The role of psychological flexibility in the meaning-reconstruction process in cancer: The intensive longitudinal study protocol.

OBJECTIVES: Meaning-making is an important element of adapting to disease. However, this process is still poorly understood and the theoretical model has not been comprehensively verified yet, particularly in terms of complexity, dynamics, and intraindividual variability. The aim of this study is a deeper understanding of the meaning-reconstruction process in cancer and empirical verification of the integrative meaning-making model of coping extended by the psychological flexibility model. We postulate that psychological flexibility can foster the meaning-making in cancer by building more flexible and workable meaning-making explanations of disease.
DESIGN: A daily-diary study conducted for 14 days in patients following the first autologous or allogeneic hematopoietic cell transplantation (HCT).
METHODS: Participants (at least 150) will be requested to complete the daily-diary related to daily situational meaning, meaning-related distress, meaning-making, psychological flexibility, meanings made, and wellbeing for 14 days after hospital discharge following HCT. Also, baseline and follow-up assessment of global meaning, wellbeing, and meanings made will be performed. Statistical analysis of the data will be conducted using the multilevel and dynamic structural equation modeling.
CONCLUSIONS: The study will fill in the gaps in health psychology in the understanding of the meaning-reconstruction process in cancer by within- and between-person verification of the integrative meaning-making model and its extension by the psychological flexibility model. The data obtained will be used in further research on the development of meaning-making by means of interventions based on psychological flexibility.

Introduction

Meaning plays a central role in our wellbeing, particularly in high stress conditions such as cancer. An important element of adapting to cancer is meaning reconstruction which is described by the integrative meaning-making model of coping [1]. However, meaning-making to disease is still poorly understood and its theoretical model has not been comprehensively verified yet. Such verification would consider its complexity, dynamics, reciprocity, and intraindividual variability. Therefore, we plan to conduct the intensive longitudinal research aimed at an in-depth understanding of the meaning-reconstruction process in cancer. The theoretical basis of the research will be the integrative meaning-making model of coping [1] extended by the psychological flexibility model [2].

Integrative meaning-making model of coping

Based on the integrative meaning-making model [1], meaning-making (i.e. process of searching for meaning and explanation for adversity) depends on global meaning (i.e. core schemas through which people perceive themselves and their surroundings, interpret the past, anticipate the future and follow their behavior), situational meaning (i.e. apprised meaning of a particular situation), and distress related to the discrepancy between them. Meaning-making impacts the meanings made (i.e. the perception of positive changes resulting from successful coping with adversity; benefit finding) and then wellbeing, which makes it a mediator in the model [1]. Meaning-making refers to approach-oriented intrapsychic efforts, which involve increasing the matching (or reduction of discrepancies) between global and situational meaning by changing either the meaning of the situation itself or one’s global beliefs and goals [1].

The complete verification of the model has not been made. Reports on the relationships between global meaning (i.e. beliefs, goals, sense of purpose) and wellbeing are predominant and show their positive relationships [3], also in the affected persons [4,5]. Situational meaning can play a mediating function in these relationships through more challenging, controllable and less threatening appraisal of an event, albeit so far outside the disease context [1,6]. There are also data indicating that the disease may impair general beliefs and life goals, which is associated with patient higher distress, anxiety and depression and lower quality of life [7-9]. Research on the relationships between meaning-making and adjustment to illness brings inconsistent findings indicating positive [10,11] and negative associations [4,12,13]. The relationships between meaning-making and meanings made are poorly investigated and are inconclusive, although most studies were not disease-related. In cancer survivors, meanings made mediated the association between meaning-making and longitudinal adjustment [9]. However, outside the disease context, meaning-making completed with meanings made was necessary, unnecessary or irrelevant for better adjustment [1]. Most studies focused on the effect of meanings made on adjustment to disease, without a simultaneous assessment of meaning-making. These studies were mostly cross-sectional and indicated positive or insignificant effects [14]. A meta-analysis of benefit finding following various stress conditions found that it was related to less depression and more positive wellbeing, but unrelated to anxiety, global distress, quality of life, or subjective physical health [15]. On the contrary, the review of longitudinal studies in the disease context found a favorable effect of meanings made on physical aspects of adjustment rather than psychological ones [14].

Psychological flexibility model

Psychological flexibility is defined as an individual’s ability to freely choose the action that is consistent with one’s own goals and values, regardless of what thoughts, emotions and impressions accompany it [2]. The psychological flexibility model includes six key processes, i.e. acceptance, cognitive defusion, contact with the present moment, perspective-taking, values clarification, and committed action [2]. Acceptance and defusion are the most important skills that increase a person’s openness to direct experiences (through the attitude of interest and curiosity) and allow for diversity in action, which enables people to freely take action consistent with the values of the individual. Contact with the present moment focuses on the experiences of the present and perspective-taking allows one to view them from a broader perspective. Values clarification and committed action bring vitality and meaning to the actions taken through readiness to valuable engaging in life. Due to identification of life values, it is possible to link current behavior with what is important and meaningful. Each key process of psychological flexibility plays a decisive role in a person’s ability to adapt to adversity [2].

A number of studies have found that psychological flexibility is associated with more adaptive coping [16], adaptive psychological traits, including higher conscientiousness and openness to experience [17], and better wellbeing, including physical health, quality of life, and emotional wellbeing in the healthy population [2,18]. Favorable results of psychological flexibility on physical and emotional wellbeing were also found in patients with chronic diseases [19,20]. Psychological flexibility has also been proven to be a buffer that mitigates the effects of stress on wellbeing in healthy persons [16] and patients [21]. We have not found any research that would explicitly test the relationships between psychological flexibility and global or situational meaning, meaning-making or meanings made. However, some data indicated that people characterized by openness and curiosity showed a higher tendency to benefit finding [22,23].

Rationale for the present study

Although the process of meaning-reconstruction in disease is an important element of adaptation, little is known about it. Earlier studies failed to address the complexity or dynamics of the meaning-making process. As a result, the model has not been fully verified and the available data apply only to the between-person differences. The solution to this problem is to conduct the real-life research using the intensive longitudinal approach which allows for studying the dynamic intraindividual variability [24]. Research on the meaning-making process in disease should also consider all the components of the model to determine the adaptive value of the process. Previous research did not differentiate between the process and its results. Most studies did not measure meaning-making and meanings made simultaneously. Therefore, drawing clear conclusions is difficult in terms of whether meaning-making is associated with adjustment to disease to the extent that meaning is made. It is likely that meaning-making adaptability depends on meanings made. However, this has not been clearly confirmed yet [1]. Furthermore, studies should examine moderation and mediation relationships. Data are missing on what mechanisms lie behind the meaning-making process. Completing the model with psychological flexibility seems to be a promising solution. Psychological flexibility promotes acceptance of what is difficult to change or is not subject to change, taking responsibility for one’s own experiences and actions, and creating a meaningful life by engaging in activities that are consistent with one’s values. Increasing psychological flexibility should therefore foster the creation of meaning in disease by building more flexible and workable meaning-making explanations of disease. Thus, psychological flexibility may constitute the missing mechanism of meaning-making strategies in the integrative meaning-making model.

The purpose of our research will be (i) the identification of individual trajectories and sources of variation of the meaning-reconstruction process during a chronic disease, (ii) the investigation of psychological flexibility as a possible mediator of the meaning-reconstruction process, and (iii) the determination of within-person dynamic and reciprocal associations in the extended meaning-making model (see Fig 1) in an observational intensive longitudinal study among patients following hematopoietic cell transplantation (HCT). HCT is a highly invasive and life-threatening treatment of hematologic neoplasms associated with burdensome adverse effects and a strong medical regimen for patients [25]. However, this procedure gives patients hope for recovery or long-term remission. Therefore, HCT can represent a mini-seismic event during coping with cancer (the turning point in patient lives) posing a challenge to the patient meaning structures. The post-HCT period may prompt reflection on the meaning of HCT and the patient current situation, which are part of meaning-making. In addition, HCT is mostly performed after the period known as the shock and denial phase. Potentially, this is the period during which the patient can start more reflective, meaning-making coping.

Fig 1

Research model: The meaning-making model of coping with a chronic disease (solid lines) extended by psychological flexibility (dashed lines).

Study research questions and hypotheses

We formulated the following research questions: (1) If and what are the individual trajectories of meaning-making across first 14 days after discharge (within-person level) and how do those trajectories differ from person to person (between-person level)? (2) What processes underlie the individual meaning-making fluctuations and how do the patients differ in this process? In particular: (a) Does daily meaning-making mediate the effect of daily fluctuations in situational meaning and distress on fluctuations in meanings made and wellbeing? (b) Does daily meaning-making mediate the effect of baseline to follow-up changes in global meaning, meanings made, and wellbeing? (c) Do daily meanings made moderate the association between daily fluctuations in meaning-making and wellbeing? (d) Does psychological (in)flexibility mediate the effect of daily fluctuations in distress on fluctuations in meaning-making? (e) Does psychological (in)flexibility mediate the effect of daily fluctuations in meaning-making on fluctuations in meanings made? (f) Do these relationships occur when the direction of the relationships between variables is reversed? (g) Do demographic, situational and individual factors moderate the individual trajectories and tested relationships?

We expect that various trajectories of meaning-making following HCT will be identified with various directions (increase vs. decrease) and dynamics over time (Hypothesis 1; H1). In addition, we expect the support for assumptions of the meaning-making model, importance of daily psychological (in)flexibility in this process, and reciprocal associations between variables in the extended meaning-making model. Based on the integrative meaning-making model, we predict that daily meaning-making will mediate between daily fluctuations in antecedents/distress and outcomes (H2), as well as between baseline and follow-up changes in global meaning and outcomes (H3). Also, positive effects of daily fluctuations in meaning-making on wellbeing will occur on the days when meaning is given (H4). Referring to the psychological flexibility model, we assume that daily psychological flexibility can determine meaning-making and therefore can mediate between daily distress and meaning-making (H5). Alternatively, daily psychological flexibility can be determined by meaning-making and can mediate between daily meaning-making and meanings made (H6). Without hypotheses, but more exploratively, we also postulate the existence of additional pathways of relationships of a reciprocal nature, both in relation to the relationships between distress, psychological (in)flexibility and meaning-making, and the other elements of the model, i.e. global and situational meaning, as well as outcomes of the meaning-making process. Finally, we suppose that demographic (e.g. age and sex of patients), situational (e.g. time since the diagnosis) and individual factors (e.g. global and situational meaning, baseline wellbeing) could be potential moderators of the meaning-reconstruction process.

Materials and methods

Ethics

The study received ethical approval from the Ethical Review Board at SWPS University of Social Sciences and Humanities, Faculty of Psychology in Warsaw (Decision No. 26/2022 of April 12, 2022) and adheres to the ethical guidelines of the Declaration of Helsinki. All participants will be requested to give written informed consent prior to participation.

Design

This is an observational study with an intensive longitudinal design. Patients admitted for autologous (patient’s own stem cells) or allogeneic (donor stem cells) HCT will be recruited.

Setting

Patients will be recruited from the Department of Bone Marrow Transplantation and Oncohematology of the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) Gliwice Branch, Poland. Approximately 215 primary transplants are performed there annually (approx. 246 HCT in total).

Participants and sample size

The sample size was estimated using a target power of 80%, at alpha of 0.05, and was calculated relative to the small effect size in the latent growth analysis using an a-priori sample size calculator [26]. A minimum of 125 patients should be sufficient to obtain the adequate power analyses. Considering the potential attrition rate of 20%, the final sample is 150 patients. Similar values (for two-level model with random slopes and within-person mediation model) come from simulation studies using the Monte Carlo approach [24,27].

The inclusion criteria will include qualification of the patient for the first autologous or allogeneic HCT due to hematologic and lymphatic cancer, ≥ 18 years, and written informed consent. The exclusion criteria will be as follows: the presence of any other major medical or psychiatric disorder other than cancer that would impede the ability to participate in the study, insufficient reading and writing skills of patients, and the evidence of patient unreliability.

Recruitment process

Recruitment will start after elective admission to the transplantation unit due to HCT. We assume that it will take place approximately two days after admission and before the conditioning treatment. Every two days, research team member (AK) will review the lists of patients enrolled for HCT. Then, another research team member (recruiter) will ask patients who met the study criteria about their interest in participating in the study. Those interested will attend an individual initial meeting during which the recruiter will describe the course of the study in detail and will ask for consent to participate. The patient will be enrolled in the study if they provide written informed consent. The consent can be withdrawn at any time without any negative consequences for participants. The recruitment is anticipated to cover the period from May 2022 to January 2024 (approx. 21 months; considering the decline rate of approximately 40%), depending on the COVID-19 pandemic. Participants will be paid PLN 100 (~USD 22) for the participation in the study.

Data collection methods

Data will be collected via self-reported electronic surveys at baseline and follow-up, and a 14-day diary (Table 1). The baseline survey will be administered directly after obtaining written informed consent. Daily-diary will start on the second day after hospital discharge and will take 14 days. A follow-up survey will be administered on Day 15. All tools within the diary procedure will be shortened so that the number of items measuring any given indicator ranges from two to six, which is a common practice in such research [24]. Participants who will give their written approval will receive daily text messages that will remind them to complete a diary. During the study, research team member (JD) will contact the participant by phone to resolve any issues and answer questions.

Table 1

Standard protocol items of the study.

Time points	Enrollment + Baseline		Day1	Day2	(. . .)	Day9	Day14	Follow-up
Enrollment		transplant engraftment … isolation … hospital discharge
Identification	X
Eligibility screening	X
Informed consent	X
Data collection
Demographics	X
Clinical data								X
Global meaning	X							X
Situational meaning			X	X	X	X	X
Distress			X	X	X	X	X
Meaning-making			X	X	X	X	X
Psychological flexibility			X	X	X	X	X
Meanings made	X		X	X	X	X	X	X
Wellbeing	X		X	X	X	X	X	X

Day1-Day14 = days of daily-diary study after post-HCT hospitalization discharge; Follow-up = Day 15.

Measures

Patients will be asked to complete the following measures at baseline and follow-up:

Global meaning

Global meaning will include a sense of meaning and illness perception, which will be assessed using the 10-item Meaning in Life Questionnaire (MLQ) [28] and the 8-item Illness Perception Questionnaire (B-IPQ) [29], respectively.

Meanings made

Meanings made (i.e. positive psychological changes) will be measured using the modified 10-item Post-Traumatic Growth Inventory-Short Form (C-PTGI-SF) [30,31]. The modification consists in changing the wording of the items to refer to the current state instead of recalling and comparing pre- and post-event status [31].

Wellbeing

Wellbeing will include symptoms of depression, anxiety, loneliness, and the indicators of health-related quality of life (HRQOL), which will be assessed with the 10-item Centre for Epidemiological Studies Depression Scale Short Form (CES-D-SF) [32,33], the 7-item Generalized Anxiety Disorder Scale (GAD-7) [34], the 20-item Revised UCLA Loneliness Scale [35], and the 30-item EORTC QLQ-C30 Questionnaire [36,37], respectively.

In daily-dairy, patients will be asked to complete the following measures:

Situational meaning

Daily situational meaning will be measured using indicators of primary and secondary appraisal of the current situation following HCT using five items from the Stress Appraisal Measure (SAM) adapted to the daily procedure and study context [38]. The secondary appraisal will be additionally measured with six items from the Coping Self-Efficacy Scale (CSE) adapted to this study [39].

Distress

Daily meaning-related distress refers to daily beliefs and goal violation and will be assessed using selected nine items from the Global Meaning Violation Scale (GMVS) adapted to the daily procedure and study context [40].

Meaning-making

Daily meaning-making will be measured using selected six items from the Core Beliefs Inventory (CBI) [41] and eight items from the Perceived Ability to Cope with Trauma (PACT) scale adapted to the daily procedure [42]. Both tools measure meaning-making efforts, i.e. CBI—reconsideration of global beliefs [40], whereas PACT—remembering the event and reflecting on its meaning (subscale: trauma focus) [43].

Meanings made and wellbeing

Daily meanings made will be measured using five items from the modified Post-Traumatic Growth Inventory-Short Form (C-PTGI-SF) [31]. Daily wellbeing will include daily somatic symptoms and affect, which will be assessed using the self-reported symptom checklist [44] and the 12-item adjective scale (reflecting positive and negative affect of various arousal) based on the circumplex model of emotion by Larsen and Diener [45], respectively.

Psychological flexibility

Psychological flexibility will be measured with the short form of the Multidimensional Psychological Flexibility Inventory (MPFI) adopted to the daily procedure. This inventory assesses six flexible and six inflexible processes [46].

Other measures

At baseline, the demographic data (i.e. age, gender, education, marital status, employment, having children, socioeconomic status) will be assessed. Clinical data (i.e. diagnosis, time since diagnosis, type of HCT, conditioning, concomitant diseases, treatment toxicity, complications after HCT e.g. graft-versus-host disease in allogeneic HCT recipients) will be obtained from the medical records by a physician (MSK).

In the original and Polish versions, all the tools (except GMVS whose psychometric properties will be tested in this study) are characterized by satisfactory psychometric properties. Table 1 shows the standard protocol items of the study.

Statistical analysis

Analyses will be conducted using the latest Mplus statistical package [47] and IBM SPSS (IBM Corp.; Armonk, NY). We will use the standard p < .05 or 95% confidence interval for determination of value probability. The collected data will be first analyzed in terms of sample characteristics and comparisons (frequency, descriptive statistics; ANOVA, t-test or their nonparametric counterparts; Chi2; Pearson’s or Kendall’s correlation), missing data (frequency, multilevel modeling), and sample attrition (logistic regression analysis). Multilevel confirmatory factor analysis (MCFA) will be performed to calculate the indicator reliabilities (omega coefficient) at the within- and between-person levels and establish the respective measurement models [24,48]. To examine research questions, the multilevel (MSEM) and dynamic structural equation modeling (DSEM) will be applied [24,49]. Both methods allow for the examination of time course, simple between- and within-person associations, and more advanced associations such as mediations and moderations. Moreover, they allow the most recent flexible approach to the missing data (the full information maximum likelihood) [50,51], which is possible due to the setting and daily-diary procedure.

Hypotheses 1–6 and the research question 2g will be mostly verified using MSEM. In MSEM, random coefficient models with maximum likelihood as an estimator will be applied. Predictors will be divided into within-person (the deviation from the person mean) and between-person (stable between-person mean for each person across all their diary days) indicators, which allowed separation of within-person change from between-person differences of the predictor. Centered linear time trend will be controlled in the analyses. In all models, possible confounders (i.e. demographics, clinical factors, other confounders) will be considered after preliminary selection. For exploratory reasons, lagged models that predict outcomes based on the previous-day predictors will also be considered. Significant interactions (H4, question 2g) will be graphed and probed with simple slope analyses [52].

Research question 2f and H3 will be verified using a multilevel VAR(1) model in DSEM (other hypotheses and questions can also be verified with DSEM). VAR(1) model consists of a set of regression equations, in which each endogenous variable is regressed on its own lagged values (autoregression) and the lagged values of the other variables (cross-regression) for each individual, which allows for the estimation of reciprocal associations. We will use the Mplus default priors (mean = 0, variance = 1010) and the Bayesian estimator (specific to DSEM). Within- and between-person associations will be automatically distinguished in DSEM. To compare the strength of cross-lagged associations, we will use the within standardization (i.e. standardization using the within-person variance) [53].

Limitations of the study

A limitation of the research is the restriction of observation to post-HCT patients undergoing the first transplant engraftment. However, this subgroup allows for gender balance compared to other frequently observed subgroups (e.g., breast cancer women or prostate cancer men), and for the observation of the meaning-reconstruction process after the challenging treatment procedure. Furthermore, the assumed observation time (i.e. 14 days), may turn out to be insufficient to observe the effects of fluctuations in the meaning-making process (if these processes fluctuate at longer intervals than overnight or effects of their fluctuations are time-postponed). In that case, however, the research will provide valuable information on the dynamics of meaning-making processes.

Conclusion

The presented research project will fill in the gaps in health psychology in the understanding of the meaning-reconstruction process in cancer and the mechanisms of this process by a comprehensive verification of the integrative meaning-making model and its extension by the psychological flexibility model. The data obtained in the study will be used to design the experimental research on the effects of the psychological flexibility-based intervention on the meaning-making process.

7 Jun 2022

The role of psychological flexibility in the meaning-reconstruction process in cancer: the intensive longitudinal study protocol

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The rationale for the study and the science are good. Here are my comments:

1- The authors might want to include 'evidence of patient unreliability' as an exclusion criterion

2- If possible, the authors should provide some data about how many patients receive an HCT at the institution where the study will be held, and an estimate as to how many patients might fit the inclusion criteria. This will allow the authors to justify their timeline for data gathering.

3-Small detail: the authors mention that the participants will receive PLN 100 for their participation. I assume that the equivalent provided, ~$25, is in American dollars, in which case it should read USD 25.

4- The authors mention that all the questionnaires have good psychometrics in their original version, but do they have versions in the Polish language with proper reliability and validity? If the questionnaires have been translated and the Polish versions have validation data, the authors should mention this. If the questionnaires have not been translated, the authors should explain whether they will have the questionnaires translated professionally, or whether they will provide their own translation. How the questionnaires are translated for a Polish population may affect the quality of the study and may need to be mentioned as a limitation. In any case, the authors should plan to calculate the split-half reliability of their questionnaires (coefficient alpha) for their sample. This will give an indication of the quality of the questionnaire data, and reliability also affects the strength of the correlations. This is important since this is largely a correlational study.

Reviewer #2: The aim of this study is clear; the validation of the (undlying proces of) the Meaning-Making model and extension thereof with the psychological flexibility model.

Design

The design of the study is longitudinal with a basic measure (after inclusion), during 10 days several measurements of different variables during hospitalization and treatment, and final measure op day 11. The longitudinal design is logical, but I have doubts about the short duration. I am not an expert regarding the target population but I think that Meaning-making is:

1) Not exclusive is during hospitalization and treatment or even does not happen during this period because the focus is on treatment and somatic.

2) That these processes (meaning-making and psychological flexibility) hardly fluctuate during 10 to 11 days. Consequently a longer period is needed to notice changes within the person and/or outcome. The authors indicate this point as a limitation.

It is not clear to me why this population was selected. Have these patients a good chance of healing or are there usually permanent limitation which justifies that research into meaning-making is important for this population is ? Alternatively this population may be selected for practical reasons because of the multiple measurement during the isolation. I strongly suggest to specify the reason.

Method

In some cases only subscales from a questionnaire are used and other scales are shortened (justified by ref 24). Can the authors explain how this impact the validity of the measurements?

There may be a problem with the similarities of the proces variables (acceptance, and values out of psychological flexibility measurement) and the outcome variables (acceptance and sense of meaning in life from the psycholocical flexibility measurement). I have the impression that the overlap is so great that you measure approximately the same, what influences the results.

The outcome well being is measured for depression, anxiety, lonelyness and a HRQL measurement that is primarely oriented towards the symptoms. I can imagine that the subject meaning-making formulated as a positively formulated outcome measure of wellbeing could be chosen as supplement.

The power calculation is done for 150 persons. Considering the large number of variables (appoximately 17) this seems rather low. A statistician should be consulted to clarify this.

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25 Jun 2022

Dear Editor and Reviewers,

Re: Manuscript reference No. PONE-D-21-36245

Please find attached a revised version of the manuscript “The role of psychological flexibility in the meaning-reconstruction process in cancer: the intensive longitudinal study protocol” which we would like to re-submit for publication as a study protocol in the Plos ONE.

We wish to thank the Editor and the Reviewers for their precious suggestions and remarks concerning the manuscript. We found all the comments very useful as they provided insightful guidance on how to improve the manuscript’s quality. We highly appreciate the given chance to let us revise our manuscript and re-submit it to Plos ONE.

Please find our point-by-point responses to each comment of the Editor and the Reviewers. We provided two copies of the manuscript, in one of which all the corresponding changes in the manuscript are shown in the red font. We confirm that the manuscript meets Plos ONE’s style requirements. We also added the statement what role the funders will take in the study and the role it took in the preparation of this manuscript (The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript). Finally, we included captions for Supporting information files (ERB approval and funder confirmation) at the end of the manuscript.

We have also provided additional changes in the manuscript. We decided to move the diary measurement to the post-hospital period and therefore extend it to 14 days. 14 days of intensive follow-up is the standard period for this type of study. In addition, we decided to include in the study also patients qualified for allogeneic HCT. This group of patients is characterized by a longer time than the diagnosis, which will allow us to better test the moderating effect of this variable for the studied dependencies. There are still no unequivocal data on this subject in the literature. The modified study protocol received the approval of the Ethical Review Board.

We have indicated that data from this study will be available upon request. There are ethical restrictions on sharing a de-identified data set. The identification of each participants will be possible based on the demographics and clinical data, hence, the data will contain sensitive information and its publication will be able to infringe the anonymity of the participants. The Ethical Review Board at SWPS University of Social Sciences and Humanities, Faculty of Psychology in Warsaw may provide access upon request (psychoetyka@swps.edu.pl).

We hope that the revisions made in the manuscript and the accompanying responses will now be sufficient to make the manuscript suitable for publication.

We are looking forward to hearing from you at your earliest convenience.

Sincerely,

Authors

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Review Comments to the Author

Reviewer #1: The rationale for the study and the science are good. Here are my comments:

Response: We thank the reviewer very much for the overall evaluation of the study and its rationale.

1- The authors might want to include 'evidence of patient unreliability' as an exclusion criterion

Response: We thank the reviewer for this suggestion. We will be checking the data in this regard, so we have taken this suggestion into account. Thank you.

2- If possible, the authors should provide some data about how many patients receive an HCT at the institution where the study will be held, and an estimate as to how many patients might fit the inclusion criteria. This will allow the authors to justify their timeline for data gathering.

Response: We thank the reviewer for this suggestion. Annually, about 215 patients (who meet the criteria of the first autologous or allogeneic HCT) are admitted to the clinic. Among them, there may be people who do not meet the other criteria (the absence of any other major medical or psychiatric disorder other than cancer that would impede the ability to participate in the study and sufficient reading and writing skills), approx. 5%. This gives about 205 patients a year who meet the criteria. We estimate that approx. 40% of them will consent to participate in the study (approx. seven people per month). Hence, we estimate that the study will take about 21 months. It was similar in our earlier study in this group of patients. However, we reckon with the fact that this time, a pandemic situation may extend the time of data collection. We included this information in the Setting and Recruitment process section:

“Patients will be recruited from the Department of Bone Marrow Transplantation and Oncohematology of the Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO) Gliwice Branch, Poland. Approximately 215 primary transplants are performed there annually (approx. 246 HCT in total).” (p. 10)

“The recruitment is anticipated to cover the period from May 2022 to January 2024 (approx. 21 months; considering the decline rate of approximately 40%), depending on the COVID-19 pandemic. Participants will be paid PLN 100 (~USD 22) for the participation in the study.” (p.11)

3-Small detail: the authors mention that the participants will receive PLN 100 for their participation. I assume that the equivalent provided, ~$25, is in American dollars, in which case it should read USD 25.

Response: We thank the reviewer for paying attention to it. We corrected the error and adjusted the dollar amount based on the current exchange rate.

4- The authors mention that all the questionnaires have good psychometrics in their original version, but do they have versions in the Polish language with proper reliability and validity? If the questionnaires have been translated and the Polish versions have validation data, the authors should mention this. If the questionnaires have not been translated, the authors should explain whether they will have the questionnaires translated professionally, or whether they will provide their own translation. How the questionnaires are translated for a Polish population may affect the quality of the study and may need to be mentioned as a limitation. In any case, the authors should plan to calculate the split-half reliability of their questionnaires (coefficient alpha) for their sample. This will give an indication of the quality of the questionnaire data, and reliability also affects the strength of the correlations. This is important since this is largely a correlational study.

Response: We thank the reviewer for this comment. We have added the information about good psychometrics in the Polish version language. All tools (except SAM, CSE, and GMVS) have official Polish versions. SAM, CSE, and GMVS have been adopted by us in line with the art (back-translation method). SAM and CSE were already used by us in an earlier project in the same study group. The tools were characterized by very good psychometric properties. We have prepared GMVS for this project. The psychometric properties of this tool will be tested in the study. In a pilot study, we checked the understanding of items by potential study participants. It is not a complicated questionnaire (in part B it consists of the phrases: physical health, intimacy, social support, and community), the participants agreed that the items are clear and understandable, so we do not expect problems with the reliability or factor structure of this tool.

“In the original and Polish versions, all the tools (except GMVS whose psychometric properties will be tested in this study) are characterized by satisfactory psychometric properties. Table 1 shows the standard protocol items of the study.” (p. 13)

Of course, as in any diary study, all tools are modified for this procedure (change to instructions: asking about beliefs, emotions, behavior on a given day; matching the context: questions in the context of the patient's current health situation). It is a standard procedure in this type of research ensuring its ecological validity.

Regarding the reliability of the tools, we did not write this, but of course, it will be checked before starting the main analyses. We have added the appropriate statement in the description of the planned statistical analysis. Since the data will be hierarchical, reliability will be measured using the omega coefficient (Bolger & Laurenceau, 2013; Shrout & Lane, 2012). Using the Cronbach’s alpha coefficient for diary methods (when the primary analysis is a within-person analysis of change) is criticized (Shrout & Lane, 2012). In Cronbach’s alpha coefficient or classical test theory, all items are equally related to the underlying construct. For this reason, the use of the Cronbach’s alpha coefficient for within-person level (Level-1) data is inappropriate. We will perform the multilevel confirmatory factor analysis (MCFA), which allows for the specification of separate within-person and between-person reliability (and calculation of omega reliability at each level of analyses).

“Multilevel confirmatory factor analysis (MCFA) will be performed to calculate the indicator reliabilities (omega coefficient) at the within- and between-person levels and establish the respective measurement models [24,48].” (p. 15)

We would also like to inform you about the other modifications made. We decided to move the diary measurement to the post-hospital period and therefore extend it to 14 days. 14 days of the intensive longitudinal study is the standard period for this type of study (Bolger & Laurenceau, 2013; Mehl & Conner, 2012). In addition, we decided to include in the study also patients qualified for allogeneic HCT. This group of patients is characterized by a longer time than the diagnosis, which will allow us to better test the moderating effect of this variable for the studied dependencies. There are still no unequivocal data on this subject in the literature (Ochoa Arnedo et al., 2019; Park, 2011).

Reviewer #2: The aim of this study is clear; the validation of the (undlying proces of) the Meaning-Making model and extension thereof with the psychological flexibility model.

Response: We thank the reviewer very much for the overall evaluation and for summarizing the study aim.

Design

The design of the study is longitudinal with a basic measure (after inclusion), during 10 days several measurements of different variables during hospitalization and treatment, and final measure op day 11. The longitudinal design is logical, but I have doubts about the short duration. I am not an expert regarding the target population but I think that Meaning-making is:

1) Not exclusive is during hospitalization and treatment or even does not happen during this period because the focus is on treatment and somatic.

2) That these processes (meaning-making and psychological flexibility) hardly fluctuate during 10 to 11 days. Consequently a longer period is needed to notice changes within the person and/or outcome. The authors indicate this point as a limitation.

Response: We thank the reviewer for this comment. We decided to move the diary measurement to the post-hospital period. This was mainly due to the organizational reasons of the hospital, beyond our control. But we are sure that this change will make the study more ecologically valid. As suggested by the reviewer, the deliberative process over the meaning of transplantation may become more active in the post-hospital period. This change extended the diary measurement to 14 days. Two weeks is a standard for this type of research (Bolger & Laurenceau, 2013; Mehl & Conner, 2012). Importantly, we are primarily interested in the effects of day-to-day fluctuations in variables, and not changes throughout the study period. We took into account the length of the study in its limitations, but as a rule, the duration of the study has a greater influence on the observed changes in the variables over time, and not on their daily fluctuations. Therefore, the 14-day period seems to be sufficient to observe the effects of interest to us.

In addition, we decided to include in the study also patients qualified for allogeneic HCT. This group of patients is characterized by a longer time than the diagnosis, which will allow us to better test the moderating effect of this variable for the studied dependencies. There are still no unequivocal data on this subject in the literature (Ochoa Arnedo et al., 2019; Park, 2011).

It is not clear to me why this population was selected. Have these patients a good chance of healing or are there usually permanent limitation which justifies that research into meaning-making is important for this population is ? Alternatively this population may be selected for practical reasons because of the multiple measurement during the isolation. I strongly suggest to specify the reason.

Response: We thank the reviewer for this comment. We have modified the rationale for why it is worth measuring the meaning-making process in this group and this period.

“The purpose of our research will be (i) the identification of individual trajectories and sources of variation of the meaning-reconstruction process during a chronic disease, (ii) the investigation of psychological flexibility as a possible mediator of the meaning-reconstruction process, and (iii) the determination of within-person dynamic and reciprocal associations in the extended meaning-making model (see Fig 1) in an observational intensive longitudinal study among patients following autologous hematopoietic cell transplantation (HCT). HCT is a highly invasive and life-threatening treatment of hematologic neoplasms associated with burdensome adverse effects and a strong medical regimen for patients [25]. However, this procedure gives patients hope for recovery or long-term remission. Therefore, HCT can represent a mini-seismic event during coping with cancer (the turning point in patient lives) posing a challenge to the patient meaning structures. The post-HCT period may prompt reflection on the meaning of HCT and the patient current situation, which are part of meaning-making. In addition, HCT is mostly performed after the period known as the shock and denial phase. Potentially, this is the period during which the patient can start more reflective, meaning-making coping.” (pp. 7-8)

Method

In some cases only subscales from a questionnaire are used and other scales are shortened (justified by ref 24). Can the authors explain how this impact the validity of the measurements?

Response: The decision to choose items have depended on the number of items making up a given subscale. The optimal number of items per one indicator in the diary study is 5 (Bolger & Laurenceau, 2013). To be able to count the reliability of a given indicator, at least 2 items are needed. We created the protocol in such a way that - if possible - we should include at least 5 items for the indicator of a given variable (minimum 2). We managed to do it for almost all daily-diary measures (SAM – 5 items; CSE – 6 items, 2 per subscale; GMVS – 5 and 4 for each subscale; CBI – 6 items; C-PTGI-SF – 5 items; daily affect – 6 items per subscale). For example, it was not possible for psychological flexibility. The questionnaire MPFI-24 consists of 2 items for a given indicator, so we had to use it in its entirety. Besides, we included 8 items of PACT as meaning-making is a crucial variable in our study. Also, somatic symptoms are measured by a much greater number of items than five, because they cover possible somatic ailments of people after transplantation.

There may be a problem with the similarities of the proces variables (acceptance, and values out of psychological flexibility measurement) and the outcome variables (acceptance and sense of meaning in life from the psycholocical flexibility measurement). I have the impression that the overlap is so great that you measure approximately the same, what influences the results.

Response: We thank the reviewer for paying attention to it. We also had such concerns when we started this project. For this reason, we did not select the most commonly used measures for meaning-making such as acceptance and positive reframing from the COPE questionnaire. We were afraid that they would contaminate the measurement of psychological flexibility. In addition, we selected two tools (PACT and CBI) for meaning-making measurement. While the former may interfere with psychological flexibility, the latter should not (the items relate to other aspects of experience processing). For this reason, we also selected 8 PACT items for the study – to be able to remove those that will contaminate the MPFI-24. In addition, we will perform the multilevel confirmatory factor analysis (MCFA) which will not only allow us to estimate the reliability of the indicators but also test the measurement models before starting the specific analyzes (Bolger & Laurenceau, 2013; Shrout & Lane, 2012).

The outcome well being is measured for depression, anxiety, lonelyness and a HRQL measurement that is primarely oriented towards the symptoms. I can imagine that the subject meaning-making formulated as a positively formulated outcome measure of wellbeing could be chosen as supplement.

Response: Thank you for your attention. It may look like this. In the daily measurements of wellbeing, the proportion between pathogenetic and salutogenic indicators is maintained. In baseline and follow-up measurements, quality of life is supposed to be a salutogenic indicator. We have not decided to include, for example, Ryff’s SWB, because it may contaminate the acceptance measures (psychological flexibility) and sense of meaning (global meaning). In addition to well-being, we are going to see if the global sense of meaning (positively oriented) is changing (pre-HCT to post-HCT), which corresponds to what the reviewer wrote about.

The power calculation is done for 150 persons. Considering the large number of variables (appoximately 17) this seems rather low. A statistician should be consulted to clarify this.

Response: We thank the reviewer for this comment. We based the group calculation on statistical calculations. Similar values (125 and 140, respectively) come from the simulation study (for multilevel structural equation modeling: two-level models with random slopes and within-person mediation models) based on the Monte Carlo approach (Bolger & Laurenceau, 2013; Sagan, 2019). We have added this information in the manuscript:

“The sample size was estimated using a target power of 80%, at alpha of 0.05, and was calculated relative to the small effect size in the latent growth analysis using an a-priori sample size calculator [26]. A minimum of 125 patients should be sufficient to obtain the adequate power analyses. Considering the potential attrition rate of 20%, the final sample is 150 patients. Similar values (for two-level model with random slopes and within-person mediation model) come from simulation studies using the Monte Carlo approach [24,27].” (p. 10)

It is worth mentioning that 17 parameters will not be analyzed simultaneously. From our experience, even in a very large group (in this case it would have to be several thousand), with such a large number of variables, there would be a problem with model convergence. Our research hypotheses are testing the meaning-making model in pieces, taking into account key mediations and moderations. A group of about 150 people should be enough. If necessary, Bayesian estimation (standard on DSEM) will be used, which is recommended for small sample sizes. In studies in a clinical group, gathering a group of several thousand respondents is very difficult.

References:

Bolger, N., & Laurenceau, J.-P. (2013). Intensive longitudinal methods: An introduction to diary and experience sampling research. Guilford Press.

Mehl, M. R., & Conner, T. S. (2012). Handbook of research methods for studying daily life. Guilford Press.

Ochoa Arnedo, C., Sánchez, N., Sumalla, E. C., & Casellas-Grau, A. (2019). Stress and growth in cancer: Mechanisms and psychotherapeutic interventions to facilitate a constructive balance. Frontiers in Psychology, 10. https://doi.org/10.3389/fpsyg.2019.00177

Park, C. L. (2011). Meaning, coping, and health and well-being. In S. Folkman (Ed.), The Oxford handbook of stress, health, and coping (pp. 227–241). Oxford University Press.

Sagan, A. (2019). Sample size in multilevel structural equation modeling – the Monte Carlo approach. Econometrics, 23, 63–79. https://doi.org/10.15611/eada.2019.4.05

Shrout, P. E., & Lane, S. P. (2012). Psychometrics. In M. R. Mehl & T. S. Conner (Eds.), Handbook of research methods for studying daily life (pp. 302–320). The Guilford Press.

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28 Sep 2022

The role of psychological flexibility in the meaning-reconstruction process in cancer: the intensive longitudinal study protocol

PONE-D-21-36245R1

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1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

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The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

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4 Oct 2022

PONE-D-21-36245R1

The role of psychological flexibility in the meaning-reconstruction process in cancer: the intensive longitudinal study protocol

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