Exploring scientific misconduct

This paper was written by a student for a senior seminar on Science in Society at Bryn Mawr College. It's made available, with the student's permission, as a contribution to ongoing discussion of issues at the interface between science and the wider society of which it is a part.

 

It's All the Little Things:
How Misdemeanors in Scientific Misconduct are as Bad as Fabrication and Falsification

Elena Plionis
December 2007

The consequences of even the most infamous cases of scientific misconduct usually have not reverberated beyond the scientific community. When investigations revealed that Hwang Woo-Suk had faked data proving he cloned embryonic, human stem cells, there was shock and disappointment (Woo-Suk Hwang et al, 2004). Yet, the health and wellbeing of the public was largely unaffected; his research had not been implemented into any government action or medical use. Unfortunately, this is not true for all misconduct in biomedical and psychopharmacological research, where the results have a direct relevance and impact on the public. Here, misconduct can be particularly costly and even deadly. This thesis will present three major cases and counterexamples that will reveal the impact of scientific misconduct on the public.

Theses

At the heart of all scientific misconduct is distortion of truth. There is a spectrum of misconduct, ranging in degree of ill intent and consciousness involved. However, the consequences of an infraction will not always equal the infraction’s magnitude on this scale. As a result, a misdemeanor, such as hiding a conflict of interest, can be as devastating as wholesale fabrication of data.

There is also another form of misconduct that has not been included in any existing definitions: over-interpreting and publicly presenting results that are not supported by adequate and/or accurate information. The end result, as with all other infractions, is that the audience is misled. It is possible to deal with alarming but preliminary data in a less damaging manner. This can be done without accumulating data over a significantly long time since this may result in recommendations that are no longer relevant or effective.

Types of Misconduct
What is the range of misconduct? Scientific misconduct is traditionally thought to take three forms: fabrication, falsification, and plagiarism, with the first two being the most relevant to this study. The Office of Research Integrity (ORI) defines fabrication as, “…making up data or results and recording or reporting on them”, while falsification consists of, “…manipulating research materials, equipment, or processes, or changing or omitting data or results…” so that the overall presentation is inaccurate (Definition of Research Misconduct, 2006). An example of the latter would be changing a picture of an electrophoresis gel or ‘cleaning’ up data by leaving out skewing data points. Kenneth Pimple, a researcher who developed a new classification of misconduct, further clarifies that the difference between fabrication and falsification is the severity; both distort the truth, one replacing it entirely and the other only changing elements of it (Pimple, 2002). These two can be called ‘high’ misconduct.

Not as flagrant or perhaps as conscious as high misconduct are the misdemeanors. However, these still introduce bias and distortion. Michael Zigmond and Beth Fischer of the University of Pittsburg describe some of them: not disclosing conflicts of interest or sources of funding, which removes a significant part of the context the data can be interpreted in; providing authorship to an individual that has not met the proper criteria for this status, which may violate this author’s rights and provide undeserved status to the paper; in a published study, not citing papers that contradict the one’s hypothesis, which also restricts the context of the paper’s results (2002). This by no means includes all the misdemeanors possible, but these are some of the most relevant for this particular study.

How Misconduct Hurts the Public

How does misconduct cause damage? The misconduct reduces the quality of the science itself. Povl Riis of the British Medical Journal defines research as an attempt to discover causal links (instead of coincidences), translate these to exact questions, and follow a ‘bias-controlled’ methodology (Lock, Well, and Farthing, 2001). This connects the original question to proper answers. Misconduct results in researchers deviating from this process usually because they are following a bias.

Where does this bias come from? Having examined several cases, I believe that this bias can derive from external pressures, internal pressures, or a mix of both. Perhaps there is pressure to find a positive result for the company that is funding one’s research. Or the researcher is so convinced of a certain outcome proving a given theory that he or she abridges the experimentation process. This can be conscious and willful or more subtle; an honest mistake may be made, but it is interpreted according to a bias.

The end result is the same though: the science loses objectivity and precision. Thus, the conclusions drawn from it are not as reliable and valid as possible, likewise affecting any policies or actions based on it. Since origin of bias is subjective, it is often difficult to determine when examining a case. Thus, this point will not be explored further.

What is the impact of misconduct in biomedical and related research on the public? The overarching result of distortion is misinformation, which ripples from the large scale of federal organizations to the personal level of individuals. The government will take available research into account when determining public policy, such as whether or not a vaccine is really harmful. Thus, there is a possibility of acting on data that is not accurate or non-existent, possibly inflicting more harm than good on a large number of people. Individuals will also be making their own opinions and decisions about how to act, such as deciding whether or not to get their child vaccinated.

These misguided actions can also lead to bodily harm and death; a child that is not vaccinated may contract a disease. The harm can be psychological as well, arousing unnecessary panic and fear in the population.
What can exacerbate this? The greater the publicity of a study, the greater an audience and thus the effect it has. This is especially heightened when a controversy is involved, such as what the best way to treat mentally retarded children or whether vaccines are truly safe. Also, updates and corrections on the research are not always reported widely, meaning that information put in the public sphere and its detrimental effects can persist for a while.

A New Form of Misconduct

One can understand then how disseminating preliminary, un-replicated findings in a sensational and very public way can be counted as misconduct. This exaggerates the degree of misinformation and amplifies its presence in the public sphere. Either researchers or others will derive critical conclusions where it is inappropriate. For example, if a new study claims to decide a controversy, one side will implement and promote it as part of its agenda. Confusion may also be created when bold claims are then retracted, hindering the decisions government and individuals can make; if a vaccine is said to be dangerous and then perfectly fine, people may hesitate to be vaccinated just to ‘play it safe’.

However, there is also a time limit on gathering data. Thereafter, it loses its timeliness. If one suspects that a vaccine causes developmental problems, but it takes two decades to determine that this is the case, harm was not successfully prevented. The recommendations of the study are attenuated in their usefulness and effectiveness. How then does one warn the public of potential, genuine threats to health without risking inciting hysteria and spreading misinformation? The answer is that the study is based on proper science, without any type of misconduct, and is presented in a non-alarmist manner. Reporting and proposals are directed at the relevant groups and are logical and cautious, not dramatic.

Case Study: Ritalin

The first example of misconduct involves Stephen Breuning’s research on the effect of the psychoactive drug Ritalin on the hyperactivity of mentally retarded children. It is a severe case of misconduct, where fabrication was involved over a long span of time in a large body of influential work.

Methylphenidate, also known as Ritalin, acts as a stimulant in the central nervous system. It results in greater focus and decreased hyperactivity (InfoFacts: Methylphenidate, 2006). Stimulants like Ritalin were studied in non-mentally challenged children earlier on in the twentieth century (Helsel, Hersen, and Lubetsky, 1988). It has been found useful in addressing the academic and behavior problems associated with what is now known as Attention Deficit Hyperactivity Disorder (ADHD) (InfoFacts: Methylphenidate, 2006). ADHD is defined as distractibility, impulsivity, motor overflow (excessive motor function) and inattentiveness present for at least six months and at a significantly disruptive level (Attention Deficit/Hyperactivity, 2005). Stimulants, including Ritalin, continue to be a major treatment in this disorder, with twenty million prescriptions written in the U.S. in 2000 (Rowland, 2001).

Over the same time span but to a lesser extent were studies that tested stimulants’ effectiveness for ADHD-affected, mentally retarded children (Helsel, Hersen, and Lubetsky, 1988). While earlier studies suffered from methodological and design errors, studies by the 1980s had found inconsistent but significant improvement in ADHD symptoms and academic performance (Helsel, Hersen, and Lubetsky, 1988). Tranquilizers were the traditional treatment for the behavioral and emotional disturbances seen in institutionalized, mentally retarded children. By 1986, 30-50 % of these children received tranquilizers. However, long-term use came with significant side effects such as tardive dyskinesia (Holden, 1986). Similar to Parkinson Disease, it involves involuntary, repetitive, stereotyped movements, such as lip smacking (NINDS Tardive Dyskinesia, 2007). The concept of less immediate intervention with stimulant drugs was becoming a popular alternative (Brand, 1987). Thus, around the time Breuning was doing his work, there was debate as to what was the best treatment for hyperactive, mentally challenged children: tranquilizers, stimulants, or other techniques? Breuning’s contribution came at a time when, “…most clinical practice and administrative policy bearing on drug treatment were based primarily on anecdote and clinical impression” (qtd. in Holden, 1987 p.1566)

Stephen Breuning did much of his research in the late 1970s and into the 1980s, focusing on this relatively small research field. Breuning’s body of work examined the effects of tranquilizers as well as those of the stimulant Ritalin (Holden, 1987). His results indicated that stimulant treatment was effective and had less compromising side effects than tranquilizers. His research was thought to prove that a change was needed in treatment, switching to stimulants instead (Holden, 1987). This information became part of a handbook, “Drugs and the Mentally Retarded”, a widely used handbook published in 1982. Even laws in some states were changed to accommodate his findings (Holden, 1987).

The whistleblower on this case, Robert Sprague, was a fellow researcher in Breuning’s discipline and a mentor to Breuning himself. He became suspicious in 1983 when Breuning submitted an abstract of a study which followed up 45 subjects from a previous study each year for two years (Sprague, 1993). These subjects came from Coldwater Regional Center in Michigan, where the Sprague and Breuning had done research. Since Breuning had already left by this time and Sprague was not present for all of Breuning’s research, Sprague called to find out more about the study. He discovered that no such research was on record for the time Breuning claimed (Sprague, 1993).

Breuning was also known for generating an enormous amount of work at a remarkable speed. Sprague looked at seven consecutive studies Breuning described in a progress report to the National Institute of Mental Health (NIMH), which funded his work and for which Sprague had lent equipment (Sprague, 1993). He calculated the time that it would take to complete the studies, given the time needed to test all the subjects, use facilities and equipment and the number of workdays. He found that it would require 273 days; however, there were only 261 such days possible. That means that Breuning was operating at 110% efficiency (Sprague, 1993).

Sprague requested to see the original data and Breuning, when pressured, only came up with 24 of the 180 possible evaluations for the 45 subjects. The rest apparently were lost or destroyed for confidentiality reasons (Sprague, 1993). After a thorough investigation, NIMH found in 1988 that Breuning had, “…willfully, knowingly and repeatedly…” engaged in misconduct (qtd in Holden, 1987 p.1566). He was convicted of two counts of submitting falsified research in grant applications and had to pay $11,352 in fines in addition to five years probation. He was the first scientist prosecuted for research fraud (“Scientist Given 60-Day”, 1988).

Evidently, a strong bias led to a gross departure from the appropriate research process. Breuning’s misconduct meant that methodologies and the subjects described were never actually devised or studied. The end result was that most of Breuning’s research at multiple institutions was fabricated or falsified. While Sprague’s suspicions began with Breuning’s studies on tranquilizers, this fabrication spread to his studies on Ritalin as well. This high misconduct was also accompanied by a misdemeanor: Breuning was found to have coerced other researchers into being coauthors (Holden, 1987). They did not meet the criteria for this and in some cases Breuning simply placed names on his papers in order to enhance the prestige of his own work. For example, in his chapter of “Dugs and the Mentally Retarded” Breuning presented a study which the ‘coauthors’ claimed they never conducted (Holden, 1987).

What were the effects of this misconduct? Breuning was one of the few researchers in his area and his work came out at a time when there was controversy about what treatment options were best for ADHD in the mentally retarded. Thus, his work had substantial influence. According to Sprague, Breuning produced, “…one-third of the literature in the psychopharmacology of the mentally retarded” (qtd. in Brand, 1987 p.1). A 1990 examination of scientific citations found that 11 of Breuning’s studies were cited between 10-26 times. This has only occurred for 7% of the studies submitted between 1955 and 1987 of the Scientific Citation Index (Garfield and Welljams-Dorof, 1990).

However, this same study proved that, once the fraud was uncovered, its influence on research was limited. Of all the citations of his studies, 40% of the citations were self-citations by Breuning and coauthors; of 101 remaining citations, 58 were neutral, 33 disagreed with Breuning’s conclusions while only 10 agreed (Garfield and Welljams-Dorof, 1990). Looking again at the 101 citations, 63 were inconsequential to the paper’s conclusions while Breuning’s research was relevant to conclusions in 38 of the citations. It turned out that 21 of these citations led to negative conclusions, negating Breuning’s evidence (Garfield and Welljams-Dorof, 1990).

Until this fraud was uncovered though, the misinformation from his research was circulated both in the psychology literature and in a handbook used by psychologists. It was pervasive and considered significant enough to be acted upon; by the government and probably by individual psychologists deciding how to help the mentally retarded. The use of Ritalin over tranquilizers was encouraged without the support of a body of data. While stimulants were more likely to be used as a result, there was now less valid information about which stimulants and doses thereof were the best (Byrne, 1988). The physical and psychological welfare of already vulnerable, mentally retarded individuals was risked. Considering the depth of Breuning’s deception, it probably also undermined the confidence the government and public had in research.

Case Study Two: MMR

The second case involves Dr. Andrew Wakefield and a paper he and his colleagues submitted to The Lancet in 1998 (Wakefield et al, 1998). The study claimed to describe a new syndrome whereby the measles, mumps, and rubella (MMR) vaccine caused gastrointestinal problems and subsequently, autism. Unlike the Ritalin case, misdemeanors in a single study were the main misconduct involved.

The diseases this vaccine protects against can lead to severe complications such as meningitis or death. At the very least, they are unpleasant with symptoms such as swollen glands, fever, and loss of appetite shared among the three (Fitzpatrick, 2004). Vaccination for all three diseases is administered at around 12 months of age to minimize the time of potential exposure to these diseases (Fitzpatrick, 2004). Following MMR’s introduction in 1988 in the United Kingdom (U.K), rates of these diseases dropped dramatically over the next seven years: mumps went down from 11 per 100,000 at its worst to less than 1 incidence per 100,000; rubella, from 400 confirmed cases to less than 100; measles, from 700,000 notifications to less than 100,000 (Fitzpatrick, 2004).

It may seem baffling then for people to attack the MMR vaccine for causing illness and damage, but this is nothing new. There has been a consistent anti-vaccination sentiment since vaccination first began in the nineteenth century (Fitzpatrick, 2004). The typical complaints against vaccines have been similar throughout the years; vaccines are outright dangerous, they are ineffective, the government does not allow enough choice in the receiving them or not to name a few (Fitzpatrick, 2004). In the 1970s, also in England, a situation similar to the MMR case occurred: a study claimed that the vaccine for pertussis (whooping cough) caused neurological damage. This was subsequently proven false, but not before the rate of this vaccination dropped from 80% to 30% (Fitzpatrick, 2004).

Autism, the disorder the MMR vaccine was blamed for causing, is a significant mental disorder involving a triad of disability: abnormal communication and language, impaired social interaction, and repetitive, stereotyped behaviors (Fitzpatrick, 2004). Some common problems for autistic children are forming relationships and great distress with changes from predictable routines. It can range in severity and responsiveness to therapy, but it is chronic with autistic adults requiring a significant amount of supervision and support to live independently (“What is Autism”, 2007; Tsai). There is neither a definitive or effective cure for this condition nor an understood cause. It is estimated that 1 in 150 individuals in America are autistic (“What is Autism”, 2007).

While there are claims that autism has risen to epidemic proportions in recent years, there is controversy surrounding this claim (Fitzpatrick, 2004). Some explain any increase as the result of greater awareness of the condition and broader definitions rather than a rise in autism itself (Fitzpatrick, 2004). However, this notion of an epidemic is well reported in the media; perpetuating the idea that a serious and debilitating disorder is on the rise, without a cure or solid explanation.

This is the atmosphere in which Wakefield et al’s paper was published. The study detailed twelve children who had two problems: gastrointestinal issues and autism (two of the twelve had psychoses similar to autism). Examinations found that these children had inflammation of the bowels (non-specific colitis) and enlargement of lymph nodes in the small intestine (ileal lymphoid nodular hyperplasia) (Wakefield et al, 1998). The parents of eight of the children had linked the MMR vaccine with the onset of their child’s symptoms. With this information, Wakefield calculated that the average time for onset was a startling six days (Wakefield et al, 1998).

Wakefield and his colleagues theorized that this was a novel, specific form of autism, dubbed ‘autistic enterocolitis’. Specifically, they thought that the measles virus in the vaccine may remain active and stay in the intestinal tissues, causing the gastrointestinal problems (Wakefield et al, 1998). As a result, toxic peptides from digested food may leach out into the bloodstream and cause trauma to the brain. They admitted though that the link between the vaccine and autistic enterocolitis was only correlational, not causal (Wakefield et al, 1998).

That did not stop Wakefield from publicly urging people to boycott the triple vaccine in favor of individual ones, twelve months apart (Deer). Yet, the government, having performed its own reviews, refused to make any such changes. The debate entered into the media and stirred up panic and confusion in the public. This may have been because there was a tendency for both sides of the controversy to be presented equally. As a result, a survey in 2002 found that 53% of people equated this with there being equal weight to each argument (Fitzpatrick, 2004).

There was a subsequent, significant drop in immunization rates. While there had been a slight (one percent) drop from 92% in 1997, before the paper came out, by 2002 rates were below 85% and even below 75% in some areas (Fitzpatrick, 2004). In 2005, the rate was still low, around 83%. Confirmed cases of measles went up from 56 in 1998 to 438 by 2003 (“MMR Doctor”, 2006). Wakefield advocated for a different schedule of vaccination, but the result was that parents refused to vaccinate their children with MMR. Since the Department of Health does not provide single vaccines for these diseases, they are probably not as available as MMR, perhaps explaining why fewer children overall were vaccinated for these diseases (Fitzpatrick, 2004). Also, herd immunity was adversely affected. Herd immunity is a certain level whereby even those without immunization are effectively safe from infection (Fitzpatrick, 2004). It is a step towards eradicating diseases entirely. The vaccination rate for such immunity is 95% and rates went from about 92% before the paper to well below this afterwards (Fitzpatrick 2004).

Also, parents of autistic children were forced to ask themselves if they had directly caused their child’s debilitating condition by having them vaccinated. One mother describes this realization:
The long nights of guilt I felt as a mother, constantly wondering what I done wrong to give him autism…I was overwhelmed with rage…I was convinced my son was a cash cow for an industry that tested its products in production rather than the lab…(qtd. in Fitzpatrick, 2004 p. 58).

This statement also makes it clear how this perceived link undermined the public’s faith in the medical community and government that helped run immunization programs. This was heightened when the then prime minister, Tony Blair, refused to disclose whether his infant son had received the MMR vaccine. Many interpreted this as further evidence that the vaccine was not truly safe (Fitzpatrick, 2004).

In 2004, The Lancet retracted the paper (Deer). By 2006, Wakefield faced a number of charges by the General Medical Counsel, which, as of 2007, are still being reviewed (Deer). One of the major charges leveled at Wakefield was that he unethically subjected the children in his study to unnecessary and invasive procedures (such as a lumbar puncture). The other major charge was that he failed to disclose an obvious conflict of interest: Wakefield was paid 50,000 pounds to investigate the MMR-autism link by Richard Barr, a lawyer (solicitor) who headed a lawsuit against the MMR vaccine (Deer). There were eight autistic children where the MMR-autism link was ‘evident’ and at least four of these children were part of Barr’s lawsuit (Deer). It has also surfaced that in the months before the study was published, Wakefield was filing patent papers for a single measles vaccine (Deer). Such a vaccine would not be commercially successful unless there was something wrong with the established MMR vaccine.

This is evidence of a strong bias on Wakefield’s part against the MMR vaccine. It resulted in poor experimental design and interpretation. There was bias in selection of participants, since it was Barr who contacted MMR clients of his and referred them to Wakefield if their child had gastrointestinal problems (Deer). The sample size, twelve participants, is also extremely small to draw from any causal conclusions. The study did not recognize the possibility of recall bias on the part of parents who had made the link between the vaccine and their child’s autism; the onset of behavioral symptoms may have started earlier (Fitzpatrick, 2004). The study lastly failed to include control groups, such as normal children with MMR immunization or autistic children who had the MMR vaccine but no gastrointestinal problems.

The interpretations of the study also followed this bias instead of more logical alternatives. If the mechanism Wakefield et al proposed was correct, then there should have been traces of the measles virus in the gastrointestinal tissue of the participants. A research assistant of Wakefield’s claims such tests were done, but no measles virus was found (Deer). This information was not included in the published paper, and thus constitutes falsification. The theory is also flawed since behavioral symptoms tended to precede gastrointestinal ones (Fitzpatrick, 2004). One of the children in the study allegedly had an onset of symptoms following the vaccine within twenty-four hours. However, the pathological pathway Wakefield proposed, infection-induced vasculitis, usually requires several weeks; twenty-four hours is certainly faster than any known process of vasculitis (Fitzpatrick, 2004). The bowel symptoms described are also relatively common in children, so their presence in autistic children should not have been anything significant (Deer). Lastly, there was no attempt to compare the introduction of the MMR vaccine to the number of autism cases, which might have confirmed the correlation in the study.

While falsification was present, it was the misdemeanor of conflict of interest that caused most of the harm. Physical harm was caused by increased cases of measles, mumps, and rubella. The drop in immunization rates was significant and set back efforts to reach herd immunity. Wakefield’s paper also supported the replacement of MMR with individual vaccines. These help delay herd immunity and increase the window of time that a child can become infected with the disease, which counters the point of immunization. Even in the face of several studies refuting Wakefield’s hypothesis, the original confusion and fear aroused by the paper continues to persist (Taylor et al, 2002; “MMR Vaccination Safe”, 2004). Thus, vaccination rates and the risk of harm continue to persist.

Psychologically, faith in the medical community and vaccines was undermined, fear was aroused, and some parents were convinced that they were directly responsible for their child’s condition. While the government resisted changing their vaccine policy, the public was negatively influenced, leading some individuals to avoid vaccinating their children with MMR.

Case Three: MDMA

The final case features George Ricaurte and his team at Johns Hopkins University who studied the potential effects of the drug MDMA (street name “Ecstasy”) on the brain. Like the MMR case, the damage caused here only involved misdemeanors in a single study.

MDMA was synthesized in the early 1900s, but only became a popular street drug in the 1980s (Holland, 2001). It acts as both a stimulant and a psychedelic, mostly via its influence on the neurotransmitter, serotonin (InfoFacts:MDMA, 2006). Serotonin is involved with various processes, such as temperature regulation, mood, and appetite. As a result, it is produces feelings of euphoria, but also has side effects like hyperthermia (InfoFacts:MDMA, 2006). MDMA has become part of a ‘subculture’, featured in raves or all-night dances (Cloud, 2000). When it was declared a Schedule I drug (harmful, without application) by the Drug Enforcement Association in 1985 there was considerable debate (Holland, 2001). There are still those, like the Multidisciplinary Association for Psychedelic Studies (MAPS), who maintain that MDMA may have psychotherapeutic value for conditions like post-traumatic stress disorder (PTSD) (Cloud, 2000). Others point out though that MDMA use can lead to overdose or death and believe that it is at ‘raves’ that youths are introduced to other drugs (Reducing Americans’ Vulnerability, 2002).

What are the long-term risks of MDMA use? Previous research with animal models has found neurotoxicity for serotonin neurons (McNeil, 2003). One study, using non-human primates, found that MDMA exposure for four days caused damage to axon terminals that could be seen several years later. However, there is debate about how accurately these findings can be generalized to humans (InfoFacts:MDMA, 2006). Human studies to date are not entirely conclusive about MDMA’s effect on the brain either and there is no proof that it causes permanent brain damage (McNeil, 2003). This is usually because it is hard to gather MDMA users. Moreover, it’s hard to find individuals who use only MDMA (or guarantee that the purity of the MDMA they use) and no other illicit drugs (McNeil, 2003). Neither human nor animal studies have found neurotoxicity for dopamine neurons, with the exception for mouse models (where no serotonin neurotoxicity occurred) (Ricuarte et al, 2002).

To continue resolving this question, the National Institute on Drug Abuse (NIDA) in 2002 funded Ricaurte and his team to determine how MDMA may affect the human brain. The researchers injected ten non-human primates with three spaced, consecutive doses. This was meant to mimic a typical night of the drug’s use. Two weeks later, they analyzed the primate brains for anatomical and physiological changes to compare with controls (Ricaurte et al, 2002).

What they found was startling: both serotonin and dopamine neurons suffered cell death. For serotonin neurons, there was a 40, 48 and 37% reduction in SERT (serotonin receptors), 5-HIAA (serotonin metabolites) and the neurotransmitter serotonin respectively (Ricaurte et al, 2002). Even worse though was the neurotoxicity for dopamine neurons: reduction in DAT (dopamine transporters) by 51%, DOPAC (a dopamine metabolite) by 65% and dopamine itself by 77%. No other neurotransmitters were affected (Ricaurte et al, 2002). Dopamine has diverse functions in the CNS and cardiovascular system (“Dopamine”). Deficits in this neurotransmitter are what cause the tremors and uncontrolled movement seen in Parkinson Disease (Ricaurte et al, 2002).

The researchers concluded that even one night’s use of MDMA could cause severe brain damage. They postulated that the decrease of dopamine could lead to early-onset Parkinson Disease (Ricaurte et al, 2002). While no such trend between MDMA use and incidence of Parkinson was obvious, the researchers thought that the correlation simply had not been made. They also pointed out that Parkinson Disease does not show symptoms until 70-80% of dopamine had been lost (Ricaurte et al, 2002). As for the unusual dopamine neurotoxicity, Ricaurte suggested explanations: previous studies had used higher, but more spaced doses of MDMA. Ricaurte’s study gave lower doses, but closer together, which would lead to a more sustained exposure of MDMA. This might make the dopamine neurons more susceptible to damage. They also speculated that in these circumstances, the accompanying hyperthermia may have altered MDMA’s toxicity (Ricaurte et al, 2002).

What effects did this study have? The study was widely reported in the media. In an unusual move, the study was publicly endorsed by Alan Leshner, chief executive of the American Association for the Advancement of Science (AAAS) when he said, “It sends an important public-health message—don’t experiment with your own brain”(qtd. in Knight, 2003). A proposed piece of legislation, Reducing Americans’ Vulnerability to Ecstasy Act (RAVE Act), was under debate in 2002. It recommended making club owners responsible for MDMA use in their establishments with fines up to $250,000. Ricaurte’s study was cited by Asa Hutchinson, administrator of the DEA during testimony on this act, highlighting the ‘severe brain damage’ MDMA caused and how this damage, “…could stay hidden for years…”(Reducing Americans’ Vulnerability, 2002).

Also in 2002, through the work of MAPS, preparations were underway in Spain for an experiment to determine MDMA’s potential benefit for victims of Post-Traumatic Stress Disorder (PTSD) (Doblin, 2004). Before it began Ricaurte’s study was published and not long after, Ricaurte himself came to speak about his results in Madrid. The experiment was ultimately never carried out (Doblin, 2004).
However, Ricaurte faced criticism from the outset within the scientific community. In a letter to Science in June 2003, three researchers criticized how the experiment was performed (Mithoefer, Jerome, and Doblin, 2003). The first flaw was that two of the ten subjects died immediately after receiving their doses. Since the broader evidence doesn’t support such a level of lethality in humans, the researchers claimed that Ricaurte’s human-primate dose scaling was obviously wrong (Knight, 2003; Mithoefer, Jerome, and Doblin, 2003). Second, while Ricuarte claimed in the paper that oral administration of MDMA hardly attenuates the drug’s neurotoxicity, a study he himself conducted in 1988 showed that subcutaneous injection in non-human primates is twice as lethal as oral consumption (Mithoefer, Jerome, and Doblin, 2003).

The researchers point out other errors in Ricaurte’s interpretation. Firstly, MDMA had been in use for at least twenty years before the study. If MDMA really was causing young-onset Parkinson Disease, then this would be confirmed by broader evidence, which it hasn’t (Mithoefer, Jerome, and Doblin, 2003). Secondly, the changes to dopamine neurons recorded in this study are known as a potential effect of two prescriptions drugs, d-amphetamine and d-methamphetamine (Mithoefer, Jerome, and Doblin, 2003). This implies that the dopamine neurotoxicity is originating from a source other than MDMA. Lastly, Ricaurte did not cite previous studies showing no dopamine neurotoxcity in both in vivo and post-mortem analyses of heavy MDMA users. This directly contradicts their hypothesis and should have prompted serious questions about how the study was conducted (Mithoefer, Jerome, and Doblin, 2003). Such design and interpretation flaws should have been taken into account in their analysis of the data.

After failing to replicate their results, Ricaurte and his team discovered that methamphetamine (street name ‘Meth’ or ‘Speed’) was mistakenly used in all but one of the primates (Knight, 2003). This would explain the dopamine neurotoxicity as well as the lethality seen in the subjects. Ricaurte et al retracted their paper September 2003, explaining that the bottles had been mislabeled (Knight, 2003).

So what misconduct occurred? No one has accused of Ricaurte et al of purposely switching the bottles and the data was real and uncorrupted, so neither of the high-level forms of misconduct is involved. At least one misdemeanor was present: not citing studies that contradict one’s hypothesis. As the letter to Science showed, there were at least three studies, Reneman et al (2002), Semple et al (1999) and Kish et al (2000), which showed that MDMA did not cause dopamine damage (Mithoefer, Jerome, and Doblin, 2003). This misdemeanor reflects a bias on Ricaurte’s part towards showing MDMA-induced, long-term brain damage. Perhaps it was introduced by Ricaurte’s own agenda to prove MDMA’s destructiveness or externally through expectations from NIDA and the government to justify harsher regulation of MDMA

The bias affected the interpretation of a research study and probably explains how they overlooked confounds introduced in the study’s design and execution. The explanations Ricaurte et al provided ignored the simpler ones: mistakes in the scaling, differences in administration pathways, perhaps even that the wrong substance was used (since the MDMA and meth bottles came in the same package) (Knight, 2003). With such dramatically different results, it would seem prudent to replicate the study or at least make it clear in the published paper just how outstanding these results were from the existing literature. Lacking this, Ricaurte’s study lacked a complete context and background for the research question. Thus, the interpretation of the results couldn’t help but be flawed and the audience misled. It seems then that all the objections that the letter to Science raised were validated.

This case especially makes it clear how strongly a bias can influence a study and its consequences. The use of methamphetamine was an honest mistake, but because there was a bias, it was not caught and less likely explanations of the data sought. This reflects a loss of objectivity and thus scientific credibility in the study. The misinformation it generated helped pass a law, helped deter a study assessing the benefit of MDMA, and probably unnecessarily frightened MDMA users. Anti-drug campaigns in general may have also lost credibility since this was one more piece of ‘proof’ that turned out to be false.

Comparison of Cases

How do these three cases compare in terms of misdirecting public action, risking/causing bodily harm, and risking/causing psychological harm?

Influence on Public Action

All three studies effectively misguided how the public acted. In the Ritalin case, some state laws were changed in accordance with Breuning’s findings. Considering the timing and influence of his work, it’s likely that stimulants became more widely used by psychologists. Fortunately, it seems that once the misconduct was uncovered, the impact this misinformation had on the literature was attenuated. In the MMR case, while the government did not change its vaccination policy, many individuals decided against getting the MMR vaccine. This is clearly reflected in the depressed vaccination rates since 1998, when Wakefield’s paper was published. In the MDMA case, Ricaurte’s findings helped to pass legislation and discouraged what would have been the first study assessing MDMA’s psychotherapeutic benefits. It may also have affected the MDMA use of individuals.

The Ritalin and MDMA cases caused change on the federal level, while the MMR case caused change on the personal level. It is also likely, though harder to quantify, that the Ritalin and MDMA case caused changes on the personal level. All three are similar in that they had the potential, realized or not, to influence action on a large scale.

Risk of Harm: Physical

The misconduct in all of these cases risked bodily harm, amplified by the actions taken based on misinformation. In the Ritalin case, Breuning’s research promoted administration of stimulants over the tranquilizers. While stimulants had been tested and used in non-mentally challenged children, they were still being evaluated for their effect in the mentally challenged. The dosage of Ritalin that Breuning suggested was also untested. So while it is unlikely that anything very physically damaging would have occurred, stimulants were given when the effect and administration of Ritalin in this subpopulation were unknown. It’s possible that there may have been some unforeseen complication, such as an interaction between the stimulants and residue from tranquilizers.

In the MMR case, great physical harm was risked since the effect of Wakefield’s paper was to instill uncertainty in receiving the MMR vaccine. Actual harm is clear in the rise of cases of diseases as MMR vaccination rates dropped and individuals opted for individual vaccines. Receiving individual vaccines also lengthened the amount of time their children were susceptible to infection. The risk of disease was not just incurred by unvaccinated individuals but threatened the greater population by making it harder to reach herd immunity.

In the MDMA case, Ricarute’s paper acted to discourage use of MDMA. While MDMA use may not be as injurious as once thought, it is still dangerous; hyperthermia or impure MDMA can lead to death. So the paper may have actually decreased physical harm. However, one could say that the legislation Ricaurte’s results had some bearing on did risk bodily harm. This is because some argue that by making club owners responsible, the RAVE Act also makes them less likely to put out bottles of water or have cooling rooms that could be interpreted as condoning the drug use (“Ecstasy’s After Effects”, 2003). Thus, MDMA use is made less safe. This harm is theoretical though and indirectly related to Ricaurte’s paper.
Physical harm was most clear, documented, and severe in the MMR case. There was potential for direct physical harm in the Ritalin case, though it is unclear whether this was realized and if so, how damaging it was. In the MDMA case, physical harm may have been avoided, unless one considers how it indirectly influenced MDMA use in clubs.

Risk of Harm: Psychological

Lastly, psychological harm was also risked. Since Ritalin is a psychoactive drug, promoting its use introduced the possibility of harming the mental health of the children receiving it or being unduly taken off tranquilizers. The extent of the misconduct couldn’t help but challenge the confidence and trust that the public had for research scientists and psychologists.

In the MMR case, Wakefield’s study caused panic and undermined the trust people had in the medical community and government. Some parents of autistic children suffered guilt and other emotional trauma, convinced that they had caused their child’s autism.

As for the MDMA case, the study also raised fears, suggesting that those using MDMA could suffer severe, irreversible brain damage. Since it is still inconclusive whether and to what extent MDMA has on the human brain, one can’t quite say that the study decreased psychological harm by discouraging MDMA use. The subsequent retraction of the study and its results may have undermined credibility of any anti-drug education for youths; if this alarmist piece of evidence turned out to be false, how reliable was any ‘evidence’ authorities gave? Lastly, the study helped deter another study that may have pioneered MDMA use in alleviating psychological stress.

Again, psychological harm appears to be most clear and direct in the MMR case. The potential for psychological harm was direct in the Ritalin case but it is unclear whether it occurred or how severe it was. In the MDMA case, the harm is less defined and some of it may be indirectly related to the study.

Conclusions

So how do these cases measure up overall? It may be difficult to completely compare the effects of all these cases since there is no objective standard. It is obvious enough though that the misconduct in all these cases resulted in inferior science and the consequences thereof. Regardless of the magnitude of the misconduct involved, all three caused changes in the action of the public. As for physical and psychological harm, the Ritalin and MMR cases had clear, direct risks. The first involved the high misconduct of fabrication and falsification while the main misconduct in MMR was not disclosing conflicts of interest. As for the MDMA case, there was potential for direct psychological harm as well as other indirect physical and psychological harm. This originated from the misconduct of failing to cite contradictory studies in one’s paper, which reveals the bias involved. Even though the psychological and physical effects in this case are not quite as definitive or bad as in the MMR and Ritalin case, the fact that it is even somewhat comparable speaks volumes about the power of the bias in altering interpretation. Also, any risk, despite the variation in magnitude, to the wellbeing of the public is inexcusable.

There were also factors present that exacerbated this harm. Each of these studies was considered significant enough to base action on. Such influence reflects the great scope and publicity these studies had. A greater scope means that more people are affected by the misconduct, and thus there is a heightened risk of physical and psychological harm. Each case also involved controversies, which made the results of the study more relevant to the public and compelled more focus on them: the debate over which treatment was best in the Ritalin case, whether vaccines and vaccine programs are truly safe (MMR case), and whether MDMA has any benefits. It is hard to determine for each case how publicized the corrections to their misinformation have been. However, a review of MMR studies disproving the link between autism and MMR cites their lack of media coverage as a reason for the misinformation to persist (Taylor et al, 2002).
Physical and psychological harm occurred despite the type of misconduct involved, demonstrating that the hierarchy of misconduct may not indicate the magnitude of the misconduct’s consequences. In some cases, misdemeanors may lead to greater risk and harm than high forms of misconduct, such as fabrication and falsification.

A New Type of Misconduct: MMR, Infant Cold Medicine, and Popcorn

So far this thesis has examined cases in terms of existing definitions of misconduct, both major and minor. They have demonstrated how publicity and misinformation together create most of the damage originating from misconduct. It is only logical then that the direct combination of these two should be counted as misconduct in and of itself. Thus, actively publicizing and over-interpreting the results of a single or preliminary study by one of its researchers is a form of misconduct. This is different from when those outside of the research do the same thing, since a researcher cannot completely control what happens to his or her results once they are published. The MMR case is an example of public over-interpretation. Compared with two non-misconduct cases, it will help demonstrate other ways of handling alarming but preliminary results.

The MMR case exemplifies public over-interpretation well. Andrew Wakefield and his colleagues published a single study that described a new condition involving autism and gastrointestinal disease. It claimed to find a correlation between receiving the MMR vaccine with this condition. While correlation does not indicate causation, two days before the paper was even published Wakefield called a press conference (Deer). There, he urged parents to boycott the MMR vaccine in favor of single ones, claiming that it was a ‘moral issue’ for him and that he could not support MMR until this matter was resolved (Deer).

Wakefield did not seem to weigh the perceived harm done by the MMR vaccine against making statements that undermined public confidence in all vaccines. MMR vaccines rates did drop, leading to some outbreaks of the disease as well as wide-spread fear and renewal of anti-vaccine fervor. These worries have continued to last, despite many studies that prove the contrary (“MMR Vaccination ‘Safe’”, 2004; Taylor et al, 2002). Since the study had a very small sample size, it would not be appropriate to draw concrete and critical conclusions from this data anyway. Despite this, Wakefield purposefully reached out to the public and media and advised drastic action. This was worsened by the fact that the information was inaccurate as a result of the misconduct involved. Thus, with the authority of a primary investigator, the misinformation present in the paper was spread more quickly and potently.

On the other pole of this matter is a safety review that evaluated over-the-counter children’s cold medicine for effectiveness and safety. The review, produced by the Food and Drug Administration (FDA) in September of 2007, suggested that infant cough and cold medicine should be removed from the market and measuring devices standardized (“F.D.A. Panel Urges”, 2007). This is in response to decades of information, summarized in sporadic reports. They have indicated that these medicines actually are not any more effective than placebos. They could also cause harm since the lack of standardization leaves potential for overdose (“F.D.A. Panel Urges”, 2007). Between 1969 and 2006 123 children died as a result of such medicines while between the years 2004 and 2005 1,500 children under the age of 2 suffered serious health problems (“Ban Sought”, 2007). A ban on over-the-counter cold and cough medicines for children under two years was soon instituted thereafter (“F.D.A. Panel Urges”, 2007).

However, the reactions of some parents suggest that such measures are not perceived favorably. On a comments section attached to an article about the report, one parent claimed that these medicines seemed to noticeably improve a terrible cold her 18-month old daughter had (Paul, 2007). Many wondered what they were supposed to do without these medicines. Dr. Ian Paul, answering questions on an online forum, recognized that for parents, “…it is really tough to watch kids suffer with these symptoms without much to do for them” (Paul, 2007). Others expressed outrage at the ban:

I think this is ridiculous. The medicine is being yanked because some parents can’t or won’t read dosage charts…I do believe that it is wrong that the FDA is taking medicine off the shelves that they themselves say is safe (“Infant Cold Medicine Recall”, 2007)

These reactions have led some to the fear that parents will keep trying to give their young children medicines, but will have to use adult medicines instead. They will try to guess the dosage and possibly leading to more harm (“F.D.A Panel Urges”, 2007). While there had been some warnings of cold medicine use for young children, it was only until recently that a full review of all available data was done. The fact that these medicines had been used for so long and with perceived benefits has resulted in confrontation of these measures. This demonstrates that when a great time is taken to fully assess a situation it almost negates the purpose of doing so. Thus, such an approach is not appropriate either.

What is a proper approach then? A recent case illustrates an appropriate way an alarming finding can be handled. In 2007, a man came to National Jewish Medical and Research Center complaining of shortness of breath and other lung problems. His physician, Cecile Rose, took a thorough health and work history and then pinpointed the cause as bronchiolitis obliterans or ‘popcorn lung’ (Steenhuysen, 2007). This is a disorder thoroughly documented in workers at popcorn factories, mainly caused by the flavoring agent, diacetyl. Thus, this is the first and currently only case of this disease seen in a consumer (DeNoon, 2007; Steenhuysen, 2007). While it was caused by inhaling fumes from an abnormal amount of popcorn bags, there are certainly no warnings about inhaling popcorn fumes on popcorn bags (DeNoon, 2007).
Thus, Dr. Rose wrote to the FDA as well as the CDC describing the case and urging them to ban diacetyl in microwave popcorn (DeNoon, 2007). While the largest popcorn manufacturer, ConAgra, was already in the process of phasing out diacetyl, at least three other major popcorn makers soon declared thereafter that they would remove diacetyl from their products (Steenhuysen, 2007).

While some alarmist headlines can be found relating to the matter, Dr. Rose’s first move was to contact the appropriate federal agencies. She emphasized that, while only based on one case, the diacetyl flavoring was responsible and that diacetyl levels at the patient’s house equaled those seen in factories (DeNoon, 2007). She urged the logical solution of banning diacetyl, which was already shown to cause similar harm in factory workers. While the FDA has yet to act on this, some manufactures have undertaken diacetyl removal to, “…eliminate even the perception of concern for our consumers” (qtd. in Steenhuysen, 2007). In this way, a warning that diacetyl could accumulate in dangerous levels during consumer use was disseminated to the proper audience in a non-alarmist way. The result was a constructive change.

So it is neither appropriate to derive substantial conclusions from preliminary data (especially if there is misconduct involved) nor is any better to take a long time to amass solid data to back up claims. There must be a balance, which involves handling startling, preliminary results in the least destructive way. This can be achieved by not actively disseminating the information in a public and alarmist way (such as through personally contacting the media); informing the relevant people and organizations that may be able to constructively use the data; and if offering suggestions, make them in logical proportion to the certainty of the threat.

Considering that public over-interpretation is not directly related to acquiring raw data as fabrication, falsification, and plagiarism are and is not as severe as these forms of misconduct, it can be counted as a misdemeanor. Knowing this and how instrumental this form of misconduct was in causing the damage of the MMR case reinforces the main thesis: the net effect of misconduct, whether it is major or minor, is that misinformation is generated and disseminated, meaning that the public is mislead. This was demonstrated through one case of high misconduct and two cases of misdemeanor misconduct. The Ritalin case mainly involved fabrication while the MMR case involved hiding a conflict of interest and public over-interpretation. Lastly, the MDMA case involved failure to cite studies that contradict one’s hypotheses. All forms of misconduct in these cases revealed a bias in the researcher, which influenced federal and individual action. As a result, they lead to increased physical and psychological risk for citizens.

When discussing research misconduct, misdemeanors are often overshadowed by the fabrication, falsification, and plagiarism. Yet, misdemeanors are much more common and easier to prevent. Considering that the damage they cause rivals that of the major three forms, this should galvanize efforts to educate current and future researchers against committing such mistakes.

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Comments

Kalevi Korpela's picture

Follow-up of the Breuning case

see
Korpela, K. (2010). How long does it take for the scientific literature to purge itself of fraudulent material?: the Breuning case revisited. Current Medical Research & Opinion, 26, 843-847. Published online 08 February 2010; doi:10.1185/03007991003603804

 Elena&#039;s mother's picture

Elena, I am one proud

Elena,

I am one proud (PhD)mother. Congratulations to you and your seminar professor! Our money on a Bryn Mawr education was well spent!!

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