Developing a dynamic model of anomalous experiences and function in young people with or without psychosis: a cross-sectional and longitudinal study protocol

Introduction Anomalous experiences are common within the general population, but the frequency and intensity is increased in young people with psychosis. Studies have demonstrated that perceptual biases towards noticing these phenomena plays a role, but the way one thinks about one’s experience (metacognition) may also be relevant. While poor metacognitive function has been theoretically associated with anomalous experiences, this relationship is currently unclear. However, metacognition may work along a continuum with various metacognitive levels, many of which have been demonstrated as impaired in psychosis. These metacognitive components may interact via processes that maintain poor metacognition across levels, and that potentially impact both what people do in their everyday lives (functional outcome) and how people feel about their everyday lives (subjective recovery outcome) in young people with psychosis compared with healthy control participants. Methods and analysis This study will investigate the association and contribution of metacognition to anomalous experiences and outcome measures cross-sectionally and longitudinally in a 36-month follow-up. First, young people with psychosis will be compared with healthy control participants on selected measures of anomalous experience, metacognition, and function, using analysis of covariance to identify group differences. Next, the relationship between metacognitive components and processes will be explored, including processes connecting the different components, using regression analyses. Finally, mediation analyses will be used to assess the predictive value of metacognitive measures on outcome measures, both cross-sectionally and longitudinally at 36 months, while controlling for symptoms and cognition. Ethics and dissemination Ethical and Health Research Authority approval has been obtained through Camberwell St. Giles Research Ethics Committee (reference number: 17/LO/0055). This research project will be reported within a PhD thesis and submitted for journal publication. Once key predictive components of poor outcome in psychosis are identified, this study will develop a series of dynamic models to understand influences on outcome for young people with psychosis.

from more careful definitions and present the rationale of the study more clearly. This main part of the article seems chaotic. Please see below for my more detailed comments. The review can enrich the rationale for the general relation between anomalous experiences and some metacognitive biases by discussing following papers: Nelson et al., 2014 (Two papers published in Schizophrenia Research). Anomalous experiences is a very wide term referring to a rich number of various psychic phenomena. The authors should be more specific from the beginning of theoretical introduction about which anomalous experiences they investigate. It seems that the study is more focused on psychotic-like experiences (schizotypy, depersonalization). Furthermore, it is unclear and, in my opinion, unjustified, as the authors investigate anomalous experiences in psychosis, that only delusions, but not hallucinations are considered in the study. What is the rationale for that?. There are studies that addressed meta-cognition in hallucinations specifically showing no relation to delusions (e.g., Gaweda et al., 2013). What is more at the same time a line of studies have shown that meta-cognitive biases that may be not that modality-specific as the authors claim are linked to anomalous experiences in psychosis and are observed from the earliest phases of the illness (Gaweda et al., 2018, European Psychiatry). Furthermore, all these studies controlled for deficits in general performance. It is not clear what is the difference between perceptual anomalies and perceptual biases (p.3). Please clear this point. Furthermore, the authors wrote: 'Perceptual biases are noted when an individual has a bias towards stating that a stimulus was present when it was in-fact absent.'. It is misleading, as there are a different kind of perceptual biases and it seems like the authors refer to false perception specifically or signal detection biases as some authors The part about modality-specificity of anomalous experience and metacognition is unclear and need further explanation. Majority of the core self-disturbances in psychosis are not modality specific, e.g., disturbances of the first-person perspective, hyper-reflexivity, lack of ego-boundaries, derealization, etc.). The relationship between meta-cognition and functional outcomes is clearly explained. Please consider however anomalous experiences in the analyses. Anomalous experiences should be controlled along with symptoms. Furthermore, as the authors target relationship between metacognition and both anomalous experiences and functional outcomes, I suggest to include also hypothesis 5 stating your expectations about the relationship between metacognitive variables and anomalous experiences at follow up. Some minor comments: 'Metacognition is defined as "thinking about thinking" (Semerari et al., 2003) and the way one thinks about one's experience.' (p. 3). First, I suggest citing Flavel's work, as he introduced the term of metacognition. The second part of the sentence doesn't refer to metacognition (for instance 'I am worthless' is the way I am thinking about my experience of failing the exam, but it is object-level thinking according to Nelson and Narens).
There are missing citations in some sentences (e.g., 'Such experiences are suggested to be a precursor to full psychotic symptoms, e.g., hearing voices, and increasingly distressing experiences.' p. 2) Literature has demonstrated that hallucinatory experiences and delusional beliefs/ideation have been associated with metacognition (overconfidence, specifically) in both clinical and non-clinical groups (Eisenacher et  .' Please be more specific. It is misleading to say that all these groups commonly experience paranoia. We see extended phenotype (continuum), but at very different levels of expression.
'(…) that derealisation (anomalous self-experience) may be associated with metacognitive deficits. This study will empirically test this. Anomalous self-experiences have not been considered to be modality-specific. Hence this has not been reflected in the construction of the scales, and will therefore not be assessed here.' I am not sure what will and what will not be tested.
Participants: Exclusions criteria should be described in a more detailed manner (substances, controls: how mental health will be screened, family history of psychosis, etc?).

Methods:
The authors may also consider adding the Anomalous subscale Experiences of the SSI.
Experimental tasks are well designed and described. Data analysis strategy is clear.
Finally, potential shortcomings of the study should be recognized and discussed.

VERSION 1 -AUTHOR RESPONSE
Replies to reviewer 1 comments: 1. First, it would be useful if the authors consistently use "anomalous" or "unusual" experiences throughout title, abstract and text. Thank you for pointing this out. We have changed this term to anomalous experiences throughout the article, abstract and title.
2. In methods, I found difficult to understand the composition of the sample. The authors refer to a previous study; is the sample going to be comprised of new cases and data from a previous study? Is the total sample 80 or 153?
We have clarified this point: "Seventy-three young people with psychosis will be recruited. This sample will be made up of a convenience sample from first episode services and the remaining individuals will be those re-recruited from a previous first episode psychosis (FEP) sample (previous N=80), to take part in the main cross-sectional study and longitudinal follow-up aspect." 3. Do the authors envisage any limitation by applying this sample selection? We acknowledge the limitations with this sample selection within a new 'limitations' section in the discussion: "A foreseeable limitation is that the First Episode Psychosis sample will be comprised of both a previous FEP sample and new participants who are currently engaged in EIS in Sussex. Therefore, individuals will be at various stages of their recovery and support from the Early Intervention Services which adds variation in terms of symptoms and recovery. With this in mind, symptoms will be controlled in the main analysis. However, this will enable exploration of factors which predict this variation." 4. Also, it might be informative to know the strategy to identify the 73 healthy volunteers. We have clarified this, alongside the screening of mental health difficulties. "Participants will be recruited through advertisement within the local community, e.g. in libraries, cafes and on social media. Participants with current mental health problems or history of psychosis will be excluded following screening questions: i) Are you currently experiencing any mental health difficulties? ii) Are you on any psychotropic medication/substances? iii) Have you been in contact with psychological or psychiatric services for psychological problems? iv) Has anyone in your immediate family experienced an episode of psychosis? E.g. parents, siblings. If healthy control answered yes to any of the questions, these participants were deemed ineligible to take part in the study". 2. Anomalous experiences is a very wide term referring to a rich number of various psychic phenomena. The authors should be more specific from the beginning of theoretical introduction about which anomalous experiences they investigate. It seems that the study is more focused on psychoticlike experiences (schizotypy, depersonalization).
We have changed the wording to accommodate this comment: "Anomalous experiences refer to a rich number of various psychic phenomena. These experiences can include the sense that you are not "real" (anomalous self-experiences; distortions in experience of self and being), hearing sounds which cannot be accounted for by the environment (anomalous perceptual experiences: distortions of sensory events in various domains; auditory, visual; touch; taste) and experiencing unusual thoughts or beliefs (anomalous delusional beliefs). These experiences may be commonly experienced by 3. Furthermore, it is unclear and, in my opinion, unjustified, as the authors investigate anomalous experiences in psychosis, that only delusions, but not hallucinations are considered in the study. What is the rationale for that? Thank you for pointing this out. We have included an assessment of low-level hallucinations by using a measure of anomalous perceptual experiences on MUSEQ which has previously been validated against CAPS, O-LIFE (Mitchell et al., 2017). We have used this measure as we were able to capture anomalous perceptual experiences in two modalitiesvisual and auditory. We have clarified that we are using a measure of hallucinatory experiences by including the phase "However, anomalous perceptual-experiences (e.g. hallucinations) in psychosis, and in the general population, can vary in modalities (Mitchell et al., 2017)". From your suggestion below, we have also now included the SSI anomalous experience scale to confirm the MUSEQ scores, and their association with perception and metacognition, as this is a wellknown measure of anomalous experiences.
4. There are studies that addressed meta-cognition in hallucinations specifically showing no relation to delusions (e.g., Gaweda et al., 2013). What is more at the same time a line of studies have shown that meta-cognitive biases that may be not that modality-specific as the authors claim are linked to anomalous experiences in psychosis and are observed from the earliest phases of the illness (Gaweda et al., 2018, European Psychiatry). Thank you for your detailed comments about this. We acknowledge that previous work has assessed verbal vs. non-verbal performed/imagined actions in FEP and UHR with no difference of misattribution between verbal or non-verbal action. This suggests that metacognition may be deficit across modalities for those with FEP and at-risk. However, we acknowledge that anomalous perceptual experiences and perceptual/metacognitive ability can be different for individual people, in terms of the modalities of experiences ( ) and may therefore demonstrate differential association with auditory perception or metacognition. Therefore, we are particularly interested in testing whether there is a direct relationship between specific perceptual/metacognitive abilities and perceptual anomalous experiences in the same modality: visual and auditory. This will be tested in both FEP and healthy control to capture the variation in anomalous experiences and metacognition.
We have amended the section: "A recent controlled study demonstrated that individuals with FEP and those at-risk were more likely to misattribute an imagined action for a performed action, compared to healthy controls (Gaweda et al., 2018), but as there was no difference in misattribution of verbal or non-verbal actions this suggests the deficit in metacognition may be across several modalities. However, metacognitive ability (measured using meta-d') is known to be modality-specific (Fleming et al., 2014; Morales, Lau & Fleming, 2017) and anomalous perceptual-experiences (e.g. hallucinations) can vary in modalities (Mitchell et al., 2017). It has also been acknowledged that auditory anomalous experiences are most common in psychosis (Shergill, Murray, & McGuire, 1998;Waters, Allen, et al., 2012), all of which may suggest a modality-specific association with auditory or visual anomalous experiences and perception/metacognition. This present study will assess the modality-specific association between perceptual bias (signal detection bias) and metacognitions with anomalous perceptual experiences in visual and auditory modalities, whilst controlling for objective performance (see figure 1)." 5. Furthermore, all these studies controlled for deficits in general performance. We acknowledge that some studies have controlled for performance and we have noted this hence the inconsistency in the literature when performance is controlled (Gaweda et al., 2013). We have now included the phrase: "Some studies did not control for objective performance". 7. Furthermore, the authors wrote: 'Perceptual biases are noted when an individual has a bias towards stating that a stimulus was present when it was in-fact absent.'. It is misleading, as there are a different kind of perceptual biases and it seems like the authors refer to false perception specifically or signal detection biases as some authors called (Algamani et al., 2017, Cognitive Neuropsychiatry). Thank you for the recommendation. We have changed this term to "signal detection biases" and included more information on this in response to point 1. 9. The part about modality-specificity of anomalous experience and metacognition is unclear and need further explanation. Majority of the core self-disturbances in psychosis are not modality specific, e.g., disturbances of the first-person perspective, hyper-reflexivity, lack of ego-boundaries, derealization, etc.). From this, we have altered sentence: "Anomalous self-experiences have not been considered to be modality-specific, hence this has not been reflected in the construction of the scales, and these selfexperiences are hypothesised to be related to both visual and auditory perceptual biases and metacognitive ability".
10. The relationship between meta-cognition and functional outcomes is clearly explained. Please consider however anomalous experiences in the analyses. Anomalous experiences should be controlled along with symptoms. Added into hypothesis: 'Hypothesis 3: Metacognitive variables (metacognitive knowledge, metacognitive processes and metacognitive experience) will significantly predict outcome measures (functional capacity, functional outcome and subjective recovery outcome) in young people with and without psychosis, even after controlling for anomalous experiences, symptoms and IQ'. The analysis section has also been changed accordingly: 'A mediation analysis will be used to whether functional capacity, functional outcome and subjective recovery outcome are predicted by metacognition and metacognitive processes, whilst controlling for anomalous experiences, symptoms and cognition'.