the pain medications essential for most EB patients. As he explains in the article:

We don’t know what it is like to not be in pain. It’s just normal for us. […] I have a very high tolerance, and don’t take any pain medication. I cherish my mind a lot. Rather than feel like a zombie, I prefer to feel the pain and feel alive.

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Biomed Bites, Clinical Trials, Health Policy, Videos

The mathematics of clinical trials: A career

The mathematics of clinical trials: A career

Welcome to Biomed Bites, a weekly feature that introduces readers to some of Stanford’s most innovative researchers.

Math was Philip Lavori‘s first intellectual love. After earning his PhD in mathematics at Cornell University, Lavori spent his time solving tricky calculations. But the disconnect between the world of pure mathematics, and the messy outside world where people were living and dying started to bug him.

“It soon became obvious to me that I would have enormous interest in doing research that would have direct benefits to human beings,” Lavori says in the video above.

He began offering his skills as a consultant to physicians, where he discovered a new intellectual love.

“I’ve found the problems that arose in the design of clinical trials were problems that I could attack with my mathematical skills…. That quickly led to an entire career.”

Now Lavori is chair of the Department of Health Research and Policy, and he co-directs the Stanford Center for Clinical and Translational Research and Education (Spectrum).

Learn more about Stanford Medicine’s Biomedical Innovation Initiative and about other faculty leaders who are driving biomedical innovation here.

Previously: Survey confirms that small number of U.S. adults, children participate in research studies, A faster, better, cheaper clinical trial (electronic record system not included) and Re-analyses of clinical trial results rare, but necessary, say Stanford researchers

Stanford Medicine Resources: