Association of Religious and Spiritual Factors With Patient-Reported Outcomes of Anxiety, Depressive Symptoms, Fatigue, and Pain Interference Among Adolescents and Young Adults With Cancer

Key Points Question Among adolescents and young adults with cancer, is there an association between spirituality and patient-reported outcomes, and are these outcomes associated with a sense of meaning, peace, and comfort provided by faith? Findings In this cross-sectional study of 126 adolescents and young adults with cancer, structural equation modeling revealed that meaning and peace were associated with aspects of spirituality and religiousness as well as anxiety, depressive, and fatigue symptoms. Meaning In this study, participants’ sense of meaning and peace was associated with religiousness and with anxiety and depression, possibly representing an underappreciated intervention target.


Introduction
Cancer is the leading cause of disease-related death among US residents aged 15 to 24 years. 1 Despite optimism regarding improving remission rates, adolescents and young adults in treatment continue to experience numerous adverse effects as well as physical, psychological, social, and spiritual comorbidities. 2 Adolescents report anxiety, depressive symptoms, fatigue, and pain interference as among their most debilitating patient-reported outcomes (PROs). [3][4][5] Palliative care provides symptom management and psychosocial support for patients with serious illness and their families.
Symptom management is person-centered and therefore spans the biopsychosocial-spiritual spectrum of concerns. 6 Coping with anxiety, depressive symptoms, fatigue, and pain interference is multifaceted.
Approaches to palliation may be pharmaceutic, psychologic, and, for many people, spiritual. Most of the US population (75%) reports spirituality is at least somewhat important, and 53% report that it is very important to them. 7 Many adolescents and young adults (AYAs) report shifting from institutional religion toward a broader spirituality 8 ; this does not mean these issues are unimportant.
In a qualitative study of 17 AYAs (aged 14 to 25 years) with cancer, 9 only 31% reported that they were neither spiritual nor religious; most identified as spiritual (whether religious or not).
Spirituality has shown mixed associations with health outcomes. Spiritual struggles 10 have almost consistently been associated with poorer health outcomes, especially mental health outcomes, in both AYAs and adults. [11][12][13][14][15] Studies of religion, spirituality, and anxiety in AYAs are few and have shown mixed results depending on how religion and spirituality were operationalized and whether state vs trait anxiety was measured. 16 A Canadian study showed AYAs aged 15 years and older with pain who were both spiritual and religious had better psychologic well-being scores and used positive coping methods more than those who were not. 17 Religion and spirituality are recognized as integral components of palliative care practice, although they may be underappreciated constructs in other fields. 6 Religion and spirituality are multidimensional and commonly studied in bivariate analyses with health outcomes. What is unknown are the potential pathways by which religious and spiritual constructs affect PROs. This hinders designing, developing, prototyping, and testing palliative interventions that include religion and spirituality to improve PROs among AYAs with cancer. When cancer occurs during adolescence or young adulthood, there are long-term consequences to adjustment, functioning, and disease selfmanagement. It is important to understand the potential role religion and/or spirituality play in 4 outcomes AYAs with cancer indicate are the most debilitating (ie, anxiety, depression, pain interference, and fatigue) to provide comprehensive therapies. The specific aims of this study were to examine how religious and spiritual factors were individually associated with anxiety, depression, pain interference, and fatigue PROs and to develop a model of how factors comprising spiritual well-being might lie in the pathway of the association of religious and spiritual factors with anxiety, depression, pain interference, and fatigue among AYAs with cancer.

Participants
This cross-sectional study used existing data from participants at baseline in a 4-site, prospective, longitudinal randomized clinical trial of the Family Centered Advance Care Planning for Teens with Cancer intervention. 18 The sample size for the primary study was determined by a power analysis for the primary outcomes. Data were collected at enrollment, occurring between July 16, 2016, and April 30, 2019. The sites were pediatric tertiary referral hospitals (Children's National Hospital, Washington, DC; Akron Children's Hospital, Akron, Ohio; St Jude Research Hospital, Memphis, Tennessee; and the University of Minnesota Health, Minneapolis). The primary trial was approved by the institutional review boards at participating institutions. Participants were a convenience sample of AYAs with any type of cancer who were treated at these sites at any point after their diagnosis.
Inclusion criteria were that participants be aged 14 to 21 years at enrollment; not known to have any developmental delay; have a Beck Depression Inventory total score less than 26; have English as their primary language; not be actively suicidal, homicidal, or psychotic; and be aware of their cancer diagnosis.

Procedures Methods
After obtaining informed consent from a family member of participants aged 14 to 17 years and assent from the participants and the consent of AYAs aged 18 years and older, baseline data were collected from participants at their first visit. With the AYA alone in a private room, research staff read the questions aloud to the AYA and entered the response into REDCap, unless AYAs requested to enter their own responses. 19 This approach controls for issues of literacy, health literacy, and uncorrected vision, while serving as an engagement strategy and maximizing likelihood of obtaining complete data.

Measures
Covariates (and potential confounders) obtained by medical record review or self-report (ie, age, sex, race, ethnicity, time since diagnosis, treatment status [ie, completed or ongoing], education, household income, and study site) and participants' self-ranking of the importance of religion and spirituality to them were collected. We FACIT-Sp | This 23-item nontheistic scale is frequently used to study spirituality and has good psychometric properties among adolescents with chronic illness. 27,28 The FACIT-Sp has 2 subscales: meaning and peace (items 1-8; eg, "I feel peaceful," "I have a reason for living") and faith (items 9-12; eg, "I find comfort/strength in my faith," "My illness has strengthened my faith or spiritual beliefs"). adolescent populatons. 15,25,27 For the purposes of this study, investigators a priori identified 5 items associated with and sensitive to quality of life outcomes 29,30 and end-of-life decision-making 31 based on their previous research with adolescents, 30 as follows: feeling God's presence; praying privately; attending religious services; identifying as religious; and identifying as spiritual. A higher score indicates higher religiousness and/or spirituality.

Statistical Analysis
Descriptive sample statistics were reported for social demographic characteristics and outcomes.
The religious and spiritual measures were dichotomized ( Table 1). The binary associations of religious and spiritual measures with patient self-reported PROMIS measures (ie, anxiety, depression, pain interference, and fatigue) were explored using t tests. Structural equation modeling was used to estimate the conceptual model (specified a priori and depicted in the eFigure in the Supplement), in which religious and spiritual measures were associated with the PROMIS symptoms through 2 latent variables (meaning and peace with 8 indicators and faith with 4 indicators, as shown in Table 2), respectively. The basis for the model specification was prior work positing meaning and peace between religious and spiritual beliefs and practices and health outcomes, and work on meaning and peace and depression as well as spiritual struggle and depresson. [32][33][34][35] The structural equation model was estimated using Bayesian estimator in Mplus 8.3 (Muthén and Muthén) that has superior performance in small samples without reliance on asymptotic and data normality assumptions. 36-39 The Bayesian approach is a full-information estimator using all available data under a missing-at-random assumption. Such a full information approach is superior to traditional approaches, such as listwise deletion, pairwise deletion, and similar response pattern imputation. [40][41][42] The missing-at-random assumption is more plausible than the missing-completelyat-random assumption in traditional statistical methods, allowing missingness to be associated with observed covariates and/or outcome measures. 37,39,43 The convergence of Bayesian estimation was evaluated by potential scale reduction (PSR). If PSR is close to 1 (eg, between 1.0 and 1.1) for all parameters in the model, it indicates that convergence has been achieved. The goodness of fit of the model was assessed by posterior predictive checking. 44 If the model fits data well, the 95% CI of the difference between the observed and replicated χ 2 statistics should center around 0, and the posterior predictive P value should be greater than .05. 38,44 Statistical inferences were made by examining the range of parameter estimates that captured 95% of the posterior probability distribution (ie, 95% Bayesian credibility interval, CrI). If the 95% CrI of a parameter estimate did not cover 0, then it was considered statistically significant at 2-tailed α = .05 level. 39,45,46

Results
A total of 336 AYAs with cancer who were potentially eligible for the parent study were approached.
Of these, 203 AYA (60.4%) declined and 3 (0.9%) did not meet secondary eligibility criteria for decision-making, yielding an enrollment rate of 38.7%. Eligible individuals who declined to indicate their racial identification also declined participation in the trial. A total of 126 AYAs completed baseline assessments; the sample had a mean (SD) age of 16.9 (1.9) years, with 72 (57.1%) female participants, 100 (79.4%) white participants, and 76 (60.3%) Protestant participants. Demographic characteristics are presented in Table 2. Descriptive statistics for PROMIS, FACIT-Sp, and religious and spiritual measures are provided in Table 3; binary associations between PROMIS and religious and spiritual measures appear in Table 1. The internal consistency of the FACIT-Sp subscale measures was good, with a Cronbach α of 0.79 for meaning and peace as well as faith. Binary associations of PROMIS with religious and spiritual measures are reported in Table 1.    12. I know that whatever happens with my illness, things will be okay 3. indicates not at all.

Religious and Spiritual Factors and Patient-Reported Outcomes in Young People With Cancer
Thus, an AYA reporting higher anxiety, depression, or fatigue was highly likely to also report lower levels of meaning/peace and of feeling God's presence daily. There were no significant findings for pain interference among the PROs or for daily prayer or attending religious services weekly among the religiousness variables.

Discussion
To our knowledge, this is the first study to document an indirect association of meaning and peace with religiousness and spirituality as well as the likelihood of anxiety, depressive symptoms, and fatigue in AYAs with cancer. Specifically, this study went beyond a bivariate approach, demonstrating that feeling God's presence and identifying as a very religious person were associated with the extent of anxiety, depressive symptoms, and fatigue. The model proposes an indirect association through a sense of meaning and peace. Although the causal direction of these associations cannot be established from our study, these results suggest that a novel and potentially efficacious intervention target may be a sense of meaning and peace when considering ways to improve anxiety, depression, and fatigue among AYAs with cancer.
Findings from the present study are also consistent with previously published theoretical models and empirical data. Park's work on meaning, including religious and spiritual meaning, 32,47,48 posits that religious and spiritual beliefs and practices inform constructed meaning, which is related to health outcomes. Meaning-making coping mediates the association of religiosity with psychological adjustment. 33   The current study's findings support the inclusion of constructed meaning as part of AYA oncology care. 55 This approach has also been recognized by the government of the Netherlands, which recently adopted a person-centered definition of health, including attention to meaning and meaninglessness. 57 Furthermore, that country's health budget provides for care at home by a recognized spiritual caregiver to address issues of illness-related meaning, focusing on persons older than 50 years and palliative care patients (including children) and their families. 58 Demonstration of the effects of these outcomes is in progress.
We anticipated finding an association between spiritual constructs and PROs and did not find Specialty care addressing meaning and peace to improve outcomes may take several forms.
Referrals to psychologists, who routinely deal with issues of spirituality, meaning, and health, may be appropriate. 32,51 Individual and group interventions addressing meaning for people with cancer have shown efficacy for increasing spiritual well-being and for decreasing anxiety, depression, and pain. [65][66][67][68] Referrals for specialty spiritual care from clinically trained chaplains may also be beneficial. 69 Chaplains are trained to work with existential questions of meaning within the framework of the patient's beliefs. 70,71 Meaningful conclusions can be drawn from this study, moving the state of the science of spirituality forward. 72 Meaning-making is a complex 73  Finally, the religious and spiritual affiliations of participants did not reflect the US demographic characteristics for this age group. There was a risk of participants providing socially desirable responses by having questions read aloud, although responses were entered by a research assistant who was trained to ask the questions in a way that would minimize bias. If adolescents preferred to enter their own responses, they were permitted; this rarely occurred. Furthermore, this was an analysis of baseline data informing an advance care planning trial. Male patients were more likely to decline participation in the primary study; thus, selection bias may affect the generalizability of these results. Nevertheless, strengths of this study include the application of rigorous scientific methods.
First, 39% of those approached agreed to participate. While this is lower than participation rates in psychosocial intervention trials and represents a limitation, 79 it is better than the 20% or lower

Conclusions
Study results demonstrated how multiple facets of religion and spirituality were associated with anxiety, depression, and fatigue among AYAs with cancer, which were associated with their sense of meaning and peace. Future research based on this study could explore the extent to which it represents a novel and potentially efficacious focus for intervention development to improve quality of life for AYAs after a cancer diagnosis.