The sense of agency (SoA) is a multifaceted construct, which can be defined as the ability to understand the causal relationships between our actions and sensory events. Obsessive-Compulsive Disorder (OCD) patients with checking compulsions often report a “lack of action completion” sensations, which has been conceptualized in the so-called “Not Just Right Experiences” construct. An intriguing explanation of this phenomenon comes from Belayachi and Van der Linden , 2010, w SoA), that is, the feeling to cause and to be in control of those actions (and their effects) that are coherent with our own intentions and goals , which can be defined as the “non-conceptual, automatic registration of whether I am the agent or not”  A function of SoA is the differentiation between self- and externally-generated actions and thoughts  matrix, a promising approach to create a new dimensional research framework for studying mental disorders. Indeed, being conceived as a transversal theoretical account, SoA could be impaired in other mental diseases beyond schizophrenia. Belayachi and Van der Linden , linking this impairment to a deficient internal motor prediction capacity, which may in turn explain the aforementioned OCD patients’ incapability in reaching a sense of action completion and satisfaction. Interestingly, patients’ explicit judgments of agency did not differ from healthy controls (HCs) ones, thus suggesting that automatic mechanisms were at play. Nonetheless, Gentsch et al.  showed aThe previous studies refer to a widely used theoretical framework to study SoA: the comparator model  from consecutive admission to the Department of Clinical Neurosciences at IRCCS San Raffaele Turro in Milan. OCD group was recruited among both outpatients and inpatients. Patients with psychotic spectrum disorders, history of brain injuries and/or of substance use disorder were not included in the sample. All patients who were admitted at the Department in that period and met the inclusion criteria took part to the study. None of the patients asked to exit the study, either before or during the experimental session, indicating that the experimental setting was well tolerated. Twenty-one healthy volunteers (HCs), without psychiatric lifetime diagnoses, were recruited from the general population  to serve as control group. The two groups were matched for both sex and age (±3 years). Senior psychiatrists made OCD diagnosis according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) and excluded mental retardation administering the WAIS-R  is commonly used to measure trait and state anxiety  is another common tool exploited to assess contingent anxiety, as it is immediately administered before and/or after a task , while the others are administered immediately after each condition . Subjects are required to mark with a bar line their level of anxiety on a continuous line which ranges from 0  to 100 i.e., “The higher level of anxiety you can imagine”; (3) Beck Depression Inventory—II (BDI-II) is a self-report questionnaire which aims to evaluate depressive symptoms severity in adult and adolescent patients  is a self-report questionnaire used to assess the different types of causal attribution people make in their everyday life  Sanavio, . Subject Sanavio,We used the same stimuli and tasks described in our previous work . The visual stimulus was made up of gray balls (diameter 2.6 deg) that entered the display sequentially from the bottom left corner of the screen. The balls moved linearly in random directions at constant velocity (5 deg/s), colliding with each other and with the display’s borders, changing their movement energy after each rebound. The number of balls decreased progressively passing from the first to the sixth trial: 30, 15, 10, 5, 2, 1. In the 7th trial, two stationary balls were displayed at 5 deg to the left and the right of the screen center. Each trial lasted 20 s, during which participants also heard through earphones a sequence of beeps, with various inter-beep timing (see below). Participants had to guess the cause of the beeps. At the end of each trial observers reported verbally their supposition about the possible cause of the beeps and rated their confidence . When participants answered “I do not know”, a Confidence Rating (CR) of 0 was assigned. The Discovery Task consisted of four conditions. In the Saccades condition the beeps were caused by observer’s saccades (one saccade—one beep). In this condition, an 8th trial was added, identical to the 7th trial, but preceded by a pre-recorded vocal hint “Pay attention to your eyes”. In the Inflating condition participants heard a beep whenever a new ball entered the screen. In the Hemifield condition, when the observer’s gaze pointed to the right hemifield a sequence of beeps was generated (at a constant rate of 4 Hz), while no beeps were generated when observers’ gaze was directed to the left hemifield. In the “Motion” condition the beeps were generated at a rate directly proportional to the instantaneous average velocity of the balls (range: 0.67–4.76 Hz). The four conditions were administered in the following order: “Inflating → Hemifield → Motion → Saccades”, that is, alternating the presentation of an external (Inflating and Motion conditions) and an internal (Hemifield and Saccades conditions) beeps’ cause. After each condition, the experimenter revealed the origin of the beeps, regardless of whether or not participants had already reported the true cause. In this way, all participants started the next condition with the same amount of information. The Discovery Task lasts about 30 min.Performance Index (PI)—Given the binary nature of participants’ responses , for each subject and for each condition, the PI was calculated as the ratio between the number of correct responses and the number of trials of the condition of interest. Under the assumption of a monotonic increase as a function of trial number, the PI increased the sooner the observer discovered the correct origin of the beeps;Confidence Ratings (CRs)—At the end of each trial, participants gave their rate of certainty about their guessing, which ranged from 1  to 5 . 0 was given by the experimenter every time participants were not able to give any answer;Attributional Style—The four experimental conditions implemented either an external beeps’ cause (Inflating and Motion) or an internal cause (Hemifield and Saccades). Thus, we decided to evaluate the frequency of “External”, “Internal” and “Doubt” responses in the two groups, whether correct or not. An “External” response was qualitatively defined as a “response that does not refer to the subject” , an “Internal” response was defined as a “response that refers to the subject”  and we evaluated as a “Doubt” response each trial in which the subject gave “I do not know” as a response. Subjects’ responses were classified by two independent judges and the performance was quantified by measuring the frequency of each type of response;Erroneous repetitions—We used the term erroneous repetitions to indicate a response that was already excluded as a possible response . As a consequence, a response could count as an erroneous repetition only starting from Condition 2 (Hemifield). Erroneous repetitions were exploited as a measure of cognitive inflexibility.The main variables of interest were:Discovery Task, but the visual stimulus comprised always 10 balls. In half of the trials, the beeps were caused by the observer’s saccades. In the other half of the trials, the beeps were presented with the same sequence produced by the observer during a preceding trial, randomly chosen among the N-1 previous trials. These two types of trials (contingent and non-contingent) were administered randomly. At the end of each trial observers had to report whether the beeps were generated by their eyes or not by pressing a key. A response confidence rating (range 1–5) was also given, again with a key-press. The Detection Task lasted about 20 min.This task was administered always after the Discovery Task, as subjects had to be naïve in the Discovery task. The Detection task consisted of 40 trials, each lasting 10 s. Visual and auditory stimuli were basically the same as in the Accuracy—The proportion of correct responses;Confidence Ratings (CR)—At the end of each trial, participants rated their level of certainty about their guessing, which ranged from 1  to 5 ;Number of “Hits”—Subjects’ responses were categorized as “Hits” when the beeps were caused by the subject’s current saccades, and his/her response was “Eyes”Number of “False Alarms”—Subjects’ responses were categorized as “False Alarms” when the beeps were not caused by the subjects’ current saccades, but his/her response was “Eyes”;Number of “Correct Rejections”—Subjects’ responses were categorized as “Correct Rejections” when the beeps were not caused by the subjects’ current saccades, and his/her response was “Other”;Number of “Misses”—Subjects’ responses were categorized as “Misses” when the beeps were caused by the subjects’ current saccades, but his/her response was “Other”;d-prime (d′)—It is a non-dimensional measure of the difference between the z-transformed values of “Hits” and “False alarms” rates  Fixation duration (s); (b) Saccadic amplitude (deg); (c) Saccadic frequency (number of saccades/s); (d) Time spent in smooth pursuit, e.g., when following with the gaze a ball Motion (s).The main outcomes of interest were:Two-dimensional eye movements were monocularly recorded through infrared oculometry . Before the beginning of each condition in the Discovery Task, and before the beginning of the Detection Task, a 5-points calibration was performed. Gaze contingency was obtained by computing in real time the eye instantaneous tangential velocity. A beep was triggered when eye velocity exceeded the velocity threshold  and, importantly, in the Saccades condition when considering the 8th trial preceded by the hint , while for HCs’ this held true only for the Saccades condition with the hint (p = 0.016), which indicates a special difficulty for patients in the Motion condition.Our first interest was to assess whether OCD patients’ performance in the four conditions was different from that of HCs. By analyzing the various experimental conditions, a significant difference between the two groups emerged in the Motion condition  and HCs .We also evaluated the effect of hint, which turned out to increase the performance in both OCD patients , even after the hint was given .As a next step, we sought to deepen our analyses by evaluating the type of responses given by subjects. Indeed, as the beep causes could theoretically be linked to an external or internal source, our focus was to investigate what we have called the “Attributional Style” of our subjects: are OCD more prone to attribute to themselves or to external causes the origin of the beeps than HC participants? In general, both groups tended to attribute to external causes the origin of the beeps, as shown by the clear predominance of external attributions in Conditions 1–3 Figure . ConditiFinally, we have analyzed the number of erroneous repetitions, as they imply a hurdle in modifying the beeps cause theory generated by the subjects. We found that 15 OCD subjects made at least one erroneous repetition, while no HCs made any. Specifically, we evaluated the erroneous repetitions rate in each condition by computing the total number of erroneous repetitions of the condition of interest and the total number of trials, which turned out to be between 10% and 15% Figure . Erroneor = −0.524; p = 0.015) and 4  in OCD group. Negative correlations between Age and PI were also found in Condition 4  in HC group. Education was not correlated with PIs or CRs in any group: thus, despite it was significantly different among the two groups, it was not associated with any performance variables. Neither Duration nor Onset of illness were correlated with PIs or CRs in the tested conditions.Concerning demographic data, we have found negative correlations between Age and PI in Condition 1 , STAI-I , STAI-II , PADUA F3  and LoC  in OCD group, while no association has been found between any clinical variables and PIs, or CRs in HC group.Regarding clinical data, we have found negative associations between Condition 1 PI and BDI , indicates that neither patients’ nor controls’ responses were influenced by tendencies to prefer a given causal attribution.At variance with the Discovery Task, in the Detection Task, subjects already knew that their eye movements could or could not be the cause of the beeps. Indeed, in the Detection Task we found a significant difference for detection accuracy, where OCD correct response rate was lower than in HC, but not for CR Table . MoreoveGiven the difference in d-prime, we wanted to understand if this dissimilarity was related to False Alarms and/or to Hits responses. We found that only False Alarms significantly differed between the two groups: indeed, OCD subjects made more False Alarms responses than HCs Table . Moreovet = −2.794, gl = 37.26, p = 0.008), and Correct Rejections  between OCDs and HCs, while no differences were found for False Alarms and Misses CRs . These differences, however, were rather small. However, in false alarm trials, saccadic amplitude (which could in principle affect contingency detection), the difference between patients and controls was about 20% .Concerning demographic data, no associations were found in any of the two groups.r = −0.486; p = 0.035) and Total  in OCD group. We have also found negative associations between Accuracy and BDI-II , STAI-II  and LoC , and between CRs and BDI-II , STAI-II  and LoC . HC group did not show any significant correlation.Regarding clinical data, we have found negative correlations between CRs and both DY-BOCS Insight (The main interest of our explorative study was to investigate the relationship between the SoA and a specific subtype of obsessive-compulsive patients (OCDs): the checkers. To this end, we have exploited a recently developed experimental paradigm, which assessed a particular form of agency, namely, “gaze-agency”, thus allowing us to assess not only manifest alterations of agency sensitivity (Detection Task), but also more subtle signs of agency changes, such as a different attitude to explore the solution space in causal attribution  conditions. As far as the Saccades condition is concerned , it would seem that, compared to HCs, OCDs have difficulty to orient attention towards themselves and rather attribute externally the cause of the beeps, but we cannot tell whether this is more a matter of cognitive (in)flexibility  or of a tendency of patients to neglect themselves as agents (here a poor spontaneous ocular self-monitoring before the hint). On the one hand, the fact that in both HCs and OCDs the hint produced a similar and statistically significant PI increase, together with the results of the Detection experiment (see below), suggest that self-monitoring is at least moderately impaired in these patients. On the other hand, the fact that OCD—but not HC—perseverated in reporting a wrong cause of the beeps even when it was clearly wrong, together with their poor performance in the Motion condition, suggest that cognitive inflexibility is a general tract of these patients, at least with difficult tasks. In short, our results suggest that OCDs have difficulties with causal attribution, probably due to both cognitive inflexibility and less functional gaze agency.The Discovery Task revealed a difficulty of causal attribution in OCD patients. Indeed, we found a tendency to a worse performance in patients—that is, a difficulty in finding the true cause of the beeps, as assessed through the objective PI—in Motion and Saccades In the Detection Task, the main result was a lower accuracy and a smaller d′ in OCD, with no response Bias, suggesting also a lower gaze agency. Indeed, the structure of the Detection Task rules out explanations based on task difficulty. In general, results in HCs were in line with our previous findings . In Condition 3, discovering the beeps cause was also rather difficult, because it implied more abstract reasoning capacity, as velocity is the mathematical combination of two variables: space and time. In this specific condition, subjects were required to integrate both the visual and the acoustic signals in a complex way. Indeed, the beeps frequency was not the same for all the trials, as it depended on the global bubbles velocity: it decreased over trials until trial 7 in which two bubbles on the screen were still. Interestingly, most of OCD patients’ responses were focused only on one of these two variables: someone reported movement of the bubbles , other reported the presence of a standardized frequency  as the cause of the beeps. Conversely, HC subjects seemed more capable in using both types of cue in order to find the correct solution, even though their PI did not exceed the value of 0.5: they needed nearly half of the trials in order to discover the real cause of the beeps. The worse performance of OCD patients could be therefore linked to cognitive inflexibility. However, OCD patients and HCs’ CRs did not differ and were both lower than 3, indicating a general uncertainty in giving the responses. Lastly, Condition 4 was the principal condition, as it measured subjects’ capability of understanding that their eye movements were the direct cause of the beeps. To do this, observers must first become aware of their own eye movements, which is not obvious  showed a ceiling effect for both groups. Indeed, this condition seems to be the easiest one to discover, as OCD patients and HCs PIs did not significantly differ and were both nearly maximal. Condition 1 was fairly simple in its structure: every single bubble induced a single beep only when it appeared on the screen, hence beeps disappeared when all bubbles were on the screen. The idea that this condition was quite simple was corroborated by the CRs given by the subjects: indeed, they were nearly 4.5 (the range being 0–5) for both groups and were significantly higher than the other sessions’ CRs. Instead, Condition 2 (Hemifield) was a more puzzling condition, not only because it was the first condition in which the cause of the beeps was internal, but also because it had a specific restriction: the beeps were generated only when subjects moved their eyes in the right half of the screen. In fact, it seemed to be the most difficult condition among all, as OCD patients and HCs PIs did not significantly differ and were both nearly 0 . It should also be highlighted that in this condition OCD patients made the higher number of erroneous repetitions (Action Identification Theory (AIT). Indeed, Belayachi and Van der Linden exploited Vallacher and Wegner theory suggesting that OCD patients with checking compulsions can be viewed as low-level agents, who are more focused on the procedural aspect of an action and on external cues to represent their internal model of actions and choices (Belayachi and Van der Linden, Our findings are also supported by clinical evidence: indeed, OCD patients show difficulties in shifting between mental processes and adaptive behavioral responses (Gruner et al., a priori beliefs of these subjects.For what concern the agency issue the Detection Task aim was to explicitly address gaze agency, since subjects already knew that they could or could not be the cause of the beeps. We found that OCD were less accurate than HCs, since they tended to more frequently attribute to themselves the origin of the beeps. Indeed, their false alarm rate was significantly higher than in HCs nearly in a quarter of the computer-generated trials OCD patients reported that their eyes have caused the beeps and, as a consequence, their correct rejection rate was lower than HCs’ one. Neither the miss rate, nor the hit rate did significantly differ between the two groups. To date, only Gentsch et al.  have expConcerning the ocular behavior of the subjects, it should be considered that a vast body of literature had already examined eye movements, suggesting possible alterations in OCD patients, although results are highly controversial (Clementz et al., per se may interfere with agency-based judgments. Given the importance of testing an ecological scenario in which subjects are required to create their own causal hypotheses relying only on task contingencies, this is a cogent issue.We operationalized agency through the concept of “gaze agency”, which is a completely new construct, never tested in a clinical population. Due to its novelty, the present results should be considered as a first step towards a full appraisal of agency troubles in psychiatric populations. One aspect that will deserve further scrutiny in the future is to include in the protocol a measure of difficulty and cognitive load in the Discovery Task, as task difficulty CANTABeclipse™ software, which evaluates rule acquisition abilities taking into account set-shifting as an index of cognitive flexibility.Another issue that deserves further investigation is relating gaze agency performance to causal learning abilities in OCD patients, within the construct of cognitive flexibility. To this aim, we are implementing our investigation flanking Discovery Task with the Intra/Extradimensional Set Shift (IED; Owen et al., Crucial for interpreting OCDs’ performances in terms of dysfunctional neural mechanisms will be to take into account the pharmacological treatment, as a number of drugs could have played a role, such as antipsychotic, benzodiazepine and SSRI (Reilly et al., Finally, this approach based on gaze agency could be fruitfully applied also to other OCD subtypes, such as washers (Bloch et al., All the authors met the authorship criteria. MG and RMM specifically contributed to data collection, data analysis, manuscript writing and editing. CS and RGG specifically contributed to experimental design and manuscript writing. SAC specifically contributed to manuscript writing. MCC specifically contributed to clinical diagnosis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RB and handling Editor declared their shared affiliation.


This approach has two key differences from existing approaches to FDR analysis. First, it assumes that the distribution of the actual (unobserved) effects is unimodal, with a mode at 0. This “unimodal assumption” (UA), although natural in many contexts, is not usually incorporated into standard FDR analysis, and we demonstrate how incorporating it brings many benefits. Specifically, the UA facilitates efficient and robust computation—estimating the unimodal distribution involves solving a simple convex optimization problem—and enables more accurate inferences provided that it holds. Second, the method takes as its input two numbers for each test (an effect size estimate and corresponding standard error), rather than the one number usually used ( Since its introduction in in Here we consider an Empirical Bayes (EB) approach to FDR. This idea is, of course, far from new: indeed, the notion that EB approaches could be helpful in handling multiple comparisons predates introduction of the FDR e.g. . More reassume that the distribution of effects is unimodal. We provide a simple, fast, and stable computer implementation for performing EB inference under this assumption, and illustrate how it can improve inferences when the unimodal assumption (UA) is correct. The second idea is to use two numbers—effect sizes and their standard errors—rather than just one—So what is the “New Deal” here? We introduce two simple ideas that are new (at least compared with existing widely used FDR pipelines) and can substantially affect inference. The first idea is to lfsr), which is analogous to the “local false discovery rate” (lfdr)  , but whiAlthough we focus here on FDR applications, the idea of performing EB inference using a flexible unimodal prior distribution is useful more generally. For example, the methods described here can be applied directly to perform shrinkage estimation for wavelet denoising , an ideaadaptive shrinkage, or ash, to emphasize its key points: using a unimodal prior naturally results in shrinkage estimation, and the shrinkage is adaptive to both the amount of signal in the data and the measurement precision of each observation. We provide implementations in an R package, ashr, available at http://github.com/stephens999/ashr. Code and instructions for reproducing analyses and figures in this paper are at https://github.com/stephenslab/ash.We refer to our EB method as Biostatistics online.Here we describe the simplest version of the method, before briefly discussing embellishments we have also implemented. Implementation details are given in Supplementary Information, see Let Assume that the available data are estimates zero-mean normal distributions:fixed positive numbers spanning a range from very small to very big . Correlations among tests certainly arise in practice, either due to genuine correlations or due to unmeasured confounders, and their potential impact on estimated FDRs is important to consider whatever analysis methods are used  im im2.4) i1. Estimate the hyper-parameters given by , yieldin2. Compute quantities of interest from the conditional distributions The usual EB approach to fitting this model would involve two steps:http:://stephenslab.github.io/ash/analysis/IPvsEM.html.) And the conditional distributions Both steps are straightforward. Step 1 is a convex optimization problem, and can be solved quickly and reliably using interior point methods . lfdIn words, The d, Tukey , page 32... the more meaningful question: “is the evidence strong enough to support a belief that the observed difference has the correct sign?”Along the same lines, Gelman and co-workers  and with the widely used methods from qvalue), which although not formally an EB approach, shares some elements in common.Among previous methods that explicitly consider FDR, our work seems naturally compared with the EB methods of of locfdr and mixfdr), or a qvalue)—for each effect, we instead work with two numbers . It is very likely that the distribution of detectable non-zero effects will be multimodal, with one mode for detectable positive effects and another for detectable negative effects, and the UA does not contradict this.Second, our UA that the effects are unimodal about zero, is an assumption not made by existing methods, and one that we argue to be both plausible and beneficial in many contexts. Although the UA will not hold in all settings, it will often be reasonable, especially in FDR-related contexts that focus on rejecting the null hypotheses In further support of the UA, note that large-scale regression methods almost always make the UA for the regression coefficients, which are analogous to the “effects” we estimate here. Common choices of unimodal distribution for regression coefficients include the spike and slab, Laplace, e priors .Besides its plausibility, the UA has two important practical benefits: it facilitates more accurate estimates of FDR-related quantities, and it yields simple algorithms that are both computationally and statistically stable (see Results).There is also a very considerable literature that does not directly focus on the FDR problem, but which involves similar ideas and methods. Among these, a paper about deconvolution  is most More generally, the related literature is too large to review comprehensively, but relevant key-words include “empirical Bayes,” “shrinkage,” “deconvolution,” “semi-parametric,” “shape-constrained,” and “heteroskedastic.” Some pointers to recent papers in which other relevant citations can be found include. ash with existing FDR-based methods implemented in the R packages qvalue (v2.1.1!), locfdr (v1.1-8!), and mixfdr . In all our simulations we assume that the test statistics follow the expected theoretical distribution under the null, and we indicate this to locfdr using nulltype=0 and to mixfdr using theonull=TRUE. Otherwise all packages were used with default options.We compare results of ash makes the UA and other methods do not.Here we consider the effects of making the UA. To isolate these effects we consider the simplest case, where every observation has the same standard error, 1. The UA can produce quite different results from existing methods.2. The UA can yield conservative estimates of the proportion of true nulls, 3. The UA yields a procedure that is numerically and statistically stable, and is somewhat robust to deviations from unimodality.To briefly summarize the results in this section:qvalue, locfdr, mixfdr, and ash to decompose the ash and existing methods: the existing methods have a “hole” in the alternative ash, due to the UA, has a mode near 0. . To understand why the alternative distribution of locfdr and qvalue has a hole at zero, note that neither of these methods explicitly models the alternative distribution: instead they simply subtract a null distribution . However, there is “no free lunch”: if in fact some effects are exactly zero then the analysis with no point mass will tend to be anti-conservative, underestimating Biostatistics online). We conclude that if ensuring a “conservative” analysis is important then one should allow for a point mass at 0.Given that we argue for using An important advantage of our EB approach based on modelling the effects The ability of the EB approach to provide valid “post-selection” interval estimates is extremely attractive in principle. But its usefulness in practice depends on reliably estimating the distribution ash (under the UA) with the non-parametric maximum likelihood estimate (NPMLE) for REBayes::GLmix function .Motivated by this, we generalize the prior  to(3.2)} yields . Settingash with ash can produce less conservative estimates of ash models the The case ment} in  is of spash estimates of both ash can be run (with ash on As an aside, we note that with In practice, appropriate choice of We have presented an Empirical Bayes approach to large-scale multiple testing that emphasizes two ideas. First, we emphasize the potential benefits of using two numbers (opportunity: specifically, an opportunity to learn about the prior distributions, and other modelling assumptions, to improve inference and make informed decisions about significance (see also not the number of tests, but the results of the tests. Indeed, the FDR at a given fixed threshold does not depend on the number of tests: as the number of tests increases, both the true positives and false positives increase linearly, and the FDR remains the same. [If this intuitive argument does not convince, see does depend on the overall distribution of effects, and particularly on Multiple testing is often referred to as a “problem” or a “burden.” In our opinion, EB approaches turn this idea on its head, treating multiple testing as an see also . This viTwo important practical issues that we have not addressed here are correlations among tests, and the potential for deviations from the theoretical null distributions of test statistics. These two issues are connected: specifically, unmeasured confounding factors can cause both correlations among tests and deviations from the theoretical null . And altAnother important practical issue is the challenge of small sample sizes. For example, in genomics applications researchers sometimes attempt to identify differences between two conditions based on only a handful of samples in each. In such settings the normal likelihood approximation  will be  methods  to “modeqvalue can be applied to any set of Our approach involves compromises between flexibility, generality, and simplicity on the one hand, and statistical efficiency and principle on the other. For example, in using an EB approach that uses a point estimate for Supplementary DataClick here for additional data file.


Despite the relative abundance of frameworks and models to guide implementation science, the explicit use of theory is limited. Bringing together two seemingly disparate fields of research, this article asks, what can organisational theory offer implementation science? This is examined by applying a theoretical lens that incorporates agency, institutional, and situated change theories to understand the implementation of healthcare knowledge into practice.Interviews were conducted with 20 general practitioners (GPs) before and after using a resource to facilitate evidence-based sexual healthcare. Research material was analysed using two approaches – researcher-driven thematic coding and lexical analysis, which was relatively less researcher-driven.The theoretical lens elucidated the complex pathways of knowledge translation. More specifically, agency theory revealed tensions between the GP as agent and their organisations and patients as principals. Institutional theory highlighted the importance of GP-embeddedness within their chosen specialty of general practice; their medical profession; and the practice in which they worked. Situated change theory exposed the role of localised adaptations over time – a metamorphosis.This study has theoretical, methodological, and practical implications. Theoretically, it is the first to examine knowledge translation using a lens premised on agency, institutional, and situated change theories. Methodologically, the study highlights the complementary value of researcher-driven and researcher-guided analysis of qualitative research material. Practically, this study signposts opportunities to facilitate knowledge translation – more specifically, it suggests that efforts to shape clinician practices should accommodate the interrelated influence of the agent and the institution, and recognise that change can be ever so subtle.The online version of this article (10.1186/s12913-018-3121-y) contains supplementary material, which is available to authorized users. The translation of knowledge from the research-bench to the patient-bedside is pivotal to public health , 2. Yet This article asks, what can agency, institutional, and situated change theories offer knowledge translation research? This is considered by examining clinician practices when translating evidence-based practices into patient care. Although there are myriad organisational theories that are worthy of scholarship in the context of knowledge translation , 11, theThis article begins with an overview of knowledge translation. It then describes agency, institutional, and situated change theories to examine and understand it. To clarify the potential value of these theories – as per the overarching focus of this article – they were used to examine the implementation of healthcare knowledge into practice. More specifically: reflecting agency theory, the study examined how clinicians negotiate their relationships with their organisation and their patients (to whom they are accountable) to translate knowledge into practice; reflecting institutional theory, the study examined how clinicians adapt to the expectations and demands of their profession and the practice in which they worked; and reflecting the situated change theory, the study considered how clinicians exercise practice change. The article concludes with a discussion of the theoretical contribution of this study and the transferability of lessons garnered.translation being the operative word) is influenced by: clinician expertise; patient  preferences; available resources; and the context of care – this might include a consideration of the team the clinician collaborates with (within and beyond the organisation), leadership style(s), organisational culture, the political climate, and local epidemiology, among others  generic recommendation… against the particularities of a case in the here-and-now’ Guided by these theories, this article draws on their explanatory power to clarify and explain how general practitioners (GPs) translate clinical knowledge into practice. Using sexual healthcare as the focus of the study, this was achieved through a longitudinal study that involved two analytical methods to: (1) identify sources of information on evidence-based sexual healthcare among GPs; and (2) examine how this knowledge was translated into practice. To optimise rigour, the study involved: the collection of qualitative and quantitative data; three analysts (each with a distinct perspective); and two analytical methods – namely, researcher-driven coding and lexical analysis, which is relatively less researcher-driven. The study was also longitudinal as it involved data collection at two time-points. Before presenting this research, the following section provides a brief overview of the tri-focal lens used to examine knowledge translation processes and a rationale for its use.The theoretical lens adopted in this research is comprised of the agency, institutional, and situated change theories. Each is described and critiqued as follows .Professional identity is an awareness of the role and functions that one performs or is expected to perform in a social context as a member of a particular profession. It essentially concerns the self and the self in relation with others – be they individuals or organisations . ProfessHowever, agency theory is not without criticism. Its capacity to theorise performance has been questioned . It is fInstitutional theory awards greater primacy to the institution – its rules, requirements, customs, and conventions; that is, its ‘rules of thumb’ Despite these seeming benefits, an organisation’s ‘rules of thumb’ can also represent a constraint. In the absence of a systemic overhaul, change can be difficult to introduce and sustain . IndividFollowing the institutional turn in organisational research, reinforcing that institutions are worthy of scholarship , there hTo redress this imbalance, there is a need to consider institutional stories  – that iAs its name suggests, the situated change theory suggests that change is situated in an evolving context, in which individuals adapt or metamorphosise accordingly. Given its strong links to the environment, change is gradual and meaningful, rather than planned and deliberate. Change involves subtle deviations from the paths most travelled and most controlled to pursue a flexible and self-organised path . And onlGiven significant change within many national health systems – including an ageing population, the rise of chronic and preventable diseases, technological developments that enable medical breakthroughs, and the rise of healthcare costs  – the siIn addition to representing ‘adjuvant’ and ‘necessary’ theories to further knowledge translation research ,Despite their complementarity and relevance to knowledge translation research, the use of the agency, institutional, and situated change theories in this study is not intended to suggest the irrelevance or insignificance of other theories (or frameworks) – organisational or otherwise. Indeed, although beyond the scope of this study, the relevance of theories that direct scholarship to the antecedents that trigger innovation, the processes through which innovation is introduced, and/or the outcomes associated with innovation, have been acknowledged – consider for instance, the diffusion of innovation theory . Also reFollowing clearance from the relevant university ethics body, GPs affiliated with at least one Division of General Practice in NSW who were practicing within this Australian state were invited to contribute to this study. Divisions were professional bodies that supported GP-members through the provision of training, resources, and opportunities to collaborate with other health professionals . Particineeds and the delivery of primary healthcare indicates that sexual health is an appropriate focus to examine the translation of medical knowledge into practice. Second, the primary care sector in many Western nations is experiencing significant reform, the aim of which is to shift the focus from hospital care to primary care  meetings and sometimes the… issues [discussed]… are probably very compact. I think that’s probably been the most useful.we could do a lot better at having regular clinical meetings… we’ve got about six doctors [here]… and there isn’t a day goes by when we’re all here at once.Within Fig. [The] quality cycle involves a clinical audit… It involves an audit at the beginning, and then an audit to see if the changes everybody agreed on have… been implemented… We do it, but we could do it better…We haven’t incorporated it that well enough into the culture of the practice, so a few people do that, but it’s not generalised.Figure my supervisor’s got a lot of information… I can just call him … he’s my main resource… he’s got quite an evidence-based mind, so I feel comfortable asking him what he thinks about something because often it’s not just his opinion; he would have read a lot and done a lot of research on the particular topic… if you notice over… time that [a doctor]… always prescribe[s] an antibiotic for upper respiratory tract infections, or they always give a steroid for itchy skin… you kind of go, ‘Well, obviously you’re just doing that because you don’t want to think about it’. So, I’ve just stopped asking those kinds of people.The aforesaid excerpt helps to clarify this penchant for familiar resources that lie beyond the immediate organisational domain – not only why particular resources were used, but how their value came to be recognised. As the excerpt suggests, some GPs thoughtfully observed whether their colleagues dutifully complied with what their profession or their organisation expected, and how they deviated from these expectations to deliver what they understood to be evidence-based care.Figure I don’t use guidelines as a backup tool; I use research as a backup tool… guidelines come from somewhere, and unless you know exactly where they come from – it’s a summary… When someone asks you for proof, I don’t want to use a tool as proof.Figure I don’t pretend… that I’m an expert… but I certainly am aware of, especially in young people, the potential problems.here, it’s pretty much suburbia; it’s not like in Kings Cross [a city suburb]… we are aware of the STDs [sexually transmitted diseases] among certain age groups… So we just raise the index of suspicion and screen them if it’s possible.Conversely, those who graduated before 1982 are connected with discourse on being ‘aware’. Cognisant of the potential fragility of the patient relationship, they were conversant with how to broach, discuss, and deliver sexual healthcare. Embedded within their profession, some were unable to precisely articulate how they developed these skills – yet they recognised the ways in which context, including the patients they consulted, shaped what they did and how they did it:Together, Figs. it’s very important that we have access to clear and up-to-date information on things like chlamydia, gonorrhoea, hepatitis, because it’s all so daunting for the patient and they’ve just got a horrible sinking feeling.to have things online can be very helpful in that sense, because at least you can do ongoing education.Within Fig. The thematic and lexical analyses reveal the relevance of institutional theory by highlighting the ways in which embeddedness within an organisation and a profession can shape clinical practices. Although the thematic analysis largely suggests the GPs were somewhat disconnected from institutional life, it also revealed the value of institutional savviness. Extending this finding, the lexical analysis illustrated how experience can be both an asset and a limitation when attempting to engage with, and keep abreast of evidence-based practices.The situated change theory suggests that change is emergent and evolves over time. Furthermore, subtle change is no less significant than large-scale, deliberate, orchestrated change .me and a couple other of my colleagues from a different practice… are in a study group and we look up guidelines for each sexual health problem… and then we’d go through that and then I’d base my practice largely on that.Following the thematic analysis, this was demonstrated by several GPs, particularly those who had a personal interest in sexual healthcare. While some spoke of adapting clinical guidelines to their clientele, others participated in self-initiated study groups to review and debate sexual healthcare resources:I used to photograph myself after each consultation to see how red I’d gone to… sort of mark how red I was, because I just felt very uncomfortable… now I don’t blush at all… I’m still not fully, completely comfortable, but I’m much better than I was.Similarly, a young female GP spoke of availing herself to information from an array of sources. In addition to clinical guidelines and professional development workshops, she consulted ‘as many people as possible’. Furthermore, she reflected on these discussions and identified feasible strategies to improve her own practices. For instance, inspired by a ‘long and… open’ discussion with colleagues, she recognised some of the awkwardness she experienced when consulting mature-age male patients about sexual health; this was the impetus for personal change. She endeavoured to better understand her practices, harness opportunities to deliver sexual healthcare to this cohort, and gauge improvement:I did have a look at [the STI Testing Tool]… and probably I was a little bit more aware for the first little while, but I think I’ve slipped back into my old habits, to be honest.This reliance on familiar practices is supported by GP responses to the clinical vignettes they were presented with on sexual healthcare. Although most appropriately indicated they would screen the patient for chlamydia (90%) and the Hepatitis B virus (65%), many also inappropriately noted they would screen for gonorrhoea (65%) and HIV (70%). The suggested use of these unnecessary tests was largely consistent across both stages of data collection. An interpretation here is that change does not occur instantly, but rather is characterised by a series of forwards and backwards mini-steps that require time to fully emerge, if at all.Although multiple sources of information helped this GP to transform her practice, others spoke of information-overload. Some grew indifferent towards the resources they received from the government, not-for-profit, or corporate sectors; this was because the resources needed time and concentration – assets that were largely limited. Such indifference might suggest a retreat to well-trodden cognitive paths:It’s just become a lot more in journalism and the pathology department newsletters.A thematic analysis of the research material suggests that limited responsiveness might be curbed using novel channels to communicate information, like public health campaigns and sexual health training. Some GPs indicated greater interest in sexual healthcare due to broad initiatives to promote sexual health:we had a… series of clinics that you could self-place in sexual health clinics, just sitting in and sometimes they’d let us consult… sitting in with the sexual health registrars and… specialists and… learning from them.These initiatives helped to ensure that sexual healthcare remained on the GP-radar. Similarly, sexual health training enabled the GPs to delve deeper into relatively unfamiliar territory. They had opportunity to practice skills that might have remained out-of-form:you’ve seen this before and you know how to deal with it, so… unless… the treatment’s not working, then… I think it’s easy… the more time you spend in general practice.Some GPs indicated that over time, they awarded greater primacy to their internal repositories of knowledge, except when uncertainty prompted a search for external knowledge. Knowledge thus became embodied in practice:you read about the [guidelines]… and then they just become part of my embedded practiceI certainly use the sexual health clinics… just ringing them and asking them for advice.To examine change over time, a lexical analysis was conducted by developing a concept map, in which the research material was categorised according to the stage of data collection see Fig. . The mapI had a patient who was a man who had sex with men. I was at a loss to know what to test for – here it is [picks up the STI Testing Tool]… I remember thinking, ‘Oh my God, where am I going to find out what’s the appropriate test?’The concept, ‘Clinical practices’, which denotes screening, testing, and treating, is relatively more associated with the second round of interviews, which occurred three to four months after the GPs were provided with the STI Testing Tool. This is not to suggest their practices changed; but rather, that their language changed, whereby there was greater focus on how they performed their role and enacted their knowledge:immediately after our meeting last time, it was more in the forefront in terms of actually approaching patients and actually making it part of the consultation, if that’s not what they came in for, and… I thought [about whether] it was appropriate to at least bring up the topic, even if we didn’t do anything at that consultation.I put the effort more in taking more sexual history, just asking people about the relationships and their partners and if they’ve changed partners or had more than one partner. I certainly aim to do it more, I’m aware of it more.Yet the improvisations that were triggered, in part, by the novelty of the STI Testing Tool and interviews with the researcher, sometimes paled against other contributors to their knowledge, including familiar resources that could be readily sourced within the organisation they worked, and trusted teaching aides. Consider for instance, the concept, ‘aware’, which is positioned close to the category denoting stage two of the study. Within this concept are excerpts in which the GPs spoke of myriad resources they were cognisant of, including ‘Therapeutic Guidelines… [and the] Red Book guidelines’, among others:I’m still aware of the same resources.it’s what we have been taught more than anything else. There isn’t a lot in the way of resources that I’ve been drawn attention to.They described how the initial interview, and the anticipation of the second, prompted different observations of the self and different conversations with others. This is reaffirmed by the concept, ‘meeting’, which refers to meeting with the researcher, rather than ‘meetings’ with clinical colleagues:The advantages of emergent change include its capability to increase readiness for and receptiveness to… change and to institutionalize whatever sticks… sensitivity to local contingencies… experimentation, learning, and sensemaking; comprehensibility and manageability; likelihood of satisfying needs for autonomy, control, and expression; proneness to swift implementation; resistance to unraveling; ability to exploit existing tacit knowledge; and tightened and shortened feedback loops from results to action As such, seemingly trivial change in patient consultations, the consideration of resources, or recognition of awkwardness around sexual healthcare might prime the GP towards evidence-based care – not necessarily as defined by accredited organisations, but rather, as a practice that reflects the situated blend of clinician expertise; patient  preferences; available resources; and the context of care. This is supported by the relative infrequency of those exceptional strategies used by a small number of GPs to explicitly change their sexual healthcare practices. The challenges that GPs face in familiarising with, synthesising, and adhering to ‘evidence’, while managing their workload and accommodating patient expectations, might suggest that these exceptional strategies are precisely that; the exception. Most of their counterparts appeared to inhabit a space that either: primed them to varying degrees of  change; or pushed them back towards the familiar.Reflecting situated change theory, this concept map illustrates the dynamic, gradual, vacillating, and faltering nature of change. The mere exposure to, and comprehension of knowledge artefacts is unlikely to simply align individual behaviours with evidence, as defined by accredited organisations. But rather, knowledge artefacts might help to ignite (even if temporarily): reflectivity and reflexivity  around wAlthough the thematic analysis elucidated the factors that influenced change among the GPs, the lexical analysis clarified the dynamic nature of change. This confirms the complementary value of the two approaches.Following calls a broader approach to knowledge translation research – one that draws from organisation studies , this argeneral practitioners, sexual healthcare did not always remain on the GP-radar, but was often overshadowed by other priorities – including the need to manage their limited time (which was eased by primarily attending to patient priorities), as well as the need to maintain a broad approach to primary care. Institutional theory revealed how familiarity with norms and practices can be advantageous to clinicians. Although not all GPs were familiar with the ways their organisation functioned, some suggested that fluency in organisational processes, including how they and their colleagues made sense of the organisation, and of organising, can be used to ensure that sexual healthcare is delivered by a practice predominantly comprised of GPs who are less comfortable with this area. Finally, situated change theory revealed the importance of incrementalism. For some GPs, gradually changing what they did and how they did it helped to transform clinical practices. Although exposure to multiple sources of information can aid this process, it can also be debilitating. Overwhelmed by the wealth of healthcare information received from the government, not-for-profit, academic, and corporate sectors, some GPs appeared to disengage from resources that were aimed to improve their clinical practices.Theoretically, the findings suggest that agency, institutional, and situated change theories each help to reveal different aspects of knowledge translation. Agency theory drew attention to the interests that influenced GP capacity to deliver evidence-based care. Despite their role as Extending this analysis further, agency theory  with itsMethodologically, the findings from this study demonstrate the value of both thematic and lexical analyses. Thematic analysis, which was relatively researcher-driver, helped to reveal the relevance of agency , instituFor instance, manually coding the research material helped to reveal the influence of time on clinical practices. Time shaped patient consultations, professional development, and the delivery of evidence-based care. These findings complemented the lexical analyses, which did not speak to the significance of time in the same way. Similarly, the lexical analyses help to focus attention on particular GP characteristics, like years of experience. This was achieved by seeding concepts of theoretical importance – namely, ‘clinical knowledge’ and ‘clinical practice’ – and tagging the research material to isolate areas of conceptual significance. This approach helped to understand how the discourse was associated with ‘clinical knowledge’ and ‘clinical practice’ and draw attention to concepts that had particular analytical value, all while reducing researcher-bias. The value of both manual coding and lexical mapping reflects previous research .Despite the value of the findings presented in this article, two limitations deserve mention. First, because GPs were self-selected, there is no claim they constitute a representative sample of primary care clinicians. Second, the reliance on interview transcripts limits the lifespan of the identified findings, particularly because of the potential for social desirability bias.Notwithstanding the aforesaid limitations, this study is important for theoretical, methodological, and practical reasons. Theoretically, this study is the first to examine knowledge translation using a framework premised on agency, institutional, and situated change theories. It revealed that the use of clinical information and the delivery of evidence-based sexual healthcare are shaped by the agent  and the institution ; furthermore, the influence of the agent and the institution can be subtle. This finding helps to strengthen an area of research that is largely atheoretical. Related to this, lessons garnered from this study have potential relevance further afield. Methodologically, this study highlights the complementary value of researcher-driven and researcher-guided analysis of qualitative research material. Each revealed different understandings of knowledge translation processes. Practically, this study unveils opportunities to facilitate knowledge translation. More specifically, it suggests that one-off, stand-alone initiatives to promote evidence-based care are likely to have limited impact. Rather, efforts to shape clinician practices should accommodate the potential interrelated influence of the agent and the institution – furthermore, they should recognise that change can be ever so subtle. These findings are particularly timely given the pressing need for healthcare that is both effective and efficient.Additional file 1Interview Schedules. Semi-structured interview schedules to collect data at stages one and two. (DOCX 33 kb)


This article examines how digital epidemiology and eHealth coalesce into a powerful health surveillance system that fundamentally changes present notions of body and health. In the age of Big Data and Quantified Self, the conceptual and practical distinctions between individual and population body, personal and public health, surveillance and health care are diminishing. Expanding on Armstrong’s concept of “surveillance medicine” to “quantified self medicine” and drawing on my own research on the symbolic power of statistical constructs in medical encounters, this article explores the impact of digital health surveillance on people’s perceptions, actions and subjectivities. It discusses the epistemic confusions and paradoxes produced by a health care system that increasingly treats patients as risk profiles and prompts them to do the same, namely to perceive and manage themselves as a bundle of health and security risks. Since these risks are necessarily constructed in reference to epidemiological data that postulate a statistical gaze, they also construct or make-up disembodied “individuals on alert”. Digital epidemiology promises exciting new insights into the occurrence and spread of diseases, into human behavior, into personal characteristics, and into the correlations among them. Its main goal is to detect health or security threats worldwide, in real time, rooted in the mining of online data, including personal data from social media and even information on health behaviors and health attitudes. In contrast to classical epidemiology that relied on reports from health experts, digital epidemiology draws on data that have been self-produced and usually for other purposes. The innumerable traces that people leave from their myriad activities online—from searching for information to Facebook posts—comprise its raw material. With a large proportion of the worldwide population leaving daily data traces of personal information, the new possibilities for health surveillance and control seem unbounded , expressly warns against drawing conclusions about individuals based on statistical laws: he forcefully stated that these laws, in accordance with the manner of their determination, no longer have anything of a specific individual about them. No concrete individual was reflected by the mirror of the “average man”. Any application to an individual person would essentially be false; it would be like using a mortality table to determine when a certain person will die  that universalize the “population gaze” that is constitutional for the regulatory techniques of biopower. In the 1990s, when Armstrong’s analyzed surveillance medicine, the epidemiological knowledge was constructed by experts in corresponding institutions; the panoptical gaze was still restricted to experts. Today, however, through clinical monitoring, self-tracking and digital data flows, patients are not only objects but also subjects of data generation and reconstruction. They are not only disciplined by internalizing the fact of being the object of observation, but are also invited to occupy a panoptical perspective themselves — on their own body as well as on others. By tracking their health and interpreting their data in the light of population statistics, they become subjects and objects of surveillance and epidemiological analysis at the same time. They are envisaged to lead a “self-monitored life that navigates through the grids of potential health threats”  then a woman who carries this mutation, from a statistical perspective, which says nothing at a personal level, has lifelong, an approximately 80-85 percent risk of developing breast cancer.” And a minute later she states that this number is “very high” and that the troubled women should “be careful” and choose regular checkups. How can a statistical imputation that “says nothing at a personal level” inform what a patient should do? Spelled out, the counselor has made the following statement about her client: If she had 100 lives, then in 80–85 of these lives she would develop breast cancer, and in 15-20 lives she would not. In reality, however, the woman has but her one life. What happens to her in this one life – the only question meaningful for her – is still written in the stars  when random mistakes occasionally happen, this corrects them. (…) There are specific protein molecules in the body that are in charge of this.” The client replies: “Like the police”. The geneticist immediately confirms: “Exactly, they are like the police. And this is ex…this is exactly the function of these genes. (…) And (…) when they do not function right, then logically such changes can persist. Other genes, (…) like the tumor suppressor genes, are on guard to make sure cells do not further mutate. And when they, when they become nonfunctional, then cancer can develop” Samerski , 103. SuApparently, the counseling client of the above extract has already been exposed to such criminological images and now pictures her own body as if it were a modern surveillance system; she sees herself as being under surveillance by a patrolling police force. The biggest enemy, these explanations suggest, does not invade from outside, but comes from inside and is part of one’s system. A biologist makes this analogy with anti-terrorist security explicit: Genes are like “terrorists”, the biologist John Turner writes: “They have the power to kill, maim, or make life downright miserable for us and our children. Some strike at birth, others ‘sleep’ for decades, and, like good terrorists, they are so well integrated into our body politic that, until the last few years, their exact whereabouts were a mystery: their individual extirpation (or more properly correction) is still well-nigh impossible” Turner , 8.This securitization of personal health, the imputation of an unsafe, precarious body within which lurk imminent threats and ominous futures, is far-reaching. First, these threats are imperceptible. In order to feel secure, at least for a short moment, the inhabitants of such a body are in constant need for surveillance and control. They cannot trust their senses anymore and literally embody the need for self-surveillance and checkups. Second, everybody is turned into a suspect. In the field of predictive policing where basically the same techniques of statistical anticipation and surveillance are implemented, criminologists call this the “generalization of suspicion”. Everybody is seen as a potential thief or terrorist until proven otherwise. Thus, technologies of prevention precariously invert a legal concept that is fundamental for a constitutional democracy: The legal concept of innocent until proven guilty. After the assessment of an increased risk, the counseled women, young and healthy, will remain a cancer suspect until a test lowers her risk to average. Once diagnosed as “at risk”, and this happens to whole populations, people stay suspect until they manage prove their health or innocence.By analyzing digital epidemiology in the context of other surveillance techniques including eHealth and self-tracking, this article has broadened the scope of discussion: It has identified three social and cultural implications that come into view when the epistemological and practical links between population surveillance and self-surveillance are made visible. By inviting patients and users to adopt a statistical gaze on themselves, digital epidemiology contributes to a disturbing transformation of health, disease and body. With the avalanche of digital data that brings everyday practices and actions as well as sentiments and social relations into the field of visibility, the possibilities for generating and attesting to pathogenic risks are limitless. Furthermore, digital devices integrate people into surveillance systems, so that the statistical alerts and feedbacks directly inform personal orientations and actions. In this world of digital health surveillance, the doctor largely disappears. He might be reduced to an operator of “Watson health” and its counterparts, facilitating the interaction between patients and digital health technologies.The term “health” once indicated a void, it meant unhurt, in sound condition. A healthy person did not miss anything. Today, striving for “health” saddles people with countless – and meaningless – risks and generates the need for surveillance. Perhaps Aldous Huxley saw most deeply into the contemporary situation when he said, “Medical science has made such tremendous progress that there is hardly a healthy human left.”


Experimental paradigms provide the framework for the understanding of cancer, and drive research and treatment, but are rarely considered by clinicians. The somatic mutation theory (SMT), in which cancer is considered a genetic disease, has been the predominant traditional model of cancer for over 50 years. More recently, alternative theories have been proposed, such as tissue organization field theory (TOFT), evolutionary models, and inflammatory models. Key concepts within the various models have led to them being difficult to reconcile. Progressively, it has been recognized that biological systems cannot be fully explained by the physicochemical properties of their constituent parts. There is an increasing call for a ‘systems’ approach. Incorporating the concepts of ‘emergence’, ‘systems’, ‘thermodynamics’, and ‘chaos’, a single integrated framework for carcinogenesis has been developed, enabling existing theories to become compatible as alternative mechanisms, facilitating the integration of bioinformatics and providing a structure in which translational research can flow from both ‘benchtop to bedside’ and ‘bedside to benchtop’. In this review, a basic understanding of the key concepts of ‘emergence’, ‘systems’, ‘system levels’, ‘complexity’, ‘thermodynamics’, ‘entropy’, ‘chaos’, and ‘fractals’ is provided. Non-linear mathematical equations are included where possible to demonstrate compatibility with bioinformatics. Twelve principles that define the ‘emergence framework of carcinogenesis’ are developed, with principles 1–10 encapsulating the key concepts upon which the framework is built and their application to carcinogenesis. Principle 11 relates the framework to cancer progression. Principle 12 relates to the application of the framework to translational research. The ‘emergence framework of carcinogenesis’ collates current paradigms, concepts, and evidence around carcinogenesis into a single framework that incorporates previously incompatible viewpoints and ideas. Any researcher, scientist, or clinician involved in research, treatment, or prevention of cancer can employ this framework. Consideration given to paradigms that provide the framework for the understanding of carcinogenesis by physicians, particularly surgeons, in every day practice of managing and treating cancer is minimal. Yet it is these frameworks that drive cancer research, translational research, drug development and ultimately treatment options, and impact on where research dollars are allocated , 2.The predominant traditional model of cancer, the somatic mutation theory (SMT), in which cancer is considered a genetic disease –7, has bNumerous authors have identified a need for a ‘systems’ approach to cancer –22.This paper presents a comprehensive framework for carcinogenesis. Through incorporating the concepts of ‘emergence’, ‘systems’, ‘thermodynamics’, and ‘chaos’, a single integrated framework for carcinogenesis has been developed, enabling existing theories to become compatible as alternative mechanisms, facilitating the integration of bioinformatics and providing a structure in which translational research can flow from both ‘benchtop to bedside’ and ‘bedside to benchtop’ , 23, 24.‘An emergence framework of carcinogenesis’ is based on extensive study of the works of numerous philosophers, researchers, scientists, and writers, including Mario Bunge  physici  that their constituents or precursors in isolation do not have. The new property is more than simply a combination of the properties of its pieces, meaning there is no simple mathematical model that explains this new property. It is a qualitative, not quantitative measure. An emergent property may  or may not  be predictable through understanding the properties of its components. Emergent phenomena are found across all areas of study, including physics, chemistry, biology, sociology, psychology, economics, and IT, and led to the development of the field of quantum physics , 26–29 aThermodynamics is a physical theory that describes a system in terms of the thermodynamic properties (heat and temperature in relation to energy and work) of the system or its parts. Thermodynamics makes no assumption about the microscopic nature of the system; it describes the macroscopic properties and remains correct even if the microscopic assumptions about a system are proved wrong , 31.Biological, or living, organisms are open thermodynamic systems that have acquired complexity through non-linear self-organizational processes and defy the second law of thermodynamics by mechanisms of metabolism. These properties cannot be deduced from molecular biological and genetic knowledge alone , 29, 31.72403 possible combinations  is largely shaped by their roles and positions within their community, or, as discussed later, their ‘system’  and how the system acts upon the environment (output). The subset of the system members that hold direct relationship with the environment are considered the system boundary ={Cgiven level that is being studied by using the intersection or logical product:As this would require an understanding of all parts of all systems at all levels, it is not practically useful. This can be limited by focusing on the So thatabcd(s) = water drop with the emergent properties of ‘P’ = surface tension; Ca(s) = molecules of H2O; Eb(s) = atmospheric temperature and pressure, gravity, air, or other surface the water drop is in contact with; Sc (s) = endogenous: the arrangement of water molecules with each other via hydrogen bonds that pull each molecule equally in every direction resulting in a net force of zero, =exogenous: interaction of the molecules at the surface that do not have the same molecules on each side causing them to be pulled inwards and contract to the minimal area; Md(s) = cohesion between water molecules being stronger than adhesion with molecules in air.Using the water drop from above in Figure F’, of the system. In a simple system that has two quantitative properties, called X and Y, which are considered to be the attributes of the system, thenTo capture the dynamics of a ‘system’, or in other words the qualitative and quantitative changes of a system over time, a state-space approach needs to also be included. The quantitative properties of a system can be combined into a single function, ‘F(t) as follows:A snapshot at a specific point in time, ‘t’, can then be represented by This is called the ‘state function’ of the system.history, ‘H’, of the system over a period of time, ‘T’:A vector that describes a trajectory from this point in the ‘state space’ can then represent changes over time. The trajectory represents the The history is confined within a box, the ‘state space’ that represents all of the really possible states of the system as determined by the law that governs the system.function (F) is swinging. It has two salient properties: momentum (q) and position (p). The law that governs the system is that ‘energy is constant’. The potential energy related to position and the kinetic energy related to momentum must always equal the total energy of the system.This can be demonstrated by considering the movement of a pendulum, which is a linear oscillator. The t’ the state of the system can be analyzed in terms of its position and momentum. This changes over time, creating a trajectory that reflects the history, ‘H’. If the energy is added from an environmental source, the trajectory will alter.At any point in time, ‘An ‘event’ is represented by an ordered couple of points in the ‘state space’.If a new property arises (emergence), the tangent of the trajectory acquires a new axis. If a property is lost (submergence), an axis is lost.While thermodynamics is a physical theory that describes a system in terms of the thermodynamic properties of the system or its parts, it makes no assumption about the microscopic nature of the system; it describes the macroscopic properties and remains correct, even if the microscopic assumptions about a system are proved wrong . MoreoveLiving systems are open systems and defy the second law of thermodynamics , by interacting with and acquiring energy from their environment. This enables the development of complexity. If their ability to acquire energy from the environment is reduced, energy is gradually dissipated as heat to surroundings and complexity is lost, as this requires energy to be maintained, and the system will degenerate. This is the process that occurs in aging and death , 29, 40.New disciplines, such as non-linear dynamics (‘chaos theory’) and fractal geometry, have brought new tools and perspectives into pathophysiology. Many physiological systems are highly complex networks, with numerous recursive feed-back and feed-forward circuits, and thus they may be especially prone to develop chaotic behaviors and display fractal structures. Non-linear dynamics and fractal models have been increasingly applied in physiology and medicine .Fractals are spatial structures and have the properties of self-similarity (consists of miniature copies of itself at different levels of magnification) and/or fractal dimensions , and/or rough outlines and infinite length –46. FracChaotic dynamics in a system is a function of time . Chaos aUltimately, cancer research and treatment can be progressed by shifting our focus from causal relationships that are non-linear and difficult to predict, to interpreting the patterns of cancer as an emergent system. To do this, a framework that can be employed anywhere from benchtop to bedside is likely to be more impactful.The emergence framework has been established through the creation of 12 principles. Each principle is presented in turn, followed by supporting evidence. Principles 1–10 encapsulate the key concepts upon which the framework is built and their application to carcinogenesis. Principle 11 relates the framework to cancer progression. The 12th principle relates to the application of the framework to translation research.Cancer is a dynamic complex system emerging at the level of the ‘functional tissue unit’.The first principle in creating an emergence framework of carcinogenesis is defining the ‘level’ at which ‘cancer’ as an emergent system arises. Cancer is characterized by alterations in cell and tissue structure, namely excessive accumulation of cells and disruption of normal tissue architecture , 54, 55.Analysis of genes alone does not make the diagnosis of cancer , 34. TheTissue-level patterns are diagnostic and tissue-level patterns may indicate mechanism , 55. It This concept is supported by the work undertaken by Bissell , 58. Bisa(s), are the lower level ‘tissue components’ that combine in a specific self-organized structure, Sc(s), to form the ‘functional tissue unit’.Identifying the level at which cancer is diagnosed allows the construct of a normal ‘functional tissue unit’ system using a systems formula. The components of the system, Cabcd(s) = functional tissue unit (mammary acinus) with the unique emergent functional property (to form glands capable of producing and releasing milk); Ca(s) = the parts of the lower hierarchical level of tissue that combine to form the functional tissue unit ; Eb(s) = the environment that interacts with the functional tissue unit or components of the functional unit ; Sc(s) = the specific arrangement and self-organization of the components of the functional tissue unit to form the functional tissue unit , the structure that enables interaction with the environment ; Md(s) = morphogenesis [collection of processes that enable formation of the functional tissue unit, including dynamic reciprocity , the ‘mammary acinus’ system is replaced by μabcd(sc), the cancer system emerging from the ‘mammary acinus’ system, ‘ductal carcinoma’abcd(sc) = ‘ductal carcinoma’ with loss of the property to form glands capable of producing and releasing milk and the new emergent properties of limitless replication, tissue invasion, and metastatic potential; Ca(sc) = the parts of the lower hierarchical level of tissue that formerly combined to form the functional tissue unit  in their altered form; Eb(sc) = the environment that interacts with the ‘ductal carcinoma’ or components of the ‘ductal carcinoma’, which still include not only systemic hormones and factors in blood, external environmental factors via ducts, but also local tumor microenvironment and tumor-promoting inflammation; Sc(sc) = the specific change in arrangement and self-organization of the components of the functional tissue unit to now form the ‘ductal carcinoma’, including altered polarity of epithelium, loss of normal tissue architecture, various stromal alterations, including angiogenesis, and loss of contact inhibition, breakdown of basement membrane, and invasion; Md(sc) = physiological processes that enable the formation of ‘ductal carcinoma’, including self-sufficiency in growth signals, insensitivity to anti-growth signals, evading apoptosis, sustained angiogenesis, deregulating cellular energetics, and avoiding immune destruction.μComparing the systems equation for the relevant functional tissue unit to the systems equation of the cancer that has emerged from that specific functional tissue unit helps to identify the factors relevant for both the loss of the functional tissue unit system and emergence of the cancer system. For each functional tissue unit, the components, environment, structure, and mechanisms will vary. So too, will the specifics of the cancer that emerges from it.Notch1 is considered an oncogene. By contrast, the functional tissue unit from which oral squamous cell carcinoma emerges is the mucous membrane, and Notch 1 is considered a tumor suppressor gene  that impact the exostructure or the way the system interacts with the environment, Eb(s), can occur as a direct response to changes in Eb(s), as a result of changes to Ca(s) impacting Sc(s), and/or the output of the system, μabcd(s), directly causing changes in Eb(s).Changes in Sabcd(s), may also create feedback affecting lower levels. This is downward causation.The output of the system, μd(s), or group of processes by which the ‘functional tissue unit’ achieves its emergent property or function, can also be impacted by upward causes, downward causes, and environmental causes. Physiological changes are as important as morphological ones.The mechanism, MCausation can flow in many directions simultaneously, there is no single privileged level of causation, and causation is not necessarily linear , 38, 63.The ‘state’ of a cell is determined by its position within the functional tissue unit and the state of the functional tissue unit as a system. All living systems metabolize and are therefore dynamic over time. Defining a ‘default’ state of a cell as quiescent or proliferative is not relevant in an emergence framework of carcinogenesis.All living tissues metabolize and, therefore, create dynamic open systems experiencing various iterations of pendulum-like swings in their morphology and physiology, which are controlled by resetting mechanisms. These are the oscillations or ‘clocks’, and molecular motors referred to in the preamble , 50–53. The ‘state’ of cells (quiescent or proliferative) is largely shaped by their roles and positions within their community . Mapped in vivo function as a community can be found in the science laboratory. Placing cells in culture disrupts tissue architecture and cell–cell relationships, allowing the emergence of cells with malignant potential, that is, those that can grow and replicate autonomously , Eb(s), Sc(s), or Md(s), beyond a point of self-organized criticality in either direction, alters the system causing disruption of the bonding structure that enables self-organization of the collection of relations among the biological tissue components, and/or their environment and/or the group of processes producing the mechanism of morphogenesis. This results in loss of the morphological and physiological properties of the functional tissue unit. Once this occurs, there is an opportunity for a new system, namely ‘cancer’ to arise.Therefore, in this framework, a change or combination of changes in Cin situ (CIS) in the larynx to invasive carcinoma can be used as an example of how this principle may be applied. While not all CIS lesions staining positive for the laminin γ2 chain of laminin 332  progressed to invasive cancer, only lesions expressing laminin 332 progressed. In this framework, these results could be interpreted that the expression of laminin 332 was an indicator of the point of self-organized criticality.The work of Nordemar et al.  in whichReduced redundancy of healthy functional tissue units through either entropy (degeneration) or excessive repair in response to tissue trauma is associated with an increased risk of cancer.‘Redundancy’ is another key feature of system resilience or robustness , 25. RedIf the metastable state passes too far toward entropy, there is an increasing inability to adapt to the environment, and the functional tissue unit moves from being an open system toward an increasingly closed one. Increased entropy results in inadequate useable energy within the functional tissue unit to maintain function and structure , 72, 73.Aging has been shown to be associated with breakdown of non-linear dynamics and fractal patterns with subsequent loss of complexity in numerous areas, including liver metabolism, cardiac physiology, and gait –78. DegeMoving to the other extreme, if a functional tissue unit is required to undergo excessive repair or growth, this could push it past the self-criticality point into chaos. ‘Trauma’ in all its manifestations, including inflammation, mechanical trauma, carcinogens, and infective causes, would push a functional tissue unit toward repair. As the natural law of the functional tissue unit is that function is inversely proportional to repair/multiplication, this will be the point where the law can no longer be maintained and the functional tissue unit as a system collapses. Loss of tissue organization architecture would also result. An emergence framework is, therefore, supported by the same evidence that supports TOFT as proposed by Sonnenschein and Soto , and theRisk factors for cancer act to reduce redundancy of functional tissue units via a number of mechanisms at a faster rate than in the natural aging process, generating an increased risk for cancer.Individuals who are exposed to various risk factors such as smoking, excessive alcohol intake, stress, exposure to radiation, and other life style insults, prematurely reduce the redundancy of the functional tissue units of various organs, reducing resilience to aging processes . ConsequAn emergence framework of carcinogenesis provides a common system end-point at the level of the functional tissue unit, reduced redundancy, and hence resilience and is consistent with the multivariate findings for risk factors linked to the majority of cancers.Loss of the properties that make a functional tissue unit a ‘system’ is a prerequisite to create the ‘initial state’ for the emergence of cancer.Prior to a new system emerging, a pre-system or ‘initial state’ exists. This is a point where potential components become randomly associated rather than being combined in a self-organized structure. Potential exists for the emergence of new systems . In carc‘Cancer’ is the emergence of a new ‘system’ arising from the tissue components of a functional tissue unit that has lost its normal self-organization arrangement and function, identifiable by changes in morphology and physiology.The events that occur in this ‘initial state’ are critical in determining the potential outcome, including apoptosis or involution, clearing by the immune system, formation of scar or fibrosis, stabilization and reformation of functional tissue units, or the formation of cancer.Cancer has commonly been described as a state of disorder and ‘chaos’. However, using the definition of ‘chaos’ as previously described, and the exquisite sensitivity to ‘initial condition’, this would imply that the likelihood of ever seeing two cancers at the same time would be extremely small , 40, 46.all the components that previously formed a healthy functional tissue unit. This means, for example, in solid epithelial tumors, such as head and neck squamous cell carcinomas, the ‘system’ includes not only the abnormal epithelial cells but the stroma as well. The importance of stroma and microenvironment is well supported by the work of many researchers  , 94–96. Mitochondria are responsible for about 80% of normal cellular energy . In canc1–5% of oxygen consumed will produce reactive oxygen species (ROS), or free radicals . In cancAngiogenesis is an identified hallmark of cancer. Recent data indicates that angiogenesis contributes to both the microscopic premalignant phase and ongoing phases of neoplastic progression . During Cachexia, which is characterized by weight loss and inflammation, is present in 40–80% of cancer patients, depending on tumor type, and is associated with metabolic changes involving carbohydrate, lipid, and nitrogen metabolism. These changes are linked with the need to maintain glycemia and to sustain tumor growth .The observation of fractals emerging at various stages of tumor progression is also supportive of viewing cancer progression as a sequence of emergent systems. As described in the preliminary description of chaos, fractals occur in space-chaos and their appearance is reflective of deterministic development with emergence of a new system with new complexity , 85, 86.Fractal patterns have been observed in the neo-angiogenesis patterns associated with tumors , 45. CanF(t) = {X(t), Y(t)}) the dynamics of each stage can be studied using data and information relevant to that stage and to the level at which investigation is being focused. Patterns can be observed, investigated, and ultimately provide guidance in management decisions.Applying the systems formula, an emergence framework enables each ‘stage’ in the progress of cancer  to be considered as a new emergent property. Using the state-space methodology, , Australia’s National Health and Medical Research Council, and the UK’s Medical Research Council. It enables the starting point to be anywhere in the system as it directs all starting points to a common level, that of the functional tissue unit. The interplay of laboratory observations, clinical outcomes, genetic studies, community patterns, or therapeutic trials can be assessed within this framework by considering how they impact on the systems equation of the functional tissue unit and/or the emergent cancer.Having a common framework provides a consistent format for investigating, allows for cross-referencing, enables integration, and facilitates the use of biosystematics and computational modeling.Living systems are dynamic, non-linear, and complex. Increasingly, biology is recognized as its own discrete discipline that cannot be adequately explained by reducing living processes to their physicochemical properties.Viewing cancer as a complex emergent system creates a new perspective that moves away from the gene-centric reductionist approach that has been the predominant theory of carcinogenesis for more than half a century. Through the integration of concepts from systems biology, physics, chemistry, and various theories of carcinogenesis, a new practical emergence framework of carcinogenesis has been proposed, based on 12 key principles. These are summarized in Table The motivation in developing an emergence framework of carcinogenesis was to create a common, comprehensive, and integrative framework for researchers, clinicians, philosophers, thought leaders, institutions, and funding bodies involved in researching and treating cancer. The authors have aimed to collate and synthesize current concepts and evidence around carcinogenesis into a single framework that incorporates previously incompatible viewpoints and ideas.It would not have been possible to construct this framework without the work of the significant body of researchers, scientists, clinicians, and philosophers who have already contributed to this field. Accordingly, the reference list is limited to key publications.“When you change the way you look at things, the things you look at change”.Max Planck, a German Physicist known as the founder of Quantum Physics and recipient of the Nobel Prize for Physics in 1918, is quoted as saying:We hope that this ‘emergence framework of carcinogenesis’ challenges the reader to look at cancer and carcinogenesis differently.ES, the primary author, was responsible for the concept, development of the framework, drafting, revising, and finalizing of the article. BW contributed to the development of the concept, provided critical feedback with suggested revisions, and was involved in finalizing the article. Both ES and BW agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.