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Chronic Disease, NIH, Patient Care, Research

NIH network designed to diagnose, develop possible treatments for rare, unidentified diseases

doctors' tools - smallVertigo, nausea, headache, fatigue, confusion. For years someone close to me has experienced severe and periodic bouts of these symptoms. It’s clear something is wrong and yet, despite countless tests and visits with specialists in cardiology, neurology, ophthalmology, pulmonology, otolaryngology, and immunology, no one has been able to figure out what that something is. At one of his last appointments – to the great disappointment of this patient and (perhaps even more so) his worried and frustrated wife – my loved one was gently told that he may have to face the very real possibility that he’ll never get a definitive diagnosis.

Unfortunately, this patient is far from alone: Plenty of people are living with mysterious symptoms that affect their quality of life (or worse), and it’s not uncommon for patients with rare diseases to have waited years for their diagnosis. With this in mind, the National Institutes of Health launched in 2008 its Undiagnosed Diseases Program, a pilot program designed to “provide answers to patients with mysterious conditions that have long eluded diagnosis” and “advance medical knowledge about rare and common diseases.” (Since that time, 600 children and adults have been evaluated, and approximately 100 patients were given a diagnosis.)

Now, the program is being expanded into the Undiagnosed Diseases Network, with the NIH announcing last week that six medical centers – including Stanford – will be joining and contributing local medical expertise. The NIH will work with experts from these centers (including Euan Ashley, MD, PhD, Stanford’s principal investigator) to, as described in a release, “select from the most difficult-to-solve medical cases and together develop effective approaches to diagnose them.” The physicians will “collect and share high-quality clinical and laboratory data, including genomic information, clinical observations and documentation of environmental exposures,” and they’ll “benefit from common protocols designed to improve the level of diagnosis and care for patients with undiagnosed diseases.”

In our online story on the network and the $7.2 million grant that Stanford received, Matthew Wheeler, MD, medical director for the grant, notes that “Stanford was chosen for our informatics expertise, our experience with clinical interpretation of whole-exome and whole-genome data, and our scientific potential to follow up any lead.” As my colleague Erin Digitale further explained:

The team will use cutting-edge genomics and medical phenotyping techniques to diagnose patients, and will also aim to understand the underlying biology of patients’ conditions so they can generate targets for new therapies, Wheeler said. “We aim to make a deep dive into each patient’s biology,” he added.

By the summer of 2017, each new clinical site is expected to see 50 or more patients per year. Referring clinicians can submit applications on behalf of undiagnosed patients on the program website.

Previously: Using crowdsourcing to diagnose medical mysteries, New search engine designed to help physicians and the public in diagnosing rare diseases and The road to diagnosis: How to be insistent, persistent and consistent
Photo by Adrian Clark

Cancer, NIH, Public Health, Research, Stanford News, Videos

NIH associate director for data science on the importance of “data to the biomedicine enterprise”

NIH associate director for data science on the importance of "data to the biomedicine enterprise"

The 2014 Big Data in Biomedicine conference was held here last month, and interviews with keynote speakers, panelists, moderators and attendees are now available on the Stanford Medicine YouTube channel. To continue the discussion of how big data can be harnessed to benefit human health, we’ll be featuring a selection of the videos this month on Scope.

During his keynote speech at Big Data in Biomedicine 2014, Philip Bourne, PhD, the first permanent associate director for data science at the National Institutes of Health, shared how the federal agency hopes to capitalize on big data to accelerate biomedicine discovery, address scientific questions with potential societal benefit and promote open science.

In the above video, he talks about how data “is becoming increasingly important to the biomedical enterprise” and the NIH’s effort to coordinate strategies related to computation and informatics in biomedicine across its 27 institutes and centers, which effectively form the basis of improvements in health care across every major medical condition. “Our goal is to create interoperability between these entities,” he says in the interview. “We see data as the catalyst to create this cross talk across these respective institutes.”

Previously: Rising to the challenge of harnessing big data to benefit patients, Discussing access and transparency of big data in government and U.S. Chief Technology Officer kicks off Big Data in Biomedicine

Big data, Events, FDA, NIH, Stanford News, Technology

Discussing access and transparency of big data in government

Discussing access and transparency of big data in government


The Big Data in Biomedicine conference of 2014 continued today with discussion around how troves of information are being stored, organized, accessed and applied in a way that’s useful to stakeholders across health care.

Yesterday afternoon, Stanford bioengineer Russ Altman, PhD, introduced keynote speaker Philip Bourne, PhD, who earlier this year began his post as the first permanent associate director for data science at the National Institutes of Health. Altman was part of the search committee that selected Bourne as part of an initiative of NIH Director Francis Collins, MD, PhD, to make use of biomedical research datasets and lead the way in coordinating effective use of Big Data.

Bourne discussed some of the factors motivating thinking on big data at the NIH, including open access to information, which was also a focus of U.S. Chief Technology Officer Todd Park‘s conference presentation. Bourne noted that currently 70 percent of research that’s funded cannot be reproduced – a statistic “of great concern to the NIH” that’s driving ongoing reproducibility studies there. But what worried him most, he said, is sustainability: How can growing databases be accommodated within the NIH’s flat budget? (“We can’t go on like this,” he said.) How can labs retain talent when competing with industry’s larger salaries offered to top scientists? (“It’s a loss to the field if you spend money making a biomedical scientist and they leave the field.”) Bourne also seeks to address “broken” areas of scholarship – a paper with “16,000 citations” that no one reads – and the reward system.

Among his solutions are applying business models to promote sustainability of research, introducing policies to ensure funding is allocated where it is most needed, sharing infrastructure where possible and treating biomedical scientists more like tenured academics. Bourne also described an NIH data commons to provide Dropbox-type storage and a collaborative compute environment for scientists.

Co-operating and data-sharing were key this morning as the conference audience heard from Taha Kass-Hout, MD, the U.S. Food and Drug Administration‘s first chief health informatics officer. He described the importance of big data to the regulatory agency’s mission “to protect and promote the public health” and in promoting information-sharing with transparency and protection of privacy. The new, scalable search and big-data analytics platform openFDA comprises more than 100 public access data sets within the FDA and  allows users to access data and run queries through APIs. ”It’s not just about the data,” Kass-Hout told the audience. Ask rather, “How can you build a community around that data?

Previously: U.S. Chief Technology Officer kicks off Big Data in BiomedicineBig Data in Biomedicine conference kicks off tomorrowBig Data in Biomedicine technical showcase to feature companies’ innovations related to big data and Euan Ashley discusses harnessing big data to drive innovation for a healthier world
Photo of Bourne by Saul Bromberger

Big data, NIH, Public Health, Research, Stanford News

NIH Director: “Big Data should inspire us”

NIH Director: "Big Data should inspire us"

Stanford systems-medicine chief Atul Butte, MD, PhD, is an intrepid data miner who firmly believes that analyzing vast reservoirs of public health information is the “fastest, least costly, most effective path to improving people’s health.” His latest paper shows how he and colleagues combed through mountains of medical information to identify new links among genes, diseases and traits. My colleague Bruce Goldman summed up the findings in a previous Scope post:

… by cross-referencing voluminous genetic data implicating particular gene variants in particular diseases with equally voluminous data associating the same gene variants with other, easily measured traits typically considered harmless, Butte and his associates were able to pick out a number of such connections, which they then explored further by accessing anonymized electronic medical records from Stanford Hospital and Clinics, Columbia University, and Mount Sinai School of Medicine.

A recent entry on the NIH Director’s Blog singled out Butte’s findings as an example of how “Big Data may provide priceless raw material for the next era of biomedical research.” Francis Collins, MD, PhD, director of the National Institutes of Health, writes:

What I find most noteworthy about this work is not the specific findings, but how the researchers demonstrate the feasibility of mining vast troves of existing data—genetic, phenotypic, and clinical—to test new hypotheses.

Indeed, we are at a point in history where Big Data should not intimidate, but inspire us. We are in the midst of a revolution that is transforming the way we do biomedical research. In some cases, rather than posing a question, designing experiments to answer that question, and then gathering data, we already have the needed data in hand—we just have to devise creative ways to sift through this mountain of data and make sense of it.

As a reminder, Butte and others from academia, industry and government are gathering here on May 21-23 for the Big Data in Biomedicine conference. Registration information can be found on the conference website.

Previously: Odd couples: Resemblances at molecular level connect diseases to unexpected, predictive traits, Nature/nurture study of type 2 diabetes risk unearths carrots as potential risk reducers, Mining medical discoveries from a mountain of ones and zeroes and Newly identified type-2 diabetes gene’s odds of being a false finding equal one in 1 followed by 19 zeroes

Genetics, NIH, Research, Science, Stanford News

Tissue-specific gene expression focus of Stanford research, grant

Tissue-specific gene expression focus of Stanford research, grant

It’s abundantly clear by now that the sequence of our genes can be very important to our health. Mutations in some key areas can lead to the development of diseases such as cancer. However, gene sequence isn’t everything. It’s necessary to know when and at what levels that mutated gene is expressed in the body’s cells and tissues.

This analysis is complicated by the fact that most of us have two copies of every gene – one from our father and one from our mother (the sex chromosomes X and Y would be an exception; people with conditions like Down syndrome that are caused by abnormal chromosomal copy numbers, another). The two copies, called alleles, are not always expressed in the same way (a phenomenon called allele-specific expression). In particular, structural changes or other modifications to the alleles, or the RNA that is made from them, can significantly affect levels of expression. This matters when one copy has a mutation that could cause a disease like cancer. That mutation could be very important if that allele is preferentially expressed, or less important if its partner is favored.

Understanding relative levels of allele expression is therefore critical to determining the effect of particular mutations in our genome. But it’s been very difficult to accomplish – in part because allele-specific expression can vary among our body’s tissues.

Recently, Stanford researchers Stephen Montgomery, PhD, an assistant professor of pathology and genetics, and Jin Billy Li, PhD, an assistant professor of genetics, devised a way to use microfluidic and deep-sequencing technology to measure the relative levels of expression of each allele in various tissues. (The research was published – subscription required – in January in Nature Methods.) Now they’ve taken the research one step further to look at the varying expression of potentially damaging alleles across ten tissues from a single individual. As Montgomery explained in an e-mail to me:

We were able to learn that as many as one-third of personal genome variants (that is, potentially damaging mutations that would be detected by genome sequencing within an individual) can be modified by allele-specific expression in ways that could influence individual outcomes. Therefore, just knowing a variant exists is only one step towards predicting clinical outcome in an individual. It is also necessary to know the context of that variant. Is the damaging allele in a gene that is abundantly expressed within and across an individual’s tissues?

Montgomery and Li published their most recent findings in today’s issue of PLOS Genetics. They were recently awarded a grant from the National Human Genome Research Institute to study allele-specific expression in thousands of tissues from 100 donors  during the next three years. The grant is part of the institute’s Genotype-Tissue Expression effort, or GTEx.

Previously: We are what we….aren’t? Cataloging deletions and insertions in the human genome

Aging, Genetics, NIH, Research

Sequencing a supercentenarian’s genome to unlock the secrets of longevity

DNA_043014In an effort to determine the genetic underpinnings of longevity, scientists at Stanford and elsewhere are mapping the human genomes of supercentenarians, individuals that have lived beyond 110 years old.

A recent entry on the NIH Director’s blog offers an in-depth overview of one such project involving a 115-year-old Dutch woman named Hendrikje “Hennie” van Andel-Schipper, who died in 2005 and donated her body to medical research. Scientists examined the genome of her blood and brain tissue and analyzed the number of somatic mutations, the type of DNA mutations that are acquired over the course of a lifetime rather than inherited. The results raised some interesting questions:

You might imagine that someone who reaches the extreme age of 115 may have a low number of somatic mutations because his or her cells have exceptional protection against DNA damage. [Scientists] rather expected this to be the case for Hennie, particularly because she’d never had leukemia, lymphoma, or any other type of blood cancer. To the researchers’ surprise, the DNA sequencing results showed that Hennie’s blood cells had accumulated about 450 mutations since she was born. That is consistent with a mutation rate of about four mutations per year of life, which is in line with previous work suggesting that laboratory-grown cells derived from younger, healthy people acquire about five mutations annually.

Recognizing that circulating blood cells are derived from a large pool of stem cells in the bone marrow, and that each stem cell may have acquired a different set of mutations during life, researchers thought it would be challenging to detect any mutations in a collection of millions of blood cells. After all, in healthy adults, bone marrow contains about 11,000 hematopoietic stem cells, of which about 1,300 are actively dividing and replenishing our blood cells. If just one of those stem cells had undergone a mutation of an A to a T, the sensitivity of current DNA sequencing technology would be very unlikely to discover it.

However, further study of Hennie’s blood genome revealed that most of her circulating white blood cells were derived from just two hematopoietic stem cells. Not only did that make the process of detecting Hennie’s somatic mutations much easier, it raised fascinating questions about how the aging process affects bone marrow. While the work still must be reproduced in other older people, the researchers speculate that as we age, the pool of hematopoietic stem cells may shrink, until all of our white blood cells are clones of just a few parent cells.

Previously: She’s so 19th century: Women pushing their hundred-and-teens and California’s oldest person helping geneticists uncover key to aging
Photo by Duncan Hull

Clinical Trials, NIH, Nutrition, Obesity, Research, Stanford News

Stanford seeks participants for weight-loss study

Stanford seeks participants for weight-loss study

Should diets come in different shapes and sizes? Stanford researchers are exploring that question and are seeking participants for a year-long weight-loss study that aims to understand why people may respond differently to the same diet. Titled “One Diet Does Not Fit All,” the study will examine how factors such as genetic influences and eating and sleeping habits have an impact on a diet’s effectiveness.

From a release:

Participants will be assigned randomly to either a very low-fat or very low-carbohydrate diet for 12 months. They will be required to attend weekly classes at Stanford for the first three months, once every other week for the following three months, and once a month for the remainder of the study. Participants must also be willing to have fasting blood samples drawn four times during the 12-month period and participate in online and written surveys. They will receive all test results at the end of the study.

The study is part of a five-year project funded by the National Institutes of Health and the Nutrition Science Initiative. Following an enrollment last year of 200, this spring researchers hope to enroll at least 135 men and women (pre-menopausal only) between the ages of 18 and 50 who are overweight or obese and are generally in good health.

For a complete list of inclusion criteria, click here. To determine eligibility for this study, complete a brief online survey. For more information, contact Jennifer Robinson at

Previously: How physicians address obesity may affect patients’ success in losing weight, To meet weight loss goals, start exercise and healthy eating programs at the same time, The trouble with the current calorie-counting system, Smaller plates may not be helpful tools for dieters, study suggests and Losing vitamins – along with weight – on a diet

Cancer, NIH, Public Health, Women's Health

Study shows daily aspirin could lower women’s risk of ovarian cancer

Study shows daily aspirin could lower women's risk of ovarian cancer

aspirinA team of researchers at the National Cancer Institute have conducted the largest study to date assessing the relationship between non-steroidal anti-inflammatory drugs and ovarian cancer risk. Their findings show that taking aspirin daily may lower women’s risk of ovarian cancer; however researchers caution that more studies are needed before clinical recommendations can be made.

In the study, researchers examined a dozen previous epidemiological studies that included roughly 8,000 women diagnosed with ovarian cancer and nearly 12,000 women who did not have the disease. According to an NCI release:

The researchers determined that participants who reported daily aspirin use had a 20 percent lower risk of ovarian cancer than those who used aspirin less than once per week. For non-aspirin NSAIDs (non-steroidal anti-inflammatory drugs), which include a wide variety of drugs, the picture was less clear: the scientists observed a 10 percent lower ovarian cancer risk among women who used NSAIDs at least once per week compared with those who used NSAIDs less frequently. However, this finding did not fall in a range that was significant statistically. In contrast to the findings for aspirin and NSAIDs, use of acetaminophen, which is not an anti-inflammatory agent, was not associated with reduced ovarian cancer risk.

This study comes on the heels of Stanford research showing that aspirin use appears to cut the risk of another type of cancer (melanoma) in women.

Previously: Can repackaging aspirin get more people to take it daily for prevention? and New research shows aspirin may cut melanoma risk
Photo by Chaval Brasil

NIH, Research, Stanford News

NIH selects Hannah Valantine as first chief officer for scientific workforce diversity

NIH selects Hannah Valantine as first chief officer for scientific workforce diversity

For the past eight years, Hannah Valantine, MD, has led efforts to foster diversity among faculty, staff and trainees at the School of Medicine. But soon she’ll start a new chapter and join the National Institutes of Health as the organization’s first chief officer for scientific workforce diversity.

As my colleague Susan Ipaktchian reports in today’s announcement, Valantine “will lead NIH efforts to diversify the biomedical research workforce by developing a comprehensive strategy to expand recruitment and retention, and promote inclusiveness and equity.”

Lloyd Minor, MD, dean of the School of Medicine, praised Valantine’s accomplishments in an e-mail to medical school faculty and staff. He wrote:

With vision and tenacity, Hannah has done so much to make Stanford Medicine a more diverse and inclusive community where innovation flourishes and equity is valued. Since Hannah took up her position in 2005, the representation of women at every rank—assistant, associate, and full professor—has increased to levels that now exceed national and peer benchmarks. Over the same time, the number of underrepresented minorities among our faculty has also increased. Much of this progress is with thanks to Hannah who has developed innovative initiatives and implemented a number of changes to our recruitment and retention strategies.

In a news release, NIH director Francis Collins, MD, PhD, welcomed Valantine to her newly appointed position saying, “Recruiting and retaining the brightest minds regardless of race, ethnicity, gender, disability and socioeconomic status is critically important not only to NIH, but to the entire U.S. scientific enterprise … Hannah possesses the experience, dedication and tenacity needed to move NIH forward on this critically important issue.”

Previously: Hannah Valantine: Leading the way in diversifying medicine and NIH awards aim to increase diversity in the sciences

Clinical Trials, Fertility, NIH, Research, Women's Health

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Testosterone therapy not effective for primary ovarian insufficiency-related depression, study finds

Primary ovarian insufficiency (POI), a condition affecting approximately 1 percent of women and teenage girls in the U.S., is characterized by ovaries that stop functioning normally before a woman is 40. POI may be a cause for irregular periods, reduced fertility, or health problems such as osteoporosis, and women with POI may also be at risk for depression and decreased quality of life. Treatments for POI may include hormone replacement therapy to restore estrogen and progesterone levels.

A recent study from the National Institutes of Health Clinical Center has examined the effect in women with POI of one year of hormone treatment that included testosterone.

From a release:

In the randomized, double-blind, placebo controlled study, 61 women used placebo patches and 67 women used patches that delivered 150 micrograms of testosterone a day, similar to the Intrinsa patch that was rejected by FDA as a treatment for low sexual desire in women.

After 12 months, testosterone levels were back up to normal for the women who got the treatment. The investigators saw no detrimental effects of testosterone, but they found no significant improvement either in measurements of quality of life, self esteem and mood compared with placebo.

Bringing testosterone back to normal doesn’t help these aspects of life, suggesting that it’s something other than testosterone that plays a role in mood problems for women with POI, concluded the researchers.

“This study makes an important contribution toward understanding what testosterone can and cannot do. With all the hype about testosterone and aging, it is important that the public have the facts,” NAMS Executive Director Margery Gass, MD, said in the release.

The study was published online in the journal Menopause.

Previously: An in-depth look at fertility and cancer survivorshipAsk Stanford Med: Expert in reproductive medicine responds to questions on infertility, Researchers describe procedure that induces egg growth in infertile women and Oh, baby! Infertile woman gives birth through Stanford-developed technique

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