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Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
Reporter: Aviva Lev-Ari PhD, RN
Article 9.2.Testing for Multiple Genetic Mutations via NGS for Patients: Very Strong Family History of Breast & Ovarian Cancer, Diagnosed at Young Ages, & Negative on BRCA Test
In her thoughtful article about her choice to undergo a double mastectomy, Angelina Jolie said the cost of genetic testing for BRCA1 and BRCA2 mutations “remains an obstacle for many women” (“My Medical Choice,” Op-Ed, May 14).
Our BRACAnalysis test has been used by more than a million women to assess their risk of hereditary breast and ovarian cancer.
The test remains widely reimbursed by insurance companies, with more than 95 percent of at-risk women covered and with an average out-of-pocket cost of about $100. And, thanks to preventive care provisions in the Affordable Care Act, many patients can receive BRACAnalysis testing with no out-of-pocket costs.
For patients in need, Myriad offers a patient assistance program that offers testing at reduced costs or free of charge.
“Jolie’s Disclosure of Preventive Mastectomy Highlights Dilemma” (front page, May 15) discusses Angelina Jolie’s decision to undergo prophylactic surgery after testing positive for a BRCA1 mutation. It should be noted that not all hereditary breast and ovarian cancer is attributable to mutations in BRCA1 and BRCA2.
An alternative dilemma exists when a patient has a very strong family history of breast and ovarian cancer, especially diagnosed at young ages, and the BRCA test is negative.
The patient is left wondering what to do next. These patients should consider a new method of testing for multiple genetic mutations via next-generation sequencing, which can often be ordered as part of a research protocol in academic centers.
Only nine of the 72 faculty members who committed research misconduct were female, which is “one-third of the number that would have been predicted from their overall representation among life sciences faculty,” the researchers write. They note, though, that they cannot rule out that women are less likely to get caught.
But what is behind this gender difference and why people committed research misconduct is unknown. Fang, Bennett, and Casadevall say that “while not excluding a role for biological factors, recent studies suggest an important contribution of social and cultural influences in the competitive tendencies of males and females” and note that “it is generally known that men are more likely to engage in risky behaviors than women.”
A review of the United States Office of Research Integrity annual reports identified 228 individuals who have committed misconduct, of which 94% involved fraud. Analysis of the data by career stage and gender revealed that misconduct occurred across the entire career spectrum from trainee to senior scientist and that two-thirds of the individuals found to have committed misconduct were male. This exceeds the overall proportion of males among life science trainees and faculty. These observations underscore the need for additional efforts to understand scientific misconduct and to ensure the responsible conduct of research.
IMPORTANCE As many of humanity’s greatest problems require scientific solutions, it is critical for the scientific enterprise to function optimally. Misconduct threatens the scientific enterprise by undermining trust in the validity of scientific findings. We have examined specific demographic characteristics of individuals found to have committed research misconduct in the life sciences. Our finding that misconduct occurs across all stages of career development suggests that attention to ethical aspects of the conduct of science should not be limited to those in training. The observation that males are overrepresented among those who commit misconduct implies a gender difference that needs to be better understood in any effort to promote research integrity.
With our colleague Grant Steen, two of us (F.F. and A.C.) recently studied all 2,047 retracted scientific articles indexed by PubMed as of 3 May 2012 (1). Unexpectedly, we found that misconduct is responsible for most retracted articles and that fraud or suspected fraud is the most common form of misconduct. Moreover, the incidence of retractions due to fraud is increasing, a trend that should be concerning to scientists and nonscientists alike. To devise effective strategies to reduce scientific misconduct, it will be essential to understand why scientists commit misconduct. However, deducing the motives for misconduct from the study of retractions alone is difficult, because retraction notices provide limited information, and many instances of misconduct do not result in retracted publications.
We therefore undertook an alternative approach by reviewing the findings of misconduct summarized in the annual reports of the U.S. Office of Research Integrity (ORI) (http://ori.hhs.gov/about-ori). The ORI is responsible for promoting the responsible conduct of research and overseeing the investigation of misconduct allegations relating to research supported by the Department of Health and Human Services. From 1994 to the present, the annual reports detail 228 individuals found by the ORI to have committed misconduct (2, 3). Fraud was involved in 215 (94%) of these cases. The total number of ORI investigations performed over this period is not known. However, data from the first ten years indicate that approximately one-half of ORI investigations conclude with a finding of misconduct (3). Although we expected most cases of misconduct to involve research trainees, we found that only 40% of instances of misconduct were attributed to a postdoctoral fellow (25%) or student (16%). Faculty members (32%) and other research personnel (28%) were responsible for the remaining instances of misconduct, and these included both junior and senior faculty members, research scientists, technicians, study coordinators, and interviewers.
We were able to determine the gender of the individual committing misconduct in all but a single case, and 149 (65%) were male. However, the gender predominance varied according to academic rank. An overwhelming 88% of faculty members committing misconduct were male, compared with 69% of postdocs, 58% of students, and 42% of other research personnel (Fig. 1). The male-female distribution of postdocs and students corresponds with the gender distribution of postdocs and students in science and engineering fields (4). However, nearly all instances of misconduct investigated by the ORI involved research in the life sciences, and the proportion of male trainees among those committing misconduct was greater than would be predicted from the gender distribution of life sciences trainees. Males also were substantially overrepresented among faculty committing misconduct in comparison to their proportion among science and engineering faculty overall, and the difference is even more pronounced for faculty in the life sciences (5). Of the 72 faculty members found to have committed misconduct, only 9 were female, or one-third of the number that would have been predicted from their overall representation among life sciences faculty. We cannot exclude the possibility that females commit research misconduct as frequently as males but are less likely to be detected.
FIG 1Gender distribution of scientists committing misconduct. The percentage of scientists sanctioned by the U.S. Office of Research Integrity who are male, stratified by rank, is compared with the percentage of males in the overall United States scientific workforce (error bars show standard deviations) (blue and green bars are from NSF data, 1999–2006 [4, 5]).
What motivates individuals to commit research misconduct? Does competition for prestige and resources disproportionately drive misconduct among male scientists? Are women more sensitive to the threat of sanctions? Is gender a correlate of integrity?
The disparity between the number of men and women in academic science fields has been considered to be evidence of biologically driven gender differences (6). Thus, it may be tempting to explain the preponderance of male fraud in terms of various evolutionary theories about Y chromosome-driven competitiveness and aggressiveness (7). For example, for more than a century the male baboon has been used to symbolize male aggression. However, stereotypes of male baboon aggression and dominance have been called into question by primatologists focusing on female social networks and competitive strategies (8). Deterministic theories based in biology have been facilely used to explain the persistent gender gap in wages and other measures in the labor market (discussed in reference 9). The pitfalls associated with such simplistic generalizations have been extensively dissected by scholars of gender in science (see, for example, references 10 and 11 and citations therein). While not excluding a role for biological factors, recent studies suggest an important contribution of social and cultural influences in the competitive tendencies of males and females (12).
Nevertheless, it is generally known that men are more likely to engage in risky behaviors than women (13) and that crime rates for men are higher than those for women. Sociologists have hypothesized that as the roles of men and women become more similar, so will their crime rates (14). There is evidence for this “convergence hypothesis” in terms of arrests for robbery, burglary, and motor vehicle theft but not for homicide (15). Similarly, while most studies show that male students cheat more frequently than female students, recent data suggest that within similar areas of study, the gender differences are small. Women majoring in engineering self-report cheating at rates comparable to those reported by men majoring in engineering (16). We did not observe a significant convergence in scientific misconduct by males and females reported by the ORI over time (Fig. 2), although the analysis was limited by the small sample size. Interestingly, we also failed to observe an overall increase in research misconduct in the ORI findings, in contrast to an increase in retractions for fraud observed in our earlier study (1), with the caveat that the present study focused on a much smaller and incompletely overlapping subset of cases.
FIG 2Gender distribution of scientists committing misconduct over time. The percentage of scientists sanctioned by the U.S. Office of Research Integrity who are male, female, or of unknown gender are shown for each reporting year. For the gender ratio in 1994–2002 (n = 120) compared with 2003–2012 (n= 108), χ2 =1.405 and P = 0.24 (calculated using the online tool athttp://www.quantpsy.org/chisq/chisq.htm).
The predominant economic system in science is “winner-take-all” (17, 18). Such a reward system has the benefit of promoting competition and the open communication of new discoveries but has many perverse effects on the scientific enterprise (19). The scientific misconduct among both male and female scientists observed in this study may well reflect a darker side of competition in science. That said, the preponderance of males committing research misconduct raises a number of interesting questions. The overrepresentation of males among scientists committing misconduct is evident, even against the backdrop of male overrepresentation among scientists, a disparity more pronounced at the highest academic ranks, a parallel with the so-called “leaky pipeline.” There are multiple factors contributing to the latter, and considerable attention has been paid to factors such as the unique challenges facing young female scientists balancing personal and career interests (20), as well as bias in hiring decisions by senior scientists, who are mostly male (21). It is quite possible that, in at least some cases, misconduct at high levels may contribute to attrition of woman from the senior ranks of academic researchers.
Our observations also raise the question of whether current efforts at ethics training are targeting the right individuals. The NIH currently mandates training in the responsible conduct of research for students and postdocs receiving support from training grants. However, these groups were responsible for only 40% of the misconduct documented in the ORI reports. The psychiatrist Donald Kornfeld has analyzed a subset of the ORI data (22) and observed “an intense fear of failure” in many trainees who committed misconduct, while some faculty members seemed to possess a “conviction that they could avoid detection.” This suggests that efforts to improve ethical conduct may also need to target faculty scientists, who in some cases are directly responsible for misconduct and in others may be unintentionally fostering a research environment in which trainees and other research personnel feel pressured to tailor results to meet expectations. Programs to help scientists become more effective mentors should be more widely implemented (23). The male predominance among senior scientists who commit misconduct also suggests that social expectations associated with gender may play a role in the likelihood of committing fraud and that the impact of culture and gender should be considered in ethics training. Curricula should become more sensitive to the heterogeneity of the target population because “one size does not fit all.”
The role of external influences on the scientific enterprise must not be ignored. With funding success rates at historically low levels, scientists are under enormous pressure to produce high-impact publications and obtain research grants. The importance of these influences is reflected in the burgeoning literature on research misconduct, including surveys that suggest that approximately 2% of scientists admit to having fabricated, falsified, or inappropriately modified results at least once (24). A substantial proportion of instances of faculty misconduct involve misrepresentation of data in publications (61%) and grant applications (72%); only 3% of faculty misconduct involved neither publications nor grant applications.
In summary, we emphasize two observations from this study: first, misconduct is distributed along the continuum from trainee to senior scientist. Second, men are overrepresented among scientists committing misconduct, with a skewed gender ratio being most pronounced for senior scientists. While we acknowledge that our observations were made from a relatively small database that focuses exclusively on research supported by the U.S. Department of Health and Human Services, we note that each case was extensively documented, and this case series may represent the most reliable information currently available. From our findings, new challenges are directed to the scientific community to maintain the integrity of the scientific enterprise. The occurrence of misconduct at every level of the scientific hierarchy indicates that misconduct is not a problem limited to trainees and requires careful attention to pressures placed on scientists during different stages of their careers. Male predominance is but another example of the scientific enterprise reflecting social and cultural contexts.
In closing, the vital importance of the ORI is acknowledged. Without public access to their investigations, it would have been impossible to carry out this study. All countries should have independent agencies with the authority and resources to ensure proper conduct of scientific research. Although our findings may cause concern regarding the scientific enterprise, recognition is a first step toward solving a problem. With so many of the world’s current challenges dependent on scientific solutions, science must look for new ways to ensure the responsible conduct of scientific research (25).
This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-ShareAlike 3.0 Unported license, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited.
. 2012. Women, minorities, and persons with disabilities in science and engineering. National Science Foundation, National Center for Science and Engineering Statistics, Washington, DC.http://www.nsf.gov/statistics/wmpd/tables.cfm. Accessed 18 October 2012.
. 2008. Thirty-three years of women in S&E faculty positions. NSF 08–308. National Science Foundation, National Center for Science and Engineering Statistics, Washington, DC. http://www.nsf.gov/statistics/infbrief/nsf08308/.
. 2012. Gender, competitiveness and socialization at a young age: evidence from a matrilineal and patriarchal society. Rev. Econ. Stat. [Epub ahead of print.]
Cardiosonic Begins Enrollment in the TIVUS I Renal Denervation Trial
April 24, 2013
April 24, 2013 — Cardiosonic Inc. announced the completion of the first phase of patient enrollment in its first-in-man (FIM) TIVUS I clinical study. The study is designed to collect data on the safety and performance of the TIVUS System, a high intensity, non-focused therapeutic ultrasound catheter system for remote tissue ablation for the treatment of hypertension by renal denervation (RDN).
The study enrolled the first five patients at Royal Perth Hospital (RPH), Australia and patient screening is continuing. Sharad Shetty, M.D., principal investigator at RPH, completed the procedures with a 100 percent acute success rate in accessing the vessels and delivering therapy. “The performance of renal denervation with an advanced, ultrasonic catheter has been shown to be quick, easy and seems to be associated with minimal pain. The TIVUS System by Cardiosonic has great potential to become an important technology for management of resistant hypertensive patients,” commented Shetty. Shetty will present interim results from the FIM trial at the Euro PCR conference, Paris, May 21 to 24.
The company completed extensive bench and animal studies and following these initial human results is submitting its next human clinical trial to 20 sites worldwide. Krishna Rocha-Singh, an advisor to the company and a leader in the rapidly growing field of RDN, from the Prairie Heart Institute at the St. John’s Hospital in Springfield, Ill., commented that, “The TIVUS system has great potential to improve the process and outcomes of RDN procedures. In addition the TIVUS system may expand the population of patients eligible for RDN therapy by obviating current anatomic and physiologic restrictions and contra-indications.”
Benny Dilmoney, Cardiosonic CEO, commented that, “We are enthusiastic about completing the first phase of enrollment and progressing towards completion of our FIM patients recruitment and follow-up. Cardiosonic has completed the development of our second generation multi-directional catheter and initiated submission for its study at 20 centers worldwide. We believe that this advanced catheter design will further improve RDN procedures.”
Renal Sympathetic Denervation: a Rapidly Evolving Field
Written by Dr. Sebastian Mafeld – Radiology Specialist Registrar, Freeman Hospital, Newcastle upon Tyne, UK and Dr. Gerard S Goh – Consultant Interventional Radiologist, St. George’s Healthcare NHS Trust, London, UK.
The 11/27/2012 paper HAS IGNORED THE ALREADY PUBLISHED LITERATURE IN THE FIELD – nothing of the mentioned in it is NEW or innovative — in 2012 that is intolerable !!
The Scientific Honesty is at Stack
PNAS Study: 2/3 of Retractions in Scientific Journals represents Fraud, Duplicate publication, and Plagiarism (Misconduct).
The study, led by Arturo Casadevall of Albert Einstein College of Medicine, estimates that the percentage of scientific papers retracted because of fraud has increased more than 10-fold since 1975.
Carl Zimmer notes in The New York Times that previous studies have concluded that most retractions were attributable to “honest errors,” but the new study “challenges that comforting assumption.”
The authors compiled more than 2,000 retraction notices published before May 3, 2012, and then dug into the reasons behind each retraction. Some reasons were cited by the journals, but the authors also found that the retraction notices for some papers did not cite fraud as the reason for the retraction.
The rise in fraudulent papers “is a sign of a winner-take-all culture in which getting a paper published in a major journal can be the difference between heading a lab and facing unemployment,” Zimmer says.
According to Casadevall, the fact that “some fraction of people are starting to cheat” should not be taken lightly, even if the overall number of fraudulent papers is relatively low. “It convinces me more that we have a problem in science,” he says.
The primary cilium is organelle that has garnered much attention in the field of cell biology during the last 15 years. It is a slender, solitary hair-like organelle that extends 5-10 uM from each mammalian cell (in the G0 cell cycle state) that is microtubule-based (9 outer doublets arranged in a circular fashion) and dependent on a process called Intraflagellar Transport (IFT). IFT is the bidirectional movement of motors (kinesin-2 in the anterograde and dynein-2 in the retrograde direction) responsible for the assembly and maintenance of the cilium (Pedersen et al., 2006).
Until this time, it had been labeled a ‘vestigial’ organelle not worthy of research. Yet, a breakthrough into the sensory role of the primary cilium came in 2000 based on Dr. Rosenbaum’s research on Chlamydomonas and the motile cilium or flagella. Along with Dr. George Whitman’s group, they were able to show the importance of Tg737 (IFT88) protein to the pathology of polycystic kidney disease in mouse (Pazour et al., 2000). Since then, research into the primary cilium has exploded and has been linked to diverse pathologies (collectively known as ciliopathies) such as
retinitis pigmentosa,
hydrocephaly,
situs inversus,
ovarian and pancreatic cancers among others (Nielsen et al., 2008; Edberg et al., 2012). Also, various
signal transduction pathways have been found to be coordinated by the primary cilia such as hedgehog, wnt, PDGF among others (Veland et al., 2008).
Thus, in 2006, the Christensen lab at the University of Copenhagen (Denmark) with the collaboration of Dr. Peter Satir’s group at Albert Einstein College of Medicine (Bronx, NY) began to investigate whether the human embryonic stem cells (hESCs) possess primary cilium and then to begin preliminary molecular dissections of the role that this organelle could play in the proliferation and differentiation profiles of these pluripotent cells. The Albert Einstein group, due to NIH restrictions, had to work with two federally-sanctioned cell lines. Working with the Laboratory of Reproductive Biology at RigsHospital, the Danish side had access to in-house derived stem cell lines from discarded blastocysts. The advantage for the Danish side was obvious since these newer cell lines hadn’t undergone as many passages as the NIH cell lines and were thus more robust. To begin preliminary characterizations of these lines, some basic hallmarks of hESCs (Bernhardt et al., 2012) had to be localized to the nucleus such as the transcription factor (TF) Oct4 (Fig. 1).
In addition, a single primary cilium can be seen denoted by the acetylated tubulin staining emanating from each cell in the micrographs. Also, the base of the cilium is marked by the presence of pericentrin and centrin which demarcate the centriole.
Fig. 1Primary cilia stained with anti-acetylated tubulin (tb, red) are indicated by arrows and undifferentiated stem cells are identified by nuclear colocalization of OCT-4 (green) and DAPI (dark blue) in the merged image (light blue). A primary cilium (tb, red, arrow) in undifferentiated hESCs emerges from one of the centrioles (asterisks) marked with anti-centrin (centrin, green). Inset shows anti-pericentrin localization to base of cilia (Pctn, green).
Together, the three labs were the first to discover primary cilia in stem cells while other groups have since then confirmed these findings(Kiprilov et al. 2008; Han et al. 2008). Attention was then to characterize different signal transduction pathways in the stem cell cilium.Since the hedgehog pathway has been shown to be important for differentiation and proliferation (Cerdan and Bhatia, 2012), the groups characterized this signal pathway in these cells using immunofluorescence, electron microscopy and qPCR techniques. One particularly interesting experiment to show that the hedgehog pathway was functional in these cells was to add the hedgehog agonist, SAG (Smoothened agonist), and then to isolate the cells for immunofluorescence at different times.
Gradually, one can see the appearance of the smoothened protein into the cilium as indicated by increasing intensity of the immunofluorescence staining. Conversely, patched levels in the cilium, decreased. This is a hallmark of hedgehog activation (Fig. 2). Fig. 2 Immunofluorescence micrographs of hESC showing smoothened (green), acetylated tubulin (red) and DAPI (blue). The micrographs from left to right represents SAG treatments at t = 0, 1 and 4 hours.
However, an additional interesting observation was made concerning these stem cells. An important characteristic for stem cells is the presence of certain transcription factors which render these cells in the pluripotent or undifferentiated state. These include Oct4, Sox2, and Nanog whose localization had been observed in the nucleus as expected for other TFs.
However, the Danish groups curiously found a subpopulation of stem cells where these TFs were additionally localized to the primary cilium (Fig. 3). This had never been observed or investigated before. Additionally, proper negative controls were carried out to exclude this phenomenon from being an artifact (e.g. bleed through). Fig. 3 Stem cell markers (Sox2, Nanog, and Oct4) localizing to the nucleus and the primary cilia (arrows) of hESC line LRB003. This and the previous figure show shifted overlay images whereby the green and red channels have been slightly shifted so that the red channel doesn’t swamp out the intensity of the green channels.
Thus, it raises an intriguing possibility that perhaps the primary cilia plays a previously uncharacterized role in the differentiation/proliferation state of the hESCs via possible modifications of these TFs perhaps analogous to the processing of the Gli transcription factors (Hui and Angers, 2011). Another curious observation is that the subpopulation of cells whose primary cilia are positive for these TFs always occur in clusters which might hint at its mechanistic explanation. In conclusion, since stem cells are now being more routinely used for regenerative medicine such as repair of severed spinal cord (Lu et al. 2012), it behooves us to better learn the molecular mechanisms that keeps these invaluable cells in an undifferentiated state so that we can harness their full therapeutic potential.
REFERENCES
Awan A, Oliveri RS, Jensen PL, Christensen ST, Andersen CY. 2010 Immunoflourescence and mRNA analysis of human embryonic stem cells (hESCs) grown under feeder-free conditions. Methods Mol Biol. 584:195-210.
Bernhardt M, Galach M, Novak D, Utikal J. 2012 Mediators of induced pluripotency and their role in cancer cells – current scientific knowledge and future perspectives. Biotechnol J. 7:810-821.
Kiprilov EN, Awan A, Desprat R, Velho M, Clement CA, Byskov AG, Andersen CY, Satir P, Bouhassira EE, Christensen ST, Hirsch RE 2008 Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery. J Cell Biol. 2008 180:897-904.
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Brock J, Blesch A, Rosenzweig ES, Havton LA, Zheng B, Conner JM, Marsala M, Tuszynski MH. 2012 Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150:1264-73.
Nielsen SK, Møllgård K, Clement CA, Veland IR, Awan A, Yoder BK, Novak I, Christensen ST. 2008 Characterization of primary cilia and Hedgehog signaling during development of the human pancreas and in human pancreatic duct cancer cell lines. Dev Dyn. 237:2039-52.
Pazour GJ, Dickert BL, Vucica Y, Seeley ES, Rosenbaum JL, Witman GB, Cole DG. 2000 Chlamydomonas IFT88 and its mouse homologue, polycystic kidney disease gene tg737, are required for assembly of cilia and flagella. J Cell Biol 151: 709-18.
Veland IR, Awan A, Pedersen LB, Yoder BK, Christensen ST. 2009 Primary cilia and signaling pathways in mammalian development, health and disease. Nephron Physiol. 111: 39-53.
The tendency of sperm to swim alone makes the cells ideal for single-cell genomics. Adam Auton, a statistical geneticist at Albert Einstein College of Medicine in New York is using sperm to study recombination, the process that shuffles genes during the formation of germ cells and therefore influences which genes are inherited. “Recombination is one of the fundamental forces that shapes genetic diversity,” he says. “In recent years we’ve learned that there is considerable variation in the recombination rate between different populations, between the sexes and even between individuals.” But pinning down the rate in people once seemed impossible because it would have required finding individuals with hundreds of children and sequencing their genomes.
The ability to sequence single cells meant that researchers could take another approach. Working with a team at the Chinese sequencing powerhouse BGI, Auton sequenced nearly 200 sperm cells and was able to estimate the recombination rate for the man who had donated them. The work is not yet published, but Auton says that the group found an average of 24.5 recombination events per sperm cell, which is in line with estimates from indirect experiments2. Stephen Quake, a bioengineer at Stanford University in California, has performed similar experiments in 100 sperm cells and identified several places in the genome in which recombination is more likely to occur. The location of these recombination ‘hotspots’ could help population biologists to map the position of genetic variants associated with disease.
Quake also sequenced half a dozen of those 100 sperm in greater depth, and was able to determine the rate at which new mutations arise: about 30 mutations per billion bases per generation3, which is slightly higher than what others have found. “It’s basically the population biology of a sperm sample,” Quake says, and it will allow researchers to study meiosis and recombination in greater detail.
The study, led by Arturo Casadevall of Albert Einstein College of Medicine, estimates that the percentage of scientific papers retracted because of fraud has increased more than 10-fold since 1975.
Carl Zimmer notes in The New York Times that previous studies have concluded that most retractions were attributable to “honest errors,” but the new study “challenges that comforting assumption.”
The authors compiled more than 2,000 retraction notices published before May 3, 2012, and then dug into the reasons behind each retraction. Some reasons were cited by the journals, but the authors also found that the retraction notices for some papers did not cite fraud as the reason for the retraction.
The rise in fraudulent papers “is a sign of a winner-take-all culture in which getting a paper published in a major journal can be the difference between heading a lab and facing unemployment,” Zimmer says.
According to Casadevall, the fact that “some fraction of people are starting to cheat” should not be taken lightly, even if the overall number of fraudulent papers is relatively low. “It convinces me more that we have a problem in science,” he says.
cMediCC! Medical Communications Consultants, Chapel Hill, NC 27517; and
dDepartment of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461
Edited by Thomas Shenk, Princeton University, Princeton, NJ, and approved September 6, 2012 (received for review July 18, 2012)
Abstract
A detailed review of all 2,047 biomedical and life-science research articles indexed by PubMed as retracted on May 3, 2012 revealed that only 21.3% of retractions were attributable to error. In contrast, 67.4% of retractions were attributable to misconduct, including fraud or suspected fraud (43.4%), duplicate publication (14.2%), and plagiarism (9.8%). Incomplete, uninformative or misleading retraction announcements have led to a previous underestimation of the role of fraud in the ongoing retraction epidemic. The percentage of scientific articles retracted because of fraud has increased ∼10-fold since 1975. Retractions exhibit distinctive temporal and geographic patterns that may reveal underlying causes.
Misconduct Widespread in Retracted Science Papers, Study Finds
By CARL ZIMMER
Published: October 1, 2012
Last year the journal Nature reported an alarming increase in the number of retractions of scientific papers — a tenfold rise in the previous decade, to more than 300 a year across the scientific literature.
Other studies have suggested that most of these retractions resulted from honest errors. But a deeper analysis of retractions, being published this week, challenges that comforting assumption.
In the new study, published in the Proceedings of the National Academy of Sciences, two scientists and a medical communications consultant analyzed 2,047 retracted papers in the biomedical and life sciences. They found that misconduct was the reason for three-quarters of the retractions for which they could determine the cause.
“We found that the problem was a lot worse than we thought,” said an author of the study, Dr. Arturo Casadevall of Albert Einstein College of Medicine in the Bronx.
Dr. Casadevall and another author, Dr. Ferric C. Fang of the University of Washington, have been outspoken critics of the current culture of science. To them, the rising rate of retractions reflects perverse incentives that drive scientists to make sloppy mistakes or even knowingly publish false data.
“We realized we would really like more hard data for what the reasons were for retractions,” Dr. Fang said.
They began collaborating with R. Grant Steen, a medical communications consultant in Chapel Hill, N.C., who had already published a study on 10 years of retractions. Together they gathered all the retraction notices published before May 2012 by searching PubMed, a database of scientific literature maintained by the National Library of Medicine.
“I guess our O.C.D. kicked in and we started trying to look at every paper we could look at,” Dr. Fang said.
The researchers analyzed the reasons for retractions cited by the scientific journals. But they also looked beyond the journals for the full story.
In the mid-2000s, for example, Boris Cheskis, then a senior scientist at Wyeth Research, and his colleagues published two paperson estrogen. Later, the scientists retractedboth papers, explaining that some of the data in them were “unreliable.” In 2010, the Office of Research Integrity at the federal Department of Health and Human Services ruled that Dr. Cheskis had engaged in misconduct, having falsified the figures.
Dr. Cheskis settled with the government. Although he neither accepted nor denied the charges, he agreed not to serve on any advisory boards for the United States Public Health Service and agreed to be supervised on any Public Health Service-financed research for two years.
Neither of the notices for the two retracted papers has been updated to reflect the finding of fraud. Dr. Cheskis could not be reached for comment.
Dr. Fang and his colleagues dug through other reports from the Office of Research Integrity, as well as newspaper articles and the blog Retraction Watch. All told, they reclassified 158 papers as fraudulent based on their extra research.
“We haven’t seen this level of analysis before,” said Dr. Ivan Oransky, an author of Retraction Watch and the executive editor at Reuters Health. “It confirms what we suspected.”
Dr. Oransky said he expected the rise to continue in the near future. He and his co-author, Adam Marcus, have been scrambling to keep up with new cases of fraud.
In July, for example, the Japanese Society of Anesthesiologists reported that Dr. Yoshitaka Fujii had falsified data in 172 papers. Most of those papers have yet to be officially retracted. “They’re headed for the fraud pile,” Dr. Oransky said.
Dr. Benjamin G. Druss, a professor of health policy of Emory University, said he found the statistics in the paper to be sound but added that they “need to be kept in perspective.” Only about one in 10,000 papers in PubMed have been officially retracted, he noted. By contrast, 112,908 papers have had published corrections.
Dr. Casadevall disagreed. “It convinces me more that we have a problem in science,” he said.
While the fraudulent papers may be relatively few, he went on, their rapid increase is a sign of a winner-take-all culture in which getting a paper published in a major journal can be the difference between heading a lab and facing unemployment. “Some fraction of people are starting to cheat,” he said.
Better policing techniques, like plagiarism-detecting software, might help slow the rise in misconduct, Dr. Casadevall said, but the most important thing the scientific community can do is change its culture.
“I don’t think this problem is going to go away as long as you have this disproportionate system of rewards,” he said.
<nyt_correction_bottom>
This article has been revised to reflect the following correction:
Correction: October 1, 2012
An earlier version of this story misstated the federal agency housing the Office of Research Integrity. It is the Department of Health and Human Services, not the National Institutes of Health. The earlier version also misstated the reason cited in the study for three-quarters of the retractions for which researchers could determine the cause. It was misconduct, not fraud. (Fraud or suspected fraud accounted for 41.3 percent of retractions; other forms of misconduct made up the rest.)
2012pharmaceutical
Amandeep Kaur
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Adina Hazan
Alan F. Kaul, PharmD., MS, MBA, FCCP
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David Orchard-Webb, PhD
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Demet Sag, Ph.D., CRA, GCP
Daniel Menzin
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