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“Unexpected Findings and Promoting Mono-Causal Claims, A Cautionary Tale” Journal of Evaluation in
Clinical Practice, 2016 (Epub ahead of print, DOI 10.1111/jep.12584)
Keywords: Unexpected Findings, Serendipity, Epistemology of Clinical Research, Evidence-Based
Medicine, Chronic Fatigue Syndrome, Causal Complexity
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Unexpected Findings and Promoting Mono-Causal Claims, A Cautionary Tale
Abstract
Stories of serendipitous discoveries in medicine incorrectly imply that the path from an unexpected
observation to major discovery is straightforward or guaranteed. In this paper, I examine a case from
the field of research about chronic fatigue syndrome (CFS). In Norway, an unexpected positive result
during clinical care has led to the development of a research programme into the potential for the
immunosuppressant drug rituximab to relieve the symptoms of CFS. The media and public have taken
up researchers’ speculations that their research results indicate a causal mechanism for CFS—
consequently, patients now have great hope that ‘the cause’ of CFS has been found, and thus a cure is
sure to follow. I argue that a mono-causal claim cannot be correctly asserted, neither on the basis of the
single case of an unexpected, though positive, result, nor on the basis of the empirical research that has
followed up on that result. Further, assertion and promotion of this claim will have specific harmful
effects: it threatens to inappropriately narrow the scope of research on CFS, might misdirect research
altogether, and could directly and indirectly harm patients. Therefore, the CFS case presents a
cautionary tale, illustrating the risks involved in drawing a theoretical hypothesis from a unexpected
observation. Further, I draw attention to the tendency in contemporary clinical research with CFS to
promote new research directions on the basis of reductive causal models of that syndrome. Particularly,
in the case of CFS research, underdetermination and causal complexity undermine the potential value of
a mono-causal claim. In sum, when an unexpected finding occurs in clinical practice or medical research,
the value of following up on that finding is to be found not in the projected value of a singular causal
relationship inferred from the finding, but rather in the process of research that follows.
Introduction
Unexpected findings during clinical practice or research can and have led to some of the most
well-known and significant discoveries in medicine. The discovery of penicillin is a classic example of
this, originating in a chance observation made by bacteriologist Alexander Fleming. Another example is
the discovery of the first antipsychotic, chlorpromazine, arising from observations made by surgeon
Henri Laborit who used it as a sedative. More recently is the discovery of Viagra, most well-known now
for a side effect opportunely observed during clinical research on a treatment for hypertension. When
stories are told of such ‘serendipitous’ discoveries they can suggest that medical progress often happens
not only by surprise, but also in leaps and bounds (1–6). However, the path from unexpected
observation to major discovery is neither straightforward nor guaranteed.
The value perceived when an unexpected finding is made is called the projected value in
analyses of serendipity (7,8). Researchers promote a projected value as a reason for following up on an
unexpected observation. For example, an unexpected positive result in clinical practice (such as a
surprising recovery from symptoms) is promoted as evidence that a particular intervention will work in
others. The intervention is the projected value of following up on that result with more research. A
projected value, however, can be importantly different from the value that unexpected observation will
ultimately have for medicine (9).
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Sometimes an unexpected observation in medicine is presumed to implicate a causal
relationship, and the projected value of that relationship dominates the rhetoric promoting a new
research direction. I argue that, when treated as a mono-causal claim, this can bring about specific
harms to both researchers and patients. A mono-causal model of a disease suggests a specific causal
relationship suffices for explaining or predicting an occurrence of that disease (10). When a mono-causal
approach to an unexpected observation is taken, a singular causal factor is seen as both necessary and
sufficient for explaining and replicating the results observed. Specific harms can result: research can be
inappropriately narrowed in scope, researchers and funding misdirected away from other equally
valuable investigations, and patients harmed by mistaken beliefs in the value of treatment options. I
show that these harms are particularly likely when a single causal factor is taken not only to account for
the effects observed unexpectedly but also to ground the projected value of research for future
patients. I conclude that it is important to instead be attentive to the value of the process of an
investigation, which may have multiple valuable outcomes, and not only to the initial projected value of
following up on an unexpected observation.
This paper draws on an example of an unexpected finding that has resulted in the establishment
of a new research direction from the field of chronic fatigue syndrome (CFS). CFS is one of several
categories describing patterns of medically unexplained symptoms, including other syndromes such as
fibromyalgia and chronic lower back pain (11,12). These conditions are medically unexplained insofar as
neither its pathology nor diagnostic biomarker have been determined. Given the potentially high value
of a discovery in these areas of medicine, because of the great need for direction in both research and
care, there is a tendency to promote new paths for investigation that are projected to lead to an
explanation of the syndrome’s origin and pathology and, ultimately, to an effective intervention. Failure
to attain a projected value that has been allowed to direct research away from other investigations and
to raise the hopes of patients will lead not only to disappointment but to real harms to researchers and
patients in this field.
The projected values of new research directions are often framed by mono-causal models of
CFS. Empirical investigations into cognitive behavioural therapy (CBT) and graded exercise therapy (GET)
as treatments for CFS have been interpreted as demonstrations that the syndrome is primarily or solely
psychiatric in nature (13). This, combined with the lack of a physiological explanation for symptoms, has
frequently led to the conclusion that the pathophysiology of CFS can be reduced to a psychological
cause (14–16). This tendency toward psychological reduction has generated opposition among
researchers and especially patients. Historically, the categorization of CFS as a primarily psychological
disorder has led to the stigmatization of patients and to the (perceived and actual) neglect of the
syndrome by medical practitioners and research (12,14,15,17). But research into biological causes and
related interventions have yet to yield sufficient explanations or effective treatments for more than
small samples of CFS patients (18–20). Thus, reductive, mono-causal approaches to CFS have so far been
unable to establish an effective standard of care for CFS patients as a group. The case I analyse in this
paper stands both as a cautionary tale for grounding the projected value of an unexpected finding in a
single causal relationship, and also against promoting a mono-causal approach to CFS. As I conclude, this
unexpected finding is rather likely to have diverse valuable contributions to make to CFS research, and
may ground a causally complex approach to treating patients diagnosed with the syndrome.
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The Norwegian rituximab trials
In 2009, the following event was described in a report on a preliminary case series, by
researchers Øystein Fluge and Olav Mella of Bergen, Norway: “A patient with CFS had unexpected,
marked recovery of CFS symptoms lasting for five months during and after cytotoxic chemotherapy for
Hodgkin’s disease” (21). While being treated for cancer, the patient in this case suddenly and
unexpectedly experienced an almost complete relief of the symptoms of CFS she had suffered with
continuously for the previous decade. The symptoms of CFS in this case and others include, “severe
fatigue, muscle and skin pain, sleep disturbance and major concentration problems,” (21) and seriously
reduce the quality of life of CFS sufferers. In this case, the patient was undergoing chemotherapy for
several weeks when she unexpectedly regained her ability to take long walks and experienced
improvements in her cognitive function. This recovery lasted for three to four months before symptoms
returned. Not a known side effect of cancer treatment, for Fluge and Mella this increase in energy and
overall function represented a direct (and unpredicted) connection between that particular treatment
and the patient’s CFS symptoms.
To confirm that connection, Fluge and Mella gave this patient and two others also diagnosed
with CFS a drug with the same action as the cancer treatment—rituximab. Rituximab is an antibody
developed by combining mouse and human DNA that binds to a protein on B-cells, the type of white
blood cell affected by Hodgkin’s disease. This drug wipes out B-cells, both cancerous and normal ones,
and thereby triggers a regenerative process that creates new, normal B-cells to replace them (22). When
they took rituximab, all three participants experienced transient relief from their CFS symptoms, to a
degree not experienced since the onset of CFS years before (21). Reasoning that it was the sudden
decrease in B-cell population that led to the participants’ temporary recovery, Fluge and Mella designed
a randomized controlled trial (RCT) with placebo to test the replicability of the results. Thus was a new
research direction derived from an unexpected result observed during one patient’s clinical treatment.
The rituximab research has received a lot of attention, both within and beyond the borders of
Norway. A considerable amount of funding from several sources was directed toward the research
group in Bergen to continue their research with rituximab. There was extensive international media
coverage of the results of the RCT published in 2011, which described symptomatic relief for two thirds
of the enrolled CFS participants (23,24). Headlines included, “Norwegian research breakthrough can
solve CFS-mystery” (25), and “Rituximab proven to treat ME/CFS” (26).
Further claims were made in headlines internationally, following the suggestion by Fluge and
Mella that the therapeutic effects of rituximab may be evidence for the pathogenesis—or cause—of
CFS. In their report on the preliminary case series, Fluge and Mella make a connection between their
results and theories that CFS is caused by immune deregulation (21); in the 2011 publication reporting
the results of the RCT, the authors speculate their observations “indicate that CFS may be an
autoimmune disease…targeting specific parts of the nervous system” (23). These suggestions as to what
mechanism may be behind the symptom-relief being observed were taken up by the media, inspiring
headlines with causal claims such as the following: “Immune system defect may cause ME” (27),
“Chronic fatigue syndrome: Study supports autoimmune disease theory” (28), and “Chronic fatigue
syndrome—A treatable autoimmune disease” (29).
Causal claims about a mechanism that could explain the unexpected finding by the Bergen team
underwrote both Fluge and Mella’s conviction that the results could be repeated in other CFS patients,
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and the optimism expressed by the media. This has in turn been picked up by patients who suffer from
CFS as a sign that both an explanation for their condition and a treatment to relieve them of its
symptoms are indicated by the outcomes of the Norwegian rituximab trials (30–32).
The value of causal thinking
In medical research, publications of unexpected findings take the form of case reports. Case
reports can guide the formation of hypotheses for clinical research (33). Rachel Ankeny argues the
epistemic role of a case report is to bring certain facts together (34). The relevance of and relationship
between facts presented within a case report are established through a process of reasoning about the
case as well as gathering further evidence. Descriptions of unexpected findings in case reports, then, can
be seen as “promissory notes about possible hypotheses” (34). As well, as Kevin Dunbar observed when
studying the reasoning practices of working laboratory scientists, unexpected findings tend to inspire
causal reasoning (35). First, a local cause for the surprise result is sought and then, if a pattern
replicating that finding emerges, a hypothesis for the cause of the series of unexpected results is
considered. When it becomes clear, that is, that an unexpected result was not incidental, arising from an
error in methodology, nor coincidence, then its cause becomes theoretically important.
When an unexpected finding occurs in medicine, seeking the cause of that finding has both
epistemic and ethical value. Namely, a causal claim can justify further clinical research by grounding
predictions about generalizability. A single, unexpected result cannot by itself justify conducting further
clinical research that entails putting human participants at risk. As in laboratory science, first
methodological and incidental factors that could have caused the result must be ruled out. A claim that
the result can be replicated, or at least that there is good reason to believe a therapeutic result is
replicable, is also needed to justify human participants taking on any risks of clinical research. A claim
about a causal relationship—a relationship that holds for all members in a group of patients and
therefore for selected research participants, that is—would do that justificatory work.
Importantly, in the reports on the rituximab trials, it was the claim that both the unexpected
finding in the original patient and the relief of CFS symptoms in later research participants were the
result of CFS being caused by a disruption to the immune system that did much of this epistemic and
ethical work. In the 2009 case series report, the authors move from reasoning that the unexpected
symptom relief observed in the original patient was due to B-cell depletion, toward arguing for further
research to confirm the therapeutic relationship and to “yield clues to disclose the pathogenesis of CFS”
(21). They conclude that the case series result was significant because it “indicates that a main
mechanism of symptom development is touched by the drug manipulation” and therefore they
“anticipate that a subset of patients with CFS will benefit from anti-CD20 B-cell depletion therapy” (21).
The 2011 report on the consequent RCT clearly uses a claim about a causal mechanism for CFS
as justification for enrolling human participants in that trial: “observations [made in the case series]
suggest that B-cells play a significant role in the ongoing clinical features of CFS, and provide clues to
possible aetiological mechanisms. To pursue these clues, we performed [this RCT]” (23). As the trial was
not without risks—while rituximab has not caused any surprising additional effects in the participants in
these trials so far, it does suppress the immune system and is known to be a risky drug (22,36)—the
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claims used to justify enrolling participants in this research have ethical as well as epistemic
implications.
It can be argued that the authors of these reports, in using language such as ‘suggests’ and
‘hints’ are not actually claiming that a single causal factor is responsible for the observed effects, and
therefore are not using such a claim to justify further research. Rather, it is the media and other readers
who take these claims to be about CFS patients in general, and not the authors themselves. However,
the theoretical claim that this research may provide evidence for a causal mechanism for ‘CFS’
(categorically) is found in the abstract of each of the three reports released about this ongoing research
from the Bergen group (21,23,37). As well, the researchers have repeated this claim in interviews about
these trials (24,25). When we consider the impact that claims made in report abstracts are known to
have on interpretations of research results (38,39), it is not unfair to ask researchers to consider the
implications of making these suggestions when and where they do.
As well, the causal claim most clearly used for justifying and promoting the continuing clinical
research with human participants is the claim about ‘the cause of CFS’, extrapolated from the results of
ongoing research. In contrast, the hypothesis suggested by the unexpected finding in the first place, and
which that research can in fact prove or disprove, is the empirical question of whether rituximab will
relieve the symptoms of at least some people diagnosed with CFS. That is, the primary and secondary
endpoints of the phase II RCT were specifically to measure the therapeutic effects of rituximab
treatment on CFS symptoms (23). Either claim—that rituximab may be effective in treating others, or
that CFS is an autoimmune disease—may indeed justify the continuation of clinical research with human
participants, given the possible benefit to those participants. However, as I detail below, the move from
a claim about the probability of effectiveness to a claim about the mechanism behind that effect has
implications beyond this research programme that ought to be considered.
In sum, by prioritizing the mechanistic causal claim in their rhetoric, the researchers are allowing
for the conflation of two kinds of causal claims, a claim about a possible causal relationship between an
intervention and its effects, and a claim about the causal factor behind the affected symptoms. This is
problematic. For one, the hypothesis that CFS is an autoimmune disease cannot be demonstrated by the
RCT as conducted, and therefore the testing of that hypothesis cannot justify continuing that clinical
research with human participants. Further, there is a lack of evidence about the mechanisms behind
rituximab’s effectiveness in cases of CFS. So long as this is true, justification for conducting this and any
other RCT can only come from an empirical claim about observed effectiveness in past participants, and
not from a theoretical claim about the reasons why it would be effective in future participants.
The difference between empirical and theoretical claims in cases like this has broader
implications for the role that individual cases, in particular those in which unexpected observations are
made, can play as evidence. Empirical claims require replication to gain validity; theoretical, particularly
mechanistic claims, tend to be judged as valid separately from their observed frequency (40). Making
the move from empirical evidence to theory-based predictions too soon runs the risk of unfounded
assumptions being made about the generalizability of research results (41,42). For instance, while a
claim about the mechanisms involved in CFS may seem to ground criteria for diagnosis and standards of
care, the empirical claim supported by the research (that some patients may respond with symptom
relief to rituximab) may not. Further, isolating a causal relationship in the context of research may not
tell us how that relationship will work in complex circumstances (40,42,43). Finally, moving from having
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possible knowledge about a potential mechanism involved in CFS to making claims about ‘the cause of
CFS’ portrays a causal simplicity that could misdirect future research.
CFS and causal complexity
I will focus in this section on one particular problem with promoting the value of the rituximab
research primarily in terms of its contribution to theory about ‘the cause of CFS’. The reports on the
rituximab research note the fact that the treatment is likely only effective for a subgroup of patients
diagnosed with CFS. Further, and importantly, the authors suggest that the rituximab responders may
constitute a subgroup of CFS patients who have a specific variant of the syndrome, possibly due to a
genetic predisposition (23,37). This suggestion has both theoretical and practical implications, for the
field of CFS research and care in general, and specifically for the design of future research with
rituximab.
The identification of a subgroup will not come as a surprise to anyone familiar with the
complexities of CFS as a medical category. Over the last few decades, several sets of diagnostic criteria
have been established, revised, and contested (44–50). Consequently, different researchers use
different diagnostic criteria, creating a problem for the systematization and application of results
(20,44,51). Further, CFS is often grouped together with myalgic encephalomyelitis, and referred to by
the combined acronym CFS/ME. Some contest this grouping (31,49,52,53), and have called for further
empirical research to determine how best to break up the category (54). A recent report by the Institute
of Medicine has gone so far as to suggest an entirely new name for the syndrome, along with proposing
another new set of criteria (47).
The category is a site of conflict as well as complexity (55). Those who argue for the segregation
of some subgroups from others do so not only for the purposes of better defining the category, but also
in order to distinguish what they see to be patients who suffer from a biomedical disease from those
whose symptoms may be thought of as psychological (51). As I noted above, there is a tendency to
approach the category of CFS as either psychological or biological. One response to the apparent
complexity of the patients who are diagnosed with CFS is to divide the diagnostic category by identifying
subgroups, segregating them according to the distinct causes of their symptoms. Subgroups such as the
one indicated by the rituximab trials, however, suggest that patients diagnosed with CFS may be diverse
but not necessarily distinct. CFS, rather, may just be causally complex, and responders to rituximab may
not belong to a separate disease category defined by a single causal relationship, but rather represent a
subgroup of patients who meet a variety of psychological and biological criteria.
The response of a subgroup to rituximab also fails to demonstrate that CFS is best understood
through the lens of a single type of causal relationship, whether psychological or biological. Nor does it
show that biomedical instead of psychological treatments should be prioritized in research or care. A
recent follow-up study analyses the presence of antibodies in both CFS patients, including participants
from the Norwegian trials, and non-CFS-diagnosed controls, to better understand the nature of the
rituximab responder subgroup. The discussion notes that such antibodies may be induced by distress
from life events as well as from infections (56). The category of CFS may thus be causally complex, as the
rituximab results do not provide evidence that either psychological or biological causes should be
prioritized in research or care(11,18,19).
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Ethics provides an additional reason why identifying the subgroup of responders must be part of
future research design. Rituximab is a risky drug for patients to take, and it is an expensive drug to
administer, so it is important to determine which patients are most likely to benefit from it as an
intervention (22,36). Researchers ought to minimize the harms and maximize the possible benefits to
research participants, and therefore to select only those participants most likely to benefit from
rituximab for future clinical trials (57). While ongoing research seeks to address these concerns (58), the
trial that has received the most enthusiastic press—the phase II RCT whose results were published in
2011—did not.
Despite the speculations of researchers and media about the causal mechanism underlying the
results of the phase II RCT, the trial itself sought to answer questions about the replicability of empirical
results, not about the mechanisms that caused those results, per se. An RCT is designed to isolate a
particular correlation and to demonstrate the statistical probability of that relationship maintaining
among members of a selected population. More specifically, an RCT that tests the effectiveness of a
medication—in this case, the probability that rituximab will relieve a patient’s CFS symptoms—asks the
question, ‘does this work?’ and not, ‘why does this work?’ (40,59).1 In other words, while the hypothesis
in question may be about causation (does rituximab cause the relief of CFS symptoms), this is not the
same as a hypothesis about the mechanism behind that causal relationship (is CFS an autoimmune
disease).
The response to rituximab of a subgroup of CFS-diagnosed participants in the trials may say
something about the statistical probability of a CFS patient responding to rituximab. But, without
additional research, it does not give the reasons why some participants respond and others do not.
Therefore, it also says little if anything about the nature of the group of CFS patients as a whole.
Conflating the two kinds of hypotheses by suggesting that the rituximab trials provide knowledge about
‘the cause of CFS’—as the media has done, and as the researchers have speculated—has implications
that can be harmful to both patients and researchers.
The possible harms of promoting a projected value
The field of CFS is an area of medicine mired in uncertainty. As a result, it has been particularly
susceptible to controversy. The specific problems that arise in this area draw attention to the potential
for the projected value of an unexpected finding in medicine—when it is seen as a definitive end rather
than as a guide to the process of research—to inappropriately narrow the scope of research, possibly
even to misdirect research and funding altogether, and to harm patients.
1 Robyn Bluhm points out that RCTs are designed based on assumptions about mechanisms—when selecting participants, for instance, the idea is to isolate a causal mechanism by controlling for factors that are predicted to interfere with that mechanism (41). Thus, the claims of the researchers in this case are justificatory insofar as they justify, for example, selecting participants with CFS for the trials. However, as the research itself cannot demonstrate the existence of those mechanisms themselves, but only the effectiveness of the drug on the selected participants, the work done to justify designing the trial as such does not transfer directly as a justification for continuing the clinical research, and I argue it does not act as the hypothesis being pursued by the research despite its role in guiding design.
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First, some fear the theoretical claim to an explanation and treatment for CFS is being used to
justify the prioritization of this area of research over other equally valuable research directions,
inappropriately narrowing the scope of research in this area of medicine (18,19). In contemporary
medical research, where resources are limited, decisions about which research directions to fund can
have considerable impact on patient care as well as on the future of research in a particular area. In the
case of CFS, the observation of a patient’s unexpected recovery has the potential to contribute to a
wider scope of future research than providing a singular causal explanation for CFS. For instance, it may
provide one among many options for treatment, it may elucidate one among many causal mechanisms
explaining the origin and pathology of CFS, or it may give rise to several new research directions both
within and beyond the field of CFS. From the perspective of philosophy of science, at least, it seems
irresponsible to direct all or most research toward a single hypothesis based on an unexpected
observation. Instead, the process of research that follows up the observation ought to serve a broader
purpose.
Second, the misdirection of research can occur in cases of unexpected findings because the
value of single cases or small case series are underdetermined. Ankeny draws on the example of the
original case series that led to the recognition of HIV as a distinct diagnosis (34). In the original case
reports, the sexual orientation of patients was emphasized, thought to be an important part of the
diagnostic category. As a result, there was a failure to diagnose women with HIV at first, because it was
thought that only gay men would contract the virus. This example illustrates the flexibility of case
reports as sources of evidence: although the original case reports contained information that would
later be dismissed as unimportant, and failed to report other details that would later become important,
their evidentiary role holds, conveying the idea that several patients were inflicted with a single disease.
The projected value of an unexpected finding may not be the same as its ultimate value, but this does
not diminish the importance of exploring that projected value through further research.
Finally, when this theoretical claim is emphasized as the aim of ongoing empirical research,
consequent assumptions about the generalizability of research results can harm patients. Institutions
often limit treatment options for patients who may require diverse approaches (60). Indirectly, harms
can take the form of reducing or dismissing patient experiences (17,61). Assumptions are made that
because a treatment works for many patients in what is known to be a broad and diverse category, it
will work for all, despite claims from patients themselves to the contrary. This has happened with regard
to the positive results that CBT and GET have produced in groups of patients diagnosed with CFS, when
they have been used as justification for reducing the treatment options available to CFS patients,
possibly even causing direct harms to some (49,62,63).
Patients can also be harmed when led to seek unproven treatments for their symptoms.
Concerns have been raised internationally that CFS patients have sought and been given rituximab
treatments off-label and outside of the context of research (32). In Norway, national support for the
Bergen group has been considerable, not only in the form of funding but also from patients who are
optimistic for their own future and the media who have lauded the findings as a local ‘breakthrough’
discovery (25,31,64). While there is indeed reason for optimism, care must be taken not to repeat the
mistakes made the last time a major breakthrough was announced, and then denounced, in the field of
CFS research—in 2009, when a viral cause for CFS was claimed as confirmed by a private lab in the
United States. The public took this as a sign that both legitimacy in a medical diagnosis and care and a
cure were on their way, with some patients even beginning to take anti-retroviral drugs in hopes of
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recovery (65,66). The lab’s results could not be replicated, however: the published results were
retracted and disappointment prevailed. Governments have been slow to reverse policies formed on the
basis of what has been shown to be faulty evidence (67). Announcements of a medical breakthrough can
have practical implications for researchers, patients, and health policy that must be carefully considered.
Concluding remarks
I have presented here a case of an unexpected finding that gave rise to a new direction in
medical research as a cautionary tale. There are important theoretical and practical risks involved in
using a mono-causal hypothesis to justify clinical research with human participants and to direct that
field of research. There is nothing wrong with hypothesizing that an unexpected finding may indicate a
causal mechanism, or that the finding may be replicated in others. There is, however, a tendency to
promote such a causal mechanism as ‘the cause’, which has broad implications for a diagnostic category
and an area of medical research and care—such as we have seen in the ways the media and public have
taken up the theoretical speculations of the researchers involved in the rituximab trials. This tendency,
in turn, can inappropriately narrow the scope of a field of research, to the point that research may be
misdirected and patients may be harmed. Particularly in an area of great uncertainty and probable
causal complexity, such as CFS, potential value remains underdetermined.
Rather than focus on the projected, high value of a potentially serendipitous discovery, then, the
process of research following up on an unexpected finding itself should be mined for potential value.
Proposals for a research direction derived from an unexpected observation in clinical research
must be careful about the claims that such early observations can support. ‘Serendipitous’ discoveries in
medicine do not arise in leaps and bounds; they come about as the result of careful epistemic work and
while abiding by ethical principles (9). The origins of such discoveries may be due to chance, but it is a
responsible research process that transforms an unexpected observation into medical progress.
Transparency about the lengthy and uncertain process involved in moving from a single case to
establishing an effective therapeutic intervention or for determining which causal mechanisms are
behind medical symptoms is needed. Promoting mono-causal claims on the basis of exciting, surprising
results may generate attention, funding and hope, but it hinders researchers, leads to errors in policy-
making, and harms patients.
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Acknowledgements
I would like to thank the participants at the workshop ‘N=1, Causal Reasoning and Evidence for Clinical
Practice’ for their feedback; Kirstin Borgerson, Stephen Mumford and Elena Rocca for comments on
earlier drafts; the detailed help of Rani Lill Anjum with the paper as a whole; the insightful comments of
two anonymous reviewers; and Vegard Bruun Wyller for directing me toward this case. Financial
support was provided by the CauseHealth project, NMBU.
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