Recently in Genetics Category
Add up to 5 new gene variants to the 5 that are already known to increase the risk of Alzheimer disease. Newly published data from huge (and I mean huge) genome-association studies in the United States and Europe provide a fresh parade of new high-risk loci*:
- CD2AP (detected by US group; confirmed by European group)
- EPHA1 (detected by US group; confirmed by European group)
- CD33 (detected by US group; confirmed by European group)
- ABCA7 (detected by US group)
- MS4A (detected by US group; confirmed by European group)
The US group also replicated previous AD associations at CR1, CLU, BIN1, and PICALM (but not EXOC3L2). And although the risk of AD appears to be increased by 10%-15% with the newly identified loci, this risk pales in comparison to that provided by the variants of the APOE allele—which can increase the risk of AD by 400%-1000%.
According to the above NCBI links, the function of the proteins of these newly recognized genes are unknown or poorly understood. Consequently their role in AD is even less apparent. EPH receptors (like that produced by EPHA1) "have been implicated in mediating developmental events, particularly in the nervous system," reveals the gene's dedicated web page.
The Nature Genetics authors, by way of coverage at GEN (Genetic Engineering and Biotechnology News), write that 5 of the new or previously detected genes (CR1, CLU, EPHA1, CD33, and ABCA7) "have putative functions in the immune system." Products of BIN1, PICALM, CD33, and CD2AP "are involved in processes at the cell membrane, including endocytosis." And APOE, CLU, and ABCA7 play some role in lipid processing.
According to Bloomberg, Harvard's Rudolph Tanzi, one of the 155 authors of the US article, is particularly jazzed about CD33. He muses that some AD-associated variant of the gene may reduce the brain's capacity to clear beta amyloid, the sheeted protein that accumulates in the illness. Conversely overactivity of the gene may trigger some pathogenic inflammation that causes or contributes to AD. The ultimate hope is that CD33 and the other high-risk loci may provide new targets for AD treatment and prevention.
Among the lay press reports covering this story is a reasonable review from the NYT's Gina Kolata. A more scientifically detailed write-up by the good folks at Nature's The Great Beyond blog is awaited.
APOE = apolipoprotein E; NCBI = National Center for Biotechnology Information.
* See the advance online publications from Nature Genetics here and here (subscription required).
Photograph of atrophied brain from person with AD: National Institute on Alcohol Abuse and Alcoholism.
04/05/11 addendum: WTF TGB? No coverage?
This time from the NEJM.
Multiple authors, lead by disgraced, former Duke geneticist Anil Potti, retracted their 2006 article, "A Genomic Strategy to Refine Prognosis in Early-Stage Non–Small-Cell Lung Cancer." (For background, start here.) The authors (all of them) wrote in a nearly inconspicuous letter to the editor that they had "tried and failed to reproduce results supporting the validation of the lung metagene model described in the article." Deep regret was expressed for "the effect of this action on the work of other investigators," but regret for any patients who enrolled in clinical trials on the basis of the unreproducible work was not mentioned.
This is now the fourth Potti-authored article to be retracted since the veracity of Potti's work was called into serious question last year in The Cancer Letter.
- A 2007 article in the Journal of Oncology was retracted in December of last year.
- A 2006 Nature Medicine article was pulled in January.
- And, on the basis of this action, a 2007 article in the Lancet Oncology was retracted, also in January.
The Duke Chronicle reports that the NEJM retraction is "somewhat unexpected," because a journal spokesperson told the web site Retraction Watch in January that there were no plans to pull the article.
Today's PubMed search reveals that "A Potti" is coauthor on 128 returned articles, beginning in 2000, and first author on 33 articles—including 2 of the 4 retracted articles. The Potti-authored articles include a self-promoting piece in an April 2010 issue of Science Translational Medicine, in which Potti (along with Richard Schilsky of the University of Chicago and Joseph Nevins, Potti's Duke mentor) wrote "that it is now imperative that future clinical trials be designed with a plan to incorporate biomarker development."
Photo of Anil Potti, formerly from Duke's ISGP web site.
On Monday, the investigative committee of the National Research Council released its review of the FBI's scientific evidence in the Amerithrax case. The conclusion: The evidence wasn't strong enough to identify flask RMR-1029 at USAMRIID in Fort Detrick, MD, as the only possible source of the Bacillus anthracis spores that were used in the attacks. The implication: That the evidence against Bruce Ivins, the USAMRIID scientist identified by the FBI as the perpetrator of the anthrax attacks, is weaker than originally proposed by the investigative agency.
But in rebuttal to the NRC report, the FBI stated Tuesday that "it was the totality of the investigative process that determined the outcome of the anthrax case." Rightly so.
It is crucial to remember that there was other compelling circumstantial evidence in the Amerithrax case, which—when taken in conjunction with the fact that flask RMR-1029 was one possible source of the anthracis spores—strongly points to Ivins. Part of that evidence is this: USAMRIID was the only relevant lab in the geographic area where the "federal eagle" envelopes that were used in the attacks were distributed and sold.
Other important evidence implicating Ivins is that 1) he worked alone in late-night shifts during September 14-16, 2001, and from September 28 to October 5, 2001, before the rounds of Post/Brokow and Leahy/Daschle letters were respectively mailed; and 2) Ivins, in highly disingenuous fashion, submitted "unusable" and false B. anthracis spores to the FBI for testing.
And, depending on how much emphasis you place on general weirdness, the guy was scarily weird. To wit, see posts "Allegation: Ivins's 1983 Letter as Former Colleague" and "Bruce Ivins as KKΓ-Obsessed "jimmyflathead."
Scanning electron micrograph of spores of Ames strain of B. anthracis from CDC/Janice Haney Carr.
Today's Duke Chronicle reports the retraction of yet another article by geneticist Anil Potti. (For important story background, go here, here, and here.) On Friday, editors of The Lancet Oncology and the article's European coauthors justified their retraction of "Validation of gene signatures that predict the response of breast cancer to neoadjuvant chemotherapy," expressing "concern over the validity of the results."
They continued:
The chemotherapy sensitivity predictions reported in the Article were based on an approach described by Anil Potti and colleagues in Nature Medicine. Re-examination of the validation datasets used for the Nature Medicine study has uncovered errors in the labeling of the clinical response in some of the datasets. Reanalysis of the predictive accuracy with correctly labeled data has shown that in two instances the reported signatures do not predict the response of the validation samples to chemotherapy.
In other words, the article was retracted because the results were founded on the flawed (ie, mislabeled) data from another retracted article by Potti et al (in Nature Medicine). An investigation into the validity of the Lancet Oncology article was begun last October, when editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers. After a damning report in July from biostatisticians at M. D. Anderson about data-labeling errors in another article by Potti et al, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
This is the third article by Potti to be retracted since his work was called into serious question last year. A 2007 article in the Journal of Oncology was retracted in December, and the Nature Medicine article was pulled this month. In October, Collingridge also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models.
On a related note, Friday's The Cancer Letter (subscription required), by way of The Great Beyond Blog, reveals that FDA auditors have visited Duke to determine if the university obtained proper approval for 3 cancer trials, which were based on the demonstrably flawed work of geneticist Anil Potti. At issue, from the agency's standpoint, is whether Duke obtained an Investigational Device Exemption (IDE), which was necessary because genomic chips were used to identify genetic biomarkers on which treatments was based.* There was evidently some confusion at Duke about whether an IDE was needed.
* The trials used Potti's (mislabeled) data to determine what anticancer drugs or combination of drugs cancer patients would receive on the basis of genetic biomarkers.
Namely the staff at Nature and the journal's The Great Beyond blog continue to investigate Anil Potti, the former Duke University researcher whose genetics work on personalized chemotherapy has been called into serious question. Potti's dubious work informed the design of several clinical trials that were haltingly reviewed and then ultimately closed by university administrators. (For important background on this story, go here and here.)
The latest development: Nature has obtained, under the US FOIA, a year-old university report on Potti's work. This report, in a more heavily redacted form, had been previously obtained by an investigative reporter from The Cancer Letter, who originally outed Potti's false claim to have been a Rhodes Scholar (or finalist) and who described the claims of M. D. Anderson biostatisticians. The biostatisticians discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.
The upshot of the Duke panel's December 2009 report: The members could validate Potti's work, but they seriously erred in not correcting Potti's mislabeling errors. Moreover one of the M. D. Anderson biostatisticians, Keith Baggerly, had contacted Duke's VP for Research and VP for Medical Affairs a month before the report was completed, alerting them to the mislabeling errors; however, Baggerly's alert was not forwarded to the panel members. In a tepid apology, the Duke VPs offered their excuses for failing to ensure that these crucial corrections be provided to the panel.
[I]t was determined that it would be best to let the data, publications, etc., speak for themselves and not bias the independent investigation for or against any party. In retrospect, we did not realize that the data provided by our investigators were flawed (as the public record now shows), rendering an outside review addressing the methodology flawed as well. In hindsight, we would have ensured that the IRB provided all communication with Dr. Baggerly, recognizing the risk of bias. We've learned considerably from this process and are introducing key changes in the way we deal with research that will be translated to the clinical arena as a result.
According to The Great Beyond blog, a second university investigation is ongoing, and a report will be submitted to the Office of Research Integrity at the DHHS.*
DHHS = Department of Health and Human Services; FOIA = Freedom of Information Act.
* Some of Potti’s work was funded through NIH grants.
Photo of Anil Potti, formerly from the ISGP web site.
Advanced Cell Technology, of Marlborough, Mass., announced yesterday that it received an FDA thumbs-up to begin a small clinical trial of human embryonic stem cells (hESCs) in a rare eye disorder. The trial is the second study of hESCs in humans to get a regulatory nod, making the idea of hESC therapy less and less of a sci-fi fantasy—and more and more of a threat to those who judge the potential benefit of hESC to be merely speculative.
The disorder of interest, Stargardt's macular degeneration, which affects about 30,000 Americans, is potentially a springboard for the study of hESCs in age-related macular degeneration (AMD), which affects nearly 2 million Americans. Stargardt's disease, an inherited blinding condition, affects the retinal pigment epithelium (RPE), which is also implicated in AMD.
Treating an eye disorder with hESCs (which are intended to replace the damaged RPE cells) is anticipated to be a relatively smooth investigatory ride, given 1) the accessibility of the eye (both to treatment and the assessment of treatment), and 2) the fact that the eye is immune privileged (making immunosuppressive therapy unnecessary).
"Long-term functional rescue" of RPEs, using hESC, has already been demonstrated in a rat model of retinal degeneration.
The cells sustained visual function and photoreceptor integrity in a dose-dependent fashion without teratoma formation or untoward pathological reactions. Near-normal functional measurements were recorded at >60 days survival...
Image of undifferentiated hESCs from http://www.nih.gov/catalyst/2007/07.01.01/page1.html.
Specifics are lacking, but geneticist and physician Anil Potti now takes "full responsibility for a series of anomalies in data handling, analysis and management that have come under scrutiny in the past months." Potti's mea culpa and resignation from Duke University is delivered by way of Hunt Willard, director of the university's Institute for Genome Sciences and Policy, through today's Duke Chronicle (what I remember as being a-not-so-terrible college newspaper).
In Friday's e-mail to the IGSP staff, Willard asked faculty members to "remember, especially at this time of year, all that Anil has done to positively influence the lives of many of his colleagues, trainees, friends and patients. The loss of any member of our family is difficult, and I ask you to keep that in your thoughts today." It's an overly gracious good-will sentiment generally and an insulting slap specifically to those researchers whose professional lives have been tarnished by proxy—not to mention the hopeful cancer patients who enrolled in clinical trials that were based on Potti's dubious work.
Potti had been on administrative leave from Duke since July, shortly after The Cancer Letter charged that he had seriously fudged his resume by falsely claiming to be a Rhodes scholar or "finalist." More important, Potti was facing allegations of research misconduct on the basis of a 2009 examination of his work by M. D. Anderson biostatisticians. Back-and-forth external and internal investigations ultimately led to the termination of several clinical trials, on which Potti's work was based, and the retraction of several published articles. The most recent literary casualty is a report cowritten by Potti that was published in Nature Medicine, reveals The Great Beyond Blog (presumably this article, published in 2006).
For its part in the Potti scandal, the Duke leadership (ie, President Richard Brodhead) has received sharp criticism from the blogging team (at least I think they're a team) at Duke.Fact.Checker ("Inside the Potti Mess: A Fact Checker Special Report"). The excoriation:
We do not find that Uncle Dick has taken any profile at all, that is to say exhibited any leadership. In particular, he has not expressed appropriate concern for the patients.
His only important comment came just after The Cancer Letter reported Potti's fake claim of a Rhodes Scholarship and the Rhodes Trust confirmed there was no award. With other credential issues looming at the time, Brodhead cautioned the editorial board of the [Durham] Herald-Sun not to reach rapid conclusions of truth or lie, for there could also be "intermediate explanation."
Pathetic. Dick, just pathetic.
Photo of Anil Potti, formerly from the ISGP web site.
An international group of researchers has unlocked another door to understanding the cause of facioscapulohumeral muscular dystrophy (FSHD), the third most common muscular dystrophy.* Reporting electronically in Science, Lemmers and colleagues add to the long-known genetics of the autosomal dominant disease.
In 1992, it was discovered that the molecular defect in FSHD localizes to the distal portion of the long arm of chromosome 4 (specifically 4q35), in which a dormant repetitive element, D4Z4, is truncated. Only individuals with 1-10 D4Z4 repeats can acquire FSHD (normal individuals have 11-100 repeats). It was further learned that the number of D4Z4 repeats in people with FSHD correlates inversely with the age of onset and disease severity; however, it was also observed that clinical manifestations among family members with the same deletion can differ. (For a free review of FSHD and its genetics, circa 2008, go here.)
The Science authors showed that, somehow, the truncated D4T4 area in FSHD patients changes the chromosomal configuration, which allows for the transcription of an internal homeobox gene, DUX4. But FSHD patients also carry specific single nucleotide polymorphisms (SNPs) distal to the D4Z4 region that encode for a transcript-stablizing poly-A tail. Therefore, in people with FSHD, the transcribed DUX4 gene, which might otherwise be chewed up, is stabilized by being polyadenylated.
What the product of the polyadenylated DUX4 transcript is and what it does remain to be discovered.
* Affecting 1 in 20,000.
Just as an astronomical white count is not an entity unto itself but a marker of a serious underlying disorder, like leukemia, so a big lie on a CV is an indicator of a grave underlying problem, like sociopathy.
Faculty members at the Duke Institute for Genome Sciences and Policy are learning this lesson the hard way thanks to the failure of someone at Duke to perform the basic HR duty of vetting Anil Potti's curriculum vitae 7 years ago. Potti, who was hired in 2003 as a physician-researcher by Duke, falsely claimed that he was a Rhodes Scholar on scientific grant proposals, according to a recent expose by Paul Goldberg in The Cancer Letter. That's a big lie and one suggesting that other big lies are possible, if not probable. Taking this very cue, Goldberg then questioned the integrity of Potti's research at Duke and found that 2 biostatisticians at M. D. Anderson discovered "a series of errors," including mislabeling errors, in a seminal article by Potti and others.
Consequently the biggest victim of Duke's remote HR lapse: cancer patients who enrolled in clinical trials, which were based on Potti's questionable work. According to the NYT, these trials have now been suspended (after stuttering efforts by Duke officials to reopen them, reported Goldberg). News coverage can also be found at NPR's Shots blog.
For yucks or groans, I performed a quick PubMed search: "A Potti" is the coauthor of 48 articles that were published within the last 5 years. Potti's articles appeared in, for example, PNAS, JAMA, JCO, PLoS One, Lancet Oncology, Nature Medicine, and the NEJM.
Photo of Anil Potti from Duke Institute for Genome Sciences and Policy.
10/24/10 addendum: As the AP reported yesterday, Lancet Oncology editor David Collingridge relayed an "expression of concern" from 15 European investigators who were coauthors with Potti and 3 other Duke researchers on a 2007 article in the journal. (The article validated the use of gene signatures to predict the response of breast cancers to neoadjuvant [perioperative] chemotherapy.) After the damning report from biostatisticians at M. D. Anderson about Potti's alleged errors in another article, the Lancet Oncology coauthors repeatedly attempted to contact their Duke colleagues, but they were ignored, wrote Collingridge.
The editor also revealed that "a large group of scientists" wrote to NCI director Harold Varmus on July 19th, expressing their concerns about the validity of a) Potti's cancer-treatment prediction models and b) 3 clinical trials that were based on these prediction models. Collingridge expressed his own concerns about the Lancet Oncology article given recent developments surrounding Potti. The journal has contacted the Duke coauthors—Anil Potti, Chaitanya Acharya, Sayan Mukherjee, and Joseph Nevins—and awaits their responses.
Hospitalizations are reduced by the upfront use of a genetic test for "warfarin sensitivity," according to new results from a comparative-effectiveness study. The Medco- and Mayo-sponsored trial of the anticoagulant (the dosing of which has caused more than one headache in physicians and patients during the last 70 years) compared hospitalization rates among warfarin-treated subjects who underwent genetic testing and those who didn't. The trial results were presented this morning at the ongoing meeting of the American College of Cardiology in Atlanta; data are also available at the company's web site.
In the study, the dose of newly initiated warfarin therapy in nearly 900 adult patients* was adjusted on the basis of Medco's genetic test (performed on blood or cheek swabs). During a 6-month period, the hospitalization rate in this group was 31% lower than that of a historical control group (N = 2688) who had not undergone genetic testing (ITT analysis: ~18% vs ~25%). The hospitalization rate for bleeding or thromboembolism was 28% lower in the genotyped group.
Results from the per-protocol analysis were even more impressive. The rate of all-cause hospitalization and the rate of hospitalization for bleeding or thromboembolism were 33% and 43% lower, respectively, in the genotyped group.
The genetic test, which is available from several companies,** assesses the function of 2 genes, CYP2DC and VKORC1. The former encodes a well-known P450 enzyme that metabolizes warfarin; the latter encodes an enzyme that activates vitamin K (which counteracts the anticoagulant properties of warfarin). The cost of a warfarin sensitivity test is quoted in the press at a range of $250-$400. The FDA first approved use of the genetic test (Verigene; Nanosphere) to inform warfarin dosing in 2007.
According to Medco, about 30 million warfarin prescriptions are written and 2 million patients start warfarin treatment each year. Warfarin is the leading cause of ED visits, hospitalizations, and drug-related deaths. One third of the variability in response to the drug is ascribed to the genetically determined function of CYP2C9 and VKORC1.
Last week, the FDA added a boxed warning to the PI for the antiplatelet drug clopidogrel (Plavix; BMS/sanofi), which may be less effective in patients with reduced function of the CYP2C19 enzyme. (To become active, clopidogrel, a prodrug, must be converted by CYP2C19.) The FDA advised that 2%-14% of Americans are "poor metabolizers" of clopidogrel. CYP2C19 testing is also commercially available through a number of companies.
ITT = intent to treat; PI = package insert.
* Patients were recruited through 29 Medco-managed prescription benefit plans.
** For example, Ambry Diagnostics and Arup Laboratories.
Image of warfarin (Coumadin) bottles from NIGMS/NIH.
