Taking back the genome

Posted on March 21, 2012 by mgwinn

Who owns the genome? The Human Genome Project was sold to the public on the promise of future health benefits. Its goals, however, promised only to “transfer related technologies to the private sector.” Ten years after its mission was accomplished, many people are wondering when their investment in public science will pay off.

Perhaps this helps explain why tests for BRCA1 and BRCA2 mutations, which predict risk for breast and ovarian cancer, have become a lightning rod for public discontent. They were discovered and patented in the 1990’s, before sequencing for the Human Genome Project began. Today they remain among the very few clinical genetic tests that are relevant to preventing common diseases.

Unlike many gene patents, those on BRCA1 and BRCA2 have been aggressively enforced, creating an effective monopoly for a single company, Myriad Genetics. The Supreme Court has not yet decided whether to hear the case that could decide whether they meet the definition of “invention” under patent law. In the meantime the ACLU, which organized the lawsuit on behalf of multiple plaintiffs, has launched a public information campaign, Take Back Our Genes. The centerpiece is a website inviting people to make videos explaining how gene patents have affected them, while holding a sign saying “I TAKE BACK MY GENES.”

But wait a minute—do we really want to take back our genes?  It’s a good slogan for getting attention but it doesn’t do much to frame the issue for public debate. The fact is, a a person’s genes are useful for predicting health or diagnosing disease only to the extent that they can be compared with others. Practically everything we know about using genes to predict and diagnose disease has come from studying genetic variation in families and populations. A single genome reveals few secrets.

As the human genome sequence continues its transformation from shiny object to commodity, the search for value is focused on mining the data. Finding ways to manage, store, analyze, and share data—not just sequences but their annotations, variations, and associations—has always been a priority for genome research. The discovery of BRCA1 itself prompted NIH to establish the Breast Cancer Information Core, an international, open access, online database of mutations found in breast cancer. Its mission is to help ensure that “the detection and interpretation of these mutations is coordinated and that this information is made available to as many qualified investigators as possible.”

Genome policy expert Misha Angrist recently reminded everyone that Myriad Genetics is one of only two laboratories that do not participate in this database, having last contributed data in 2004: the data it continues to compile from clinical tests are proprietary. An analysis published this time last year in the Genomics Law Report suggests that these data could be Myriad’s ace in the hole, regardless of the fate of their gene patents. Opponents of gene patents should note that data sharing isn’t the only available alternative—data can also be entombed as trade secrets.

More than 40 years ago, an ecologist writing in Science introduced the “tragedy of the commons” as a metaphor for the overuse of a shared resource by individuals who act independently out of rational self-interest. A generation later, a pair of legal scholars warned against the opposite:

[T]he recent proliferation of intellectual property rights in biomedical research suggests a different tragedy, an “anticommons” in which people underuse scarce resources because too many owners can block each other. Privatization of biomedical research must be more carefully deployed to sustain both upstream research and downstream product development. Otherwise, more intellectual property rights may lead paradoxically to fewer useful products for improving human health. 

Our society’s rules of membership, which apply to corporations as well as to real people, address many types of shared benefits and risks. As affirmed by the Institute of Medicine, government’s role is “striving to achieve a balance between the two great concerns in the American public philosophy: individual liberty and free enterprise on the one hand, just and equitable action for the good of the community on the other.”

The sense that benefits and risks are out of balance sometimes leads to hasty actions, such as the legislation pending in South Dakota and several other states that would create individual property rights in DNA. A new analysis in the Genomics Law Report considers potential implications of such laws that might surprise their authors. For example, would police still be allowed to collect DNA evidence at crime scenes?

Oceans of ink on these issues are free for the surfing by pundits and policy-makers. What may be missing is a way to engage the public in a broader discussion of values to redefine the genome commons. An opinion piece in The Scientist is one starting point:

 Do patents promote investment in personalized medicine or stifle innovation by suppressing competition? Do patients benefit from patented therapies, or do they suffer without treatments because they are too expensive?… 

At its heart, this debate may be more of a public policy question than a legal one. People deciding this issue must keep in mind that most university research is funded by government grants and that NIH is a federal agency. We may want taxpayer money to support this kind of research, but it raises the same specter of big government and taxpayer burden as health care reform. Is a country that may not be ready to provide universal access to proven therapies willing to invest substantial amounts in research programs that may take years to yield any benefits? 

 

 

Posted in data mining, genomic medicine, uncategorized | Comments Off

The operation didn’t succeed—but the patient didn’t die

Posted on November 18, 2011 by mgwinn

A clinical trial is designed to enroll the minimum number of patients necessary to demonstrate a meaningful difference in outcomes. Enrollment may stop early if a new treatment demonstrates overwhelming superiority, or if an excess of serious adverse events occurs in the treatment group. Sometimes, though, the trial stops because it has virtually no chance of demonstrating benefit, even if enrollment continues. In that case, the trial ends in “futility”—not with a bang, but a whimper.

Such was the recent fate of two major clinical trials of invasive interventions to prevent recurrent stroke. Both interventions focused on preventing ischemia caused by narrowed or obstructed intracranial arteries.

CT and angiogram of ischemic stroke, left middle cerebral artery

Ischemic stroke, left middle cerebral artery

They were modeled on procedures that are already widely used to treat ischemic coronary disease: bypass surgery and angioplasty with stenting. Bypass surgery creates a circulatory detour around a blocked artery; angioplasty with stenting threads a tiny tube into a narrowed artery to widen it and keep it open.

The Carotid Occlusion Surgery Study (COSS) tested a technique for bypassing an occluded carotid artery by connecting an artery outside the skull with the middle cerebral artery, which supplies blood to the cerebrum. The primary outcomes were stroke or death within the first 30 days, or an ipsilateral (same-sided) stroke within two years. After 97 patients had been randomized to surgery and 98 to medical treatment, the trial was stopped for futility: twenty events had occurred in each group, and earlier on average in the surgical group.

The Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial used the Wingspan stent, approved by FDA under its Humanitarian Device Exemption program. When the trial was stopped, 451 patients had been randomized; 14.7% of the intervention group had a stroke or died within the first 30 days, compared with 5.8% in the medical management group.

My Dad had a brush with futility in 2009. His stroke went unnoticed at first because he had Parkinson’s disease and was already struggling daily with mobility and balance. By the time he got to the hospital, it was too late for the only treatment that has been demonstrated effective in acute stroke: tissue plasminogen activator (tPA). This enzyme dissolves blood clots and helps reestablish blood flow to the brain, but only if given within the first three hours.

My three siblings and I live scattered far from our parents’ home. The first to arrive at my Dad’s bedside in the intensive care unit found him obtunded and my Mom distraught. The head of the stroke service was one of my Dad’s former students, who still thought of him as a mentor; she had rescued him from the open ward where he’d spent the night and made sure he was closely monitored. She introduced a colleague, an interventional neuroradiologist, who was enrolling patients in a clinical trial. He outlined a procedure that involved sliding a small tube into my Dad’s narrowed middle cerebral artery.

When my Mom and sister asked about the risks of the procedure and possible alternatives, he became impatient. Didn’t they see that my Dad had “a gun in his head, ready to go off?” My Dad was 80 years old, frail and weak after suffering 15 years with Parkinson’s disease. He was stressed, disoriented, drugged, and unable to talk with the doctors. My Mom didn’t want him to undergo any more procedures, especially if they were risky, so the answer she and my sister gave on his behalf was “No.”

My Dad mostly recovered from his stroke and went home, where he lived 15 more months without ever returning to the hospital. In the end, we’ll never know whether he had another stroke or just gave up the fight with Parkinson’s disease. But at least we’ll know that he didn’t die from a procedure that offered more risk than benefit. Now that the trial has stopped and the results are published, perhaps no one else will, either.

Bioethicists affiliated with the NIH Clinical Center recently commented that the stenting trial, despite its clinical failure, “represented a successful use of a policy mechanism that can balance the goal of rapid access to innovative medical procedures with the need to obtain rigorous evidence on the risks and benefits of these procedures before they become widespread in clinical practice.”

Many invasive medical procedures are introduced without substantial evidence of effectiveness; once covered by insurance, they may become widely adopted or even routine. FDA does not regulate procedures unless they involve devices; Medicare, however, will reimburse only procedures with sufficient evidence to demonstrate that they are “reasonable and necessary.”

To address the tension between strict evidence requirements and innovation, the Centers for Medicare and Medicaid Services (CMS) in 2005 introduced a new policy for “coverage with evidence development.” This policy allows the use of a new procedure only when patients are entered into a prospective clinical trial or registry. Documenting evidence while monitoring outcomes is good for patients. It’s also good for the health care system, which can’t afford to waste resources on treatments that don’t work.

 

Posted in evidence-based medicine, uncategorized | Tagged | Comments Off

The river

Posted on November 6, 2011 by mgwinn

I never knew my Dad’s father. He died in 1950 during radical chest surgery, a last-ditch attempt to contain the tuberculosis that was killing him. Born in 1900, he was one of eleven surviving offspring of parents who farmed family land in the hills settled by their pioneer forebears. They were a hardworking, enterprising family who built their home from timber on the property, along with a sawmill, a store, and a school. The sons and daughters left the farm to become railroad telegraphers, carpenters, nurses, and teachers but returned every summer for their mother’s birthday. I met many of them at reunions that continued into the 21stcentury.

In the late 1960’s, researchers at the National Cancer Institute (NCI) studied the family for clues to chronic lymphocytic leukemia (CLL), which had developed in three of the eleven siblings. NCI doctors examined seven of the eight still living and sent questionnaires to the next generation, including my Dad. Years later, I found the published study in MEDLINE. It described immune abnormalities in several of the apparently healthy siblings, as well as in the three with CLL and another with severe arthritis. The authors suggested that these could be different manifestations of an inherited immune defect—perhaps a recessive trait inherited from both parents, who were second cousins.

Fraumeni et al. Familial chronic lymphocytic leukemia. Ann Int Med, 1969

Well before genetics was a science, thousands of years of agriculture offered ample evidence for the passage of traits from one generation to the next. Charles Darwin’s longest book, The Variation of Animals and Plants Under Domestication, may have inspired his half-cousin Francis Galton to study the heredity of human traits, from height to mental ability. Galton conceived of twin studies to separate the influences of inherited and environmental influences and is credited with the expression “nature versus nurture.” He also coined the term “eugenics,” which is now associated mostly with the misguided social application of genetic theories.

Wedgwood-Darwin-Galton pedigree, Eugenics Education Society, 1909.

Common 19th-century diseases such as pellagra and tuberculosis were suspected of being hereditary because they so often occurred in multiple family members. Darwin, familiar with the effects of inbreeding on plants and animals, worried that marriage to his first cousin, Emma Wedgwood, had contributed to their daughter’s early death from tuberculosis. Two of their ten children died in infancy and of the six who eventually married, three had no children. Scientific speculation on the Darwin pedigree continues to this day.

Well after Koch’s 1882 discovery of the tubercle bacillus, heredity was considered a potentially important factor in tuberculosis. The Medical Record, a New York weekly medical journal, in 1903 published the following thoughts in an article titled “Some Questions on Heredity”:

“Pathologists assert, and seemingly with absolute justification for their assertion, that tuberculosis is not directly an inherited disease but that it is always the result of infection. We all recognize that the most we can say, certainly about pulmonary tuberculosis, so far as heredity is concerned, is that the lessened resistance to the attacks of the tubercle bacillus may be inherited.”

The author then suggested that hereditary factors could play a role in extra-pulmonary tuberculosis and might help explain why some people recovered spontaneously. He added:

“It is often observed in families that certain diseases develop at corresponding periods in the life of parent and offspring. This not infrequently extends through several generations. Tuberculosis is a notable example of this. The widespread prevalence of tuberculosis adds to the difficulty of arriving at definite conclusions, in regard to the part which heredity plays.”

The “white plague” was on the upswing in Western Europe when my Dad’s ancestors departed in 1740 for the American colonies.  Tuberculosis mortality is thought to have peaked around 1800, then declined 10-fold during the 19th century for reasons that can only be conjectured today. The first antibiotic to cure tuberculosis, streptomycin, became available for clinical use in the late 1940’s; although too late to save my grandfather, its discovery earned the 1952 Nobel Prize in medicine. Resistance to streptomycin emerged quickly, but so did effective new antimicrobials. Deaths from tuberculosis dropped precipitously.

Estimated trend in tuberculosis mortality, Western Europe 1740-1985.

Population-level trends in infectious diseases, including tuberculosis, are influenced by characteristics of the human population, the environment, and the pathogen—the epidemiologic triangle. A change in any one of these “causes” affects the apparent contribution of the others. For example, before the bacterial cause of tuberculosis was known, treatment focused on the environment: sanatoriums provided fresh air and a healthy diet. When some patients responded but others didn’t, suspicion turned to human factors, including inherited susceptibility. When antimicrobial treatment became routine, pathogen characteristics—especially drug resistance—became the focus of public health investigations.

While my Dad’s father, mother, and sister were in the sanatorium, he and his brother were sent to the country. All his life, my Dad took pleasure in remembering those months on the family farm on the New River, surrounded by aunts, uncles, and cousins. His mother and sister recovered completely in the sanatorium. Could an inherited immune defect have tipped the balance in his father’s case?

In later years, long after the NCI study was done, several more of my grandfather’s siblings developed CLL. Family members wondered whether chest X-rays, once used for routine tuberculosis screening, might have played a role; however, CLL is “one of the few malignant conditions never linked to radiation.” No more cases occurred in the next generation, which is now well beyond the age at which CLL usually appears. Perhaps a rare, recessive trait came to light and then faded into the genetic background. Perhaps something else particular to that time and place found a footing in the family that grew up there but has now dispersed.

The farm was sold in the 1960’s to a businessman who wanted to mine titanium from the sands. His venture never materialized and after the national Wild and Scenic Rivers Act passed in 1968, the riverbank became Federal property. Early plans called for the family home to become a museum of pioneer life but eventually the house fell victim to vandalism, rain, and neglect.

The New River isn’t really new but ancient, perhaps 300 million years old. People have lived along its banks for only the last 10,000 years and European settlers only for the last few hundred. Farming there has now gone the way of hunting and gathering, and the railroad, which once carried away the area’s timber and coal, is barely running. The best way to visit the place today is to put a boat in the water at the New River Gorge national river recreation area. That’s what we will do when we carry my Dad’s ashes to the place he loved most.

New River, 2002, by Tom Brown.

 

 

Posted in epidemiology, public health, uncategorized | Comments Off

It gets personal

Posted on September 18, 2011 by mgwinn

A couple of weekends ago, my son headed back to college in southern California and my husband went with him. They planned to test-drive a used car, check out a street festival in Silver Lake, run last-minute errands, and move boxes to the dorm.

They arrived Friday night and checked into their motel, an online bargain near the freeway. It was already late and the burger place next door was Yelp-recommended, so they ducked in for the special, which came with fries and slaw. But the boy doesn’t like slaw, so my husband got an extra side.

He got something else, too. Early Saturday morning, I was surprised to hear my son’s ringtone. He is not an early riser and of course it was even earlier in California. He reported that his Dad had been up all night with vomiting and diarrhea and was lying in bed exhausted. He’d asked for some Gatorade—any color but red, which can confuse the clinical picture.

My husband is a pediatrician and a kidney transplant recipient. He is an expert on vomiting and diarrhea, clear liquids, and signs that point to the emergency room. So when I heard in late afternoon that he hadn’t drunk much Gatorade or even gotten out of bed, I asked “Do you need to go to the ER?” When he answered, “I don’t know,” I told our son to take him there.

He arrived with a fever of 103 and got an EKG, which was normal. The doctor on call patted his belly and someone else cultured his nose—not for diagnosis (wrong site!) but for hospital infection control. Five hours later, as the ER overflowed with patients, he was admitted to the hospital’s telemetry unit on IV fluids and antibiotics. Nearly 24 hours after getting sick, he hadn’t had any of the many medications that he takes daily, including Prednisone.

I worried about him, his kidney, and his compromised immune system. I worried about the teeming microbiota of the country’s second-largest metropolis. I worried about the increased risk of hemolytic-uremic syndrome (HUS) in people with Shiga-toxic E. coli (STEC) infection who take steroids. (Earlier this year, STEC sickened thousands of people in an outbreak blamed on vegetable sprouts; hundreds developed HUS, which often leads to renal failure.) My worries knew no bounds.

On Sunday morning, after nervously checking airline schedules for flights to L.A., I went to the Los Angeles County Health Department’s website. It wasn’t hard to find the page to report a case of foodborne illness (the “FBI_Report”). Filling out the form online made me feel a bit better. It said, “All reports received after hours or on the weekend will be responded to on the following business day.” Really?

It was already Sunday afternoon and my husband had a return airline ticket for Monday. I hadn’t heard from the doctor, although I’d asked the nurse to have him call when he made rounds. As it turned out, he hadn’t actually been at the hospital at all—but he had called to tell my husband that he might be discharged later that day. Late Sunday evening, about 24 hours after admission, my husband got a handshake from the doctor and was sent on his way. Our son took him back to the motel, where he spent the night before flying out Monday morning.

Back in Atlanta Monday evening, he had a voice message from an investigator at the L.A. County Health Department, requesting a telephone interview. On Thursday, he heard from the inspector who had been out to the implicated restaurant, near the edge of L.A. County. He’d found that the slaw was at the correct temperature on the day of his visit but the tuna salad in another refrigerator wasn’t. Other findings that led to citations included using the same rags to clean tables and food preparation surfaces and failing to display the restaurant’s health rating in a place visible to customers.

My husband also requested a copy of his hospital chart to add to his records here. He was surprised to discover that it noted “a history of coronary artery disease,” which is one condition he doesn’t have. It also included extensive and detailed descriptions of physical examinations (from chest percussion to Romberg’s sign) that weren’t done during his hospital stay. How could this be?

Most often, telemetry units admit patients who need continuous cardiac monitoring, such as after a heart attack. My husband was served a “cardiac diet” once he quit vomiting. His roommate, a youngish guy with a drug overdose, also got an EKG before he recovered enough to walk out of the hospital against medical advice (AMA, the medical equivalent of AWOL). Could it be that my husband and the drug addict were managed as cardiac patients because they were admitted to the telemetry unit? Was my husband’s medical record cloned from electronic boilerplate?

Compare the prompt, personal attention my husband’s illness received from the local public health department with the depersonalized treatment he received at a high-tech, private community hospital.

More than 10 years ago, health technology and a skilled surgeon gave my husband a kidney transplant and a new lease on life. Health technology alone, however, does not save lives or money. It must be deployed as part of a system that includes standards and accountability. The adoption of electronic medical record (EMR) systems is an important component of healthcare reform, with the potential to improve healthcare while reducing costs. However, as RAND Corporation scientists wrote in Health Affairs:

“[I]t is increasingly clear that a lengthy, uneven adoption of nonstandardized, noninteroperable EMR systems will only delay the chance to move closer to a transformed health care system. The government and other payers have an important stake in not letting this happen. The time to act is now.”

Their article appeared in September 2005.

 

 

 

 

 

Posted in evidence-based medicine, public health, uncategorized | 3 Comments

Everyone is a remix

Posted on August 22, 2011 by mgwinn

Humans are curious about their origins. Children ask, “Where did I come from?” Teens wonder whether they were switched at birth. Seniors dig into genealogy on websites that attract thousands of users. People of all ages read about extinct humans in the news and in best-selling books. Celebrities discuss their DNA ancestry tests on television and recommend websites where viewers can buy them, too.

Google Trends "Neanderthal"

Commercial ancestry tests and the research tests used by anthropologists and population geneticists employ similar techniques, comparing test and reference samples to look for patterns of genetic similarities and differences. For example, Ancestry Informative Markers (AIMs) are sets of genetic variants that are known to differ in frequency between specific human populations. Markers derived from mitochondrial DNA (mtDNA, passed from mother to child) and the Y-chromosome (passed from father to son) are used to trace lineages.

Population genetics is a statistical science, measuring and revising estimates of genetic variation with new data. An individual person’s DNA test results can answer meaningful questions only when they are compared with results from populations (e.g., “could I have ancestors from the Middle East?”) or other individuals (e.g., “could I be related to this person with the same last name?”). Personal ancestry test results that are inconsistent or lack meaningful context can leave users confused and disappointed. To help address these issues, the American Society of Human Genetics has called for the development of “scientifically based, ethically sound, and socially attentive guidelines” for ancestry testing.

As genotyping technology gets faster and cheaper, companies and researchers alike are able to test more people using larger sets of markers, such as genome-wide panels of single nucleotide polymorphisms (SNPs). The results enrich a growing knowledge base on human evolution, migration, and genetic variation in modern populations.

A new article in Nature Reviews Genetics summarizes the challenges and implications of research that last year produced the first three genome sequences from extinct hominins. Genome-wide data from these ancient individuals and from contemporary human populations support the theory that modern humans descend from a single group that migrated from Africa and later inter-bred with two groups of now-extinct relatives, the Neanderthals and Denisovans. All non-Africans carry traces of Neanderthal DNA.

Human migration patterns can be inferred from genetic admixture, which results from inter-breeding of genetically distinct populations.  Observed patterns at the population level reflect the results of thousands of instances of sexual reproduction, which shuffles the genetic deck between generations. Recombination between inherited parental chromosomes during meiosis creates germ cells with a mixture of segments from each one. When sperm and egg combine, a new remix is born.

Recombination in meiosis

Recombination does not occur at random throughout the genome but is more likely at “hotspots.” New research published last week provides the most complete recombination maps yet developed for African-American populations. These maps will be useful not only to population geneticists but to epidemiologists searching for associations with health and disease.

In an eloquent multi-part video essay titled “Everything is a Remix,” New York-based filmmaker Kirby Ferguson draws on examples from music, film, and scientific discovery to argue that the essence of creativity is the remix: copy, transform, combine. The same process generates new variations on the human genome, creating individuals who are genetically unique, yet descended from the common ancestors of everyone alive today.

 

 

 

Posted in pattern recognition, uncategorized | 2 Comments

Quantum medicine

Posted on July 8, 2011 by mgwinn

The brain doesn’t leap to mind as a prototype for genomic medicine. Why study a system of fluctuating electrical impulses flashing across billions of networked neurons? Why not try something simpler?

For a peek behind the curtain of complexity that separates current genomic research from its future, see the new article in Cell by epilepsy researchers with Baylor University’s Ion Channel Project. Ion channels are the targets for most antiepileptic drugs and ion channel genes have been implicated in most of the rare, inherited epilepsy syndromes described to date. The authors investigated the role of genetic variation in ion channel genes in sporadic epilepsy, which affects 1-2% of the population.

Ion channels regulate the flow of ions across cell membranes, controlling the voltage gradients that generate nerve impulses. A circular assembly of ion channel proteins forms a trans-membrane pore that opens and closes, allowing only specific ions to pass through.

Fig 11-20. Molecular Biology of the Cell. 4th edition. Alberts B, Johnson A, Lewis J, et al. New York: Garland Science; 2002.

A typical ion channel

At the molecular level, the function of ion channels is well understood. The condition of a single cell, however, is a function of thousands of ion channels with overlapping and interdependent effects. In cells of different types, more than 400 ion channel proteins are expressed in assorted combinations.

Investigators in the new study sequenced the coding regions of 237 ion channel genes to create individual genetic profiles (“channotypes”) for 152 adults with epilepsy and 139 unaffected controls. They analyzed a set of 3095 validated SNPs, of which nearly a third of had not been previously reported. About 36% of SNPs were found only among cases and 8% were found only among controls; however, most (57%) were found in both groups. Every person’s channotype was unique.

Functionally “severe” (nonsense or splice site) variants appeared to be more common in the case group but this finding was not statistically significant. Nearly all of the cases had missense mutations in the 17 genes previously associated with inherited epilepsy—but so did two-thirds of controls. Furthermore, the number of such mutations was not predictive of disease status; thus, there was no evidence for the “load hypothesis,” which suggests that epilepsy occurs when the sum of small, incremental genetic effects crosses a threshold.

Using a computer model to simulate the behavior of a single neuron, the authors demonstrated dramatic variation in firing patterns with pairwise combinations of ion channel variants associated with loss or gain of function. “[T]he ability to extract predictive phenotypic information on network behavior from ion channel SNP profiles presents a formidable bioinformatic challenge,” they wrote. Nevertheless, in the absence of high-throughput, physical methods for describing combinatorial functional effects of multiple genetic variants, bioinformatics seems to be the way out.

Until recently, most published genetic association studies stopped with the associations. Those venturing a functional hypothesis often went no further than to sketch a biological pathway involving the implicated genes. The current study tackles human complexity at multiple levels, from molecules to populations. Most of the results are presented graphically, allowing the reader’s visual cortex to grasp patterns that are too subtle to summarize with tidy statistics and too complex to describe in words.  Perhaps computers and human brains working together will be able to chart new paths that neither could navigate alone.

 

 

Posted in data mining, genomic medicine, pattern recognition, uncategorized | 1 Comment

The knowledge of crowds

Posted on June 28, 2011 by mgwinn

Researchers at 23andMe, the consumer genetics company, just published the first crowd-sourced, genome-wide association study (GWAS) in PLoS Genetics. They replicated 20 of 42 previously published genetic associations with Parkinson disease (PD) and located 2 new ones, both with odds ratios of approximately 0.85. Rather than disappointing, these fairly conventional findings offer a proof of concept for an unconventional approach to human genetic research.

23andMe is the direct-to-consumer genetic testing company launched in 2007 by Linda Avey and Anne Wojcicki (who is married to Google founder Sergey Brin). In late 2008, the New York Times Fashion and Style pages featured a “spit party,” where well-heeled financial types collected saliva in tubes to get their DNA done. In those heady days before the crash, it seemed like good, if not entirely clean, fun for people with plenty of disposable income. So what if the results didn’t provide actionable health information? As the 23andMe Web site said at the time, “It’s fun to learn about your own genome.”

23andMe’s main rivals in the personal genomics sphere—deCODEme and Navigenics—both emphasize medical interpretation of test results and provide customers access to their clinical experts. In contrast, 23andMe plays up the social networking aspect of its services; for example, people who purchase genetic ancestry analysis can share their results online via “Relative Finder.” However, the communities of real interest to 23andMe are groups of people who share a common disease. The web page for company’s research arm, 23andWe, explains:

23andMe isn’t just about you. Our research arm, 23andWe, gives customers the opportunity to leverage their data by contributing it to studies of genetics. With enough data, we believe 23andWe can produce revolutionary findings that will benefit us all.

Who were the research subjects in 23andMe’s new study? The 3,426 people with PD (cases) were recruited through an email/mail campaign targeted to PD patient groups, including those sponsored by the Michael J. Fox Foundation, The Parkinson’s Institute and Clinical Center, and others. A smaller number were recruited in person at PD workshops and conferences. According to the published Materials and Methods, they “were offered the 23andMe Personal Genome Service for a nominal fee of $25.” The 29,624 controls were also 23andMe customers, who paid unknown but probably varying amounts to participate.

What did research participants receive in exchange for contributing their genetic and questionnaire data? All cases and controls received results of 23andMe’s standard DNA analysis package, some at discounted rates. They would have acknowledged the research consent document, which states, “If 23andMe develops intellectual property and/or commercializes products or services, directly or indirectly, based on the results of this study, you will not receive any compensation.” They (and all of us) can view research news on a public web page, which, surprisingly, provides no link to the article in PLoS Genetics, even though it is freely available online. And that’s about it.

Why have thousands of people paid for the privilege of filling out questionnaires and donating their DNA to a corporation that stands to profit by selling it to “external parties,” such as developers of drugs and diagnostics? Online testimonials suggest that some people want to know about their genetic risk factors for common diseases, even though current knowledge is mostly too limited to support risk predictions or health recommendations. Others are interested in diseases that run in their families. However, some may have found value that is harder to measure: the sense of belonging to a group with shared interests, of playing an important part in something big, of securing one’s place in the human community. Social networking taps into this deep desire and 23andMe has found new ways to satisfy it. (For an outstanding example, watch the video: Just what is a 5th cousin?)

Epidemiologists take note. Throughout the 20th century, epidemiology has struggled with the schism between medicine and public health and its “implication that social and biomedical models of disease sit on different sides of an academic fence.” In the mid-1990’s, advocates for the social model introduced the concept of community-based participatory research (CBPR, reviewed here), partly in reaction to epidemiology’s growing focus on individual-level risk factors, including genetics. CBPR typically engages community institutions and their representatives, rather than collections of individuals. Community-based, participatory genetic research requires a hybrid approach. The Internet provides another medium for engaging individuals and groups, including self-organized communities. They may not satisfy traditional definitions of community or traditional requirements for epidemiologic research, but here they are.

 

Posted in epidemiology, public health | Comments Off

Billions and billions

Posted on May 18, 2011 by mgwinn

A day after two new reports touted the economic impact of NIH-sponsored research, Nature published an editorial calling for a broader view of the return on public investment in science. The editorial cites policy researchers Barry Bozeman and Daniel Sarewitz, who make the case for an approach based on public values. These values include but are not limited to scientific “knowledge for its own sake” and economic impact. Particle physics and cancer research are both science, but without clear measures for comparing their value, choosing between them is not a technical but a political matter. This has been known since the 1960′s as the “chalk-and-cheese problem.”

Non-scientific, non-economic social goals often provide the rationale for public funding of research in the first place. These goals generally relate to improving the quality of life through better health, more security, added leisure time, a cleaner environment, etc. However, return on investment is much easier to measure in terms of scientific productivity (e.g., publications, journal impact factors) or economic impact (e.g., job creation, cost-effectiveness) than in social currency.

Bozeman and Sarewitz believe that public values in research deserve more attention for three important reasons:

  • They focus on outcomes that are important to most people, rather than on instrumental values (like money, which after all does not really buy happiness).
  • They are by definition widely shared. “[T]he idea that all will benefit from the economic growth ends of science and technology, even though widely asserted, has little plausibility.”
  • They are easily subverted. After serving to justify research, public values are often pushed into the background as special interests take to center stage.

Basic biomedical research is sold to the public by promising to help people lead “longer, healthier lives” (a phrase found many places, including here) and–especially since the Human Genome Project–prevention has become a watchword. One of the industry-sponsored reports published last week contains a facile though feeble echo of this promise in the title of its final section: “Preventive Medicine for Our Economy.” If corporations are persons, perhaps they need personalized medicine, too.

The other report hints at immortality, with a whiff of chalk or cheese: “One of the key realizations that must be understood regarding the human genome sequencing is that its usefulness is perpetual. While other major big science projects have a life attached to them the human genome sequence will not wear out or become obsolete…. For example, the $11 billion Superconducting Super Collider has an estimated life span of 30 years and the $1.5 billion Hubble Space Telescope has an estimated 15–20 year life.”

In the 1960’s, physics, not biology, was at the forefront of scientific discovery and the space program was at least as popular then as the Human Genome Project is now. The manned lunar landing was a spectacular achievement, watched on television by an estimated 500 million people worldwide. Yet economic misery in the 1970’s led to questions about the relative value of space exploration and investment in urban infrastructure and programs for the poor. Suddenly the moon was nothing more than green cheese.

For Earth people only: 12c off Tang.

Investments in the space program have been justified to the public in part by “spinoffs” of space technology that benefit consumers and improve the quality of life. This is sometimes called the “Tang argument,” for the orange-flavored drink consumed by astronauts (although actually invented years before manned space flight began). NASA still maintains a Spinoff website, which publishes an annual report and maintains a searchable database of commercialized NASA technology, from helicopter rotors to hair straighteners.

A Gallup poll conducted in July 2009, the 40th anniversary of the historic moon landing (and well into the current recession) found:

Americans remain broadly supportive of space exploration and government funding of it. In fact, Americans are somewhat more likely to believe the benefits of the space program justify its costs at the 40th anniversary of the moon landing than they were at the 10th, 25th, and 30th anniversaries.

Space exploration enjoys even higher support among those too young to remember watching the moon landing themselves and my guess is that their enthusiasm has nothing to do with Tang, spinoffs, or spin. Engaging the next generation in thinking about science is also a public value. Online message boards offer a medium for continuing the discussion.

Posted in public health, uncategorized | 2 Comments

A billion here, a billion there

Posted on May 15, 2011 by mgwinn

Watch out for more signal flares as the federal budget battle looms. Two new, industry-sponsored reports went online this week to highlight the economic impact of research sponsored by the National Institutes of Health (NIH).

A report for United for Medical Research (UMR) by economist Everett Ehrlich highlights the role of NIH in driving the “medical innovation sector,” which includes developers of medicines, pharmaceuticals, devices, research equipment, and other products based on NIH research. UMR is a coalition of academic research institutions, health advocacy groups, and private industry that have come together “to seek steady increases in federal funding for NIH.”

A report by Battelle for the Life Technologies Foundation (Battelle-LTF) focuses specifically on economic impact of the Human Genome Project (HGP) and subsequent federal investments in genome sequencing. LTF is the non-profit arm of Life Technologies Corporation, a global supplier of biotechnology instruments and reagents to research and industrial laboratories.

GenomeWeb Daily News usefully summarized key points in both documents (here and here) but the full reports contain a wealth of additional findings from analysis of public data.

According to the UMR report, the $26.6 billion awarded by NIH in 2010 to universities and other research institutions generated $68 billion in new economic activity. Spillover to the medical innovation sector had an even larger impact, paying $84 billion in wages and exporting $90 billion in goods and services. According to the Battelle-LTF report, the HGP was responsible for generating $67 billion in 2010 alone.

Who knows how all these figures add up? We’ve grown complacent about billions, from the 3 billion base pairs in our genomes to the 6-plus billion other people on the planet. The $31 billion NIH budget and even the $1,294 billion federal deficit seem almost ordinary (although the $14.3 trillion national debt still packs scare potential).

“A billion here, a billion there, and pretty soon you’re talking real money.”

Did Senator Everett Dirksen of Illinois ever make the remark he is most famous for? The Dirksen Congressional Center can’t say for sure–but he certainly could have. In a press conference exactly 50 years ago in June, the Senator said, “If we are going to develop a national willingness to sacrifice, the pace must be set in Washington. And the best place to start would be on a Presidential revision of the budget aimed at eliminating all but the most essential expenditures.”

Determining what is “essential” is the hard part now, as it was then. The budget has grown but so have people’s expectations of government. Where would “leave it to the private sector” actually leave the private sector, when so much seems to depend on public investment?

 

Posted in genomic medicine, public health, uncategorized | 1 Comment

Regime change

Posted on May 3, 2011 by mgwinn

Last week, limnologists from the University of Wisconsin and colleagues published the results of a fascinating experiment designed to detect early-warning signals of an ecological regime shift (Science, April 28, 2011). As human pressure on ecosystems increases around the world, the effects are not always gradual; sometimes non-linear changes produce unexpected, drastic shifts to “unwanted states.” Prior theoretical work suggests that such transitions may be preceded by statistical signals, such as a slowing return to baseline after repeated perturbations.

In their experiment, the investigators manipulated the food web in a lake populated mostly by small, planktivorous fish by gradually introducing top-level predators (largemouth bass). Prior experiments suggested that this action would destabilize the food web, precipitating a cascade that left the lake dominated by piscivores. A nearby lake already home to largemouth bass served as a reference ecosystem to control for weather and watershed influences affecting both lakes.

University of Wisconsin limnologists with plankton trap. c. 1917

Over three years, as they gradually added largemouth bass to the manipulated lake, the investigators made daily observations of the quantity and distribution of small fish, zooplankton, and phytoplankton in both lakes.  After the first year, as predicted by modeling studies, they began to detect statistical early-warning signals, including oscillations, increasing variability, and slowed return to baseline in chlorophyll measurements in the manipulated lake. By the end of the study in 2010, it had undergone a non-linear regime shift and its food web was similar to that in the reference lake.

The authors were careful to point out that modeling studies have revealed pitfalls in using early warning indicators to predict regime shifts. Potential causes of failure include spurious signals, biased or random measurement errors, and signals dampened by complex interactions. They also noted that their experiment was not designed to investigate whether early detection and intervention could reverse the progression of regime change.

The phenomena observed in this study, as well as the investigators’ caveats, have their counterparts in epidemiologic research focused on prediction of unwanted states, i.e., disease, disability, and death. Many diseases–from heart failure to major depression–have been observed to follow a non-linear course, in which disordered physiology produces progressively wider oscillations with diminished recovery to baseline.

I’ve wondered for a while whether epidemiologists and health researchers should study the methods of ecology to identify better ways of integrating diverse “risk factors” for disease at the individual and population levels. Integrating multiple, complex molecular processes to explain biological phenomena is the fundamental idea of systems biology. But why stop with molecules? Recently, Sandro Galea proposed a regime change in epidemiology to accommodate models of complex interactions at biological, behavioral, and group levels. The applicability of such models to the health of individuals, as well as populations, remains an open question.

 

Posted in epidemiology, pattern recognition, public health, uncategorized | Comments Off