For patients with end-stage lung disease, lung transplantation is now a viable treatment option to improve their quality of life (QoL) and extend their survival.1 Due to the growing number of individuals with advanced lung disease, the frequency of transplantation has increased exponentially during the past 2 decades, with nearly 42 000 patients having been transplanted; >2500 individuals were transplanted in 2016 and is projected to continue to increase in the future.2
Despite the increasing acceptance of lung transplantation as a treatment resulting in improved short-term survival, the median overall survival remains ~6 years,3 with only 26% of patients surviving to 10 years, which is markedly less than other solid organ transplants.4 Greater post-transplant mortality is primarily due to chronic lung allograft dysfunction (CLAD) as defined by a progressive decline in lung function. Even early post-transplantation has high morbidity, with as many as 4 out of 5 patients being rehospitalized within a year after transplant.5,6 This high health resource utilization results in compromised QoL and a significant economic burden to the patient, family, and healthcare system. Indeed, the importance of patients’ QoL has received growing attention as a marker of transplant success beyond just survival.7-9 Psychological distress can adversely affect recovery and impair QoL,10 while lack of regular exercise after lung transplantation is common, despite improved lung function.11,12
While lung transplantation extends survival and improves functional capacity for most patients, surprisingly, mental health QoL does not necessarily improve after transplant and actually may worsen over time.13 Prospective studies following lung transplant recipients during the first year of recovery suggest that 30% of patients experience major depression, 18% experience panic disorder, and 15% meet criteria for post-traumatic stress disorder.14 Indeed, a recent systematic review found that psychological QoL declines over time.15 Moreover, in a systematic review of psychological functioning following cardiothoracic transplantation, Dew and DiMartini16 found that post-transplant depressive and anxiety disorders are not only common, but that psychological distress following transplant was independently associated with worse clinical outcomes.
Indeed, few predictors of long-term clinical outcomes among lung transplant recipients have been identified.17 Lung allocation scores, which are used to prioritize candidates for donor lungs, are based on risk of death without a transplant and short-term survival after transplant; however, the lung allocation score only uses objective pretransplant factors including age, native disease, and disease severity, which are poorly predictive of longer-term outcomes after transplant.18 Recent evidence suggests that biobehavioral factors, particularly physical activity (PA) and psychological distress, may offer important prognostic information and may be modifiable with treatment.19-21
Poor 6-minute walk distance (6MWD) before transplant is one of the strongest predictors of pulmonary-related hospitalization20 and post lung transplant mortality,22,23 and objectively measured, leisure-time PA is more strongly associated with all-cause mortality among patients with pulmonary disease than traditional prognostic indices.24 Although regular aerobic exercise is recommended for lung recipients in the first year after transplant, most patients discontinue regular exercise on returning home following transplant, averaging 50% lower PA compared with healthy controls.25
There is now good evidence that greater functional status and higher levels of PA are associated with improved survival among patients with end-stage lung disease, including lung transplantation.22,26-29 Despite the importance of PA in patients with pulmonary disease, relatively few studies have examined PA after lung transplantation.30,31 Available evidence suggests that patients tend to engage in regular PA shortly after hospital discharge following lung transplant when participating in supervised pulmonary rehabilitation (PR), but exhibit a decrease in PA as early as 3 months following surgery,32 with a continued decline at 1 year, placing their PA level well below population norms.25 In addition, PA has been associated with preserved graft functioning in other transplant populations,33,34 and physical inactivity appears to worsen lung function,35-37 increasing the risk of poorer clinical outcomes.38,39 Moreover, evidence from small, pilot studies suggests that exercise can improve functional capacity in lung transplant recipients.40 Taken together, these data provide a strong rationale for the importance of regular aerobic exercise and increased PA as a way to improve long-term outcomes in lung transplant recipients.
There is also growing evidence that many patients experience significant psychological distress and poor psychological QoL following transplant, despite improvements in physical QoL.9,13,41 Lung transplant recipients exhibit a slower return to normal psychological functioning compared with other solid organ transplant recipients,42 and, surprisingly, it has been reported that psychological QoL fails to improve significantly following transplant,13 particularly among older patients.9 These data are important because elevated levels of psychological distress are associated with a variety of adverse events in transplant recipients, including CLAD43 and all-cause mortality,44 even after accounting for other clinical predictors. For example, in a study of 155 transplant recipients followed up to 15 years after transplant, Rosenberger et al43 found that depression assessed 1 year after transplant was associated with nearly twice the risk of chronic rejection, a 75% increase in the likelihood of graft loss, and a 65% increase in the risk of death. Similar findings in a sample of 132 lung transplant recipients assessed 6 months following transplantation demonstrated that greater psychological distress and depression, even at subclinical levels, were predictive of elevated mortality rates.45 These prognostic relationships also persisted when patients were assessed 18 months following transplant, with elevated depressive symptoms predicting a greater likelihood of death in the 10 years following transplant.44 These findings were confirmed in a small prospective study of 66 lung transplant recipients: greater depressive symptoms assessed 2 weeks after transplantation were strongly predictive of survival over a 3-year follow-up, independent of perioperative medical outcomes (eg, length of hospital stay and primary graft dysfunction).46 Similar results have been reported in other solid organ recipients. For example, DiMartini et al reported that depression following liver transplant more than doubled the risk of mortality,47 and found that treatment of depression during the post-transplant period mitigated this risk. Importantly, individuals who exhibited depressive symptoms that were subsequently treated exhibited no greater risk of mortality compared with nondepressed patients.21
Previous trials have demonstrated that behavioral interventions are effective in reducing distress and improving psychological QoL in patients with lung disease,48-51 including pretransplant patients.52 For example, coping skills training (CST), delivered to waitlisted prelung transplant candidates, has been shown to be effective in reducing psychological distress and depression, as well as to improve psychological QoL; further, improved coping and reduced distress mediated the beneficial effects of treatment.52
Exercise interventions also have been shown to reduce distress and improve depressive symptoms in a variety of clinical populations,53-57 including individuals with cardiovascular disease,58 heart failure,59-61 and chronic obstructive pulmonary disease.62 Furthermore, there is growing evidence that exercise may be comparable to the benefits of antidepressant medications in reducing depressive symptoms56,58 and has the additional benefit of improving physiological biomarkers,58,63-65 which also may contribute to long-term survival.66
Despite evidence that exercise improves muscle strength and functional capacity in post lung transplant patients,40,67 to our knowledge, few studies have examined the impact of exercise on distress, psychological QoL, and clinical outcomes in lung transplant recipients.38 In a study of chronic obstructive pulmonary disease patients, higher levels of PA were associated with lower levels of depression, and the relationship between elevated depressive symptoms and greater risk of adverse clinical events was mediated by low levels of PA.19 In addition, improvements in functional status and PA were associated with improved event-free survival, independent of traditional clinical risk markers.20 These findings suggest that exercise may play an important role in improving functional capacity, increasing PA, and reducing distress.
Surprisingly, there have been few studies that have attempted to reduce distress and improve functional capacity in lung transplant recipients. The mobile Pocket Personal Assistant for Tracking Health trial was a 1-year mobile health intervention randomized clinical trial (RCT) in post-transplant patients.68 While results showed that the mobile health participants initially performed self-monitoring more frequently, were more adherent to their medical regimens, and reported abnormal indicators more often to the clinical staff compared with usual care controls, group differences in self-management behaviors were not maintained and there was no difference in mortality or hospitalizations.68,69 Moreover, changes in psychological functioning or PA were not measured. These findings suggest that careful monitoring of self-management behaviors alone is not effective in sustaining behavior change or in improving medical outcomes. Investigational Study of Psychological Interventions in Recipients of Lung Transplant-III (INSPIRE–III) employs a RCT design, but also embraces proof-of-concept trial philosophy in which comprehensive pretreatment and post-treatment evaluations of distress, functional status, and QoL measures, as well as health behaviors targeted by the CST combined with exercise (CSTEX) intervention are performed. Figure 1 displays a conceptual model by which CSTEX aims to reduce distress and increase functional capacity, thereby improving key prognostic factors that independently impact QoL and clinical outcomes.
Promoting regular exercise and enhancing coping skills are 2 approaches that have been shown to reduce psychological distress, improve QoL, and increase functional capacity in patients with a variety of chronic conditions.48,52,61,70–72 However, despite data showing that psychological distress and physical inactivity are common in post-transplant patients, and are independently predictive of worse clinical outcomes, these strategies have not been integrated into the management of transplant recipients and, to our knowledge, no studies have targeted distress, low functional capacity, and physical inactivity in post lung transplant recipients. The resulting gap in our knowledge represents an important, unmet need to evaluate interventions designed to reduce psychological distress, improve functional capacity, and increase regular exercise in lung transplant recipients, to improve their psychological QoL, functional capacity, and ultimately, clinical outcomes.
CLINICAL TRIAL DESIGN
INSPIRE-III is a single site, parallel group RCT in which 150 lung transplant recipients will be randomly assigned with equal allocation to 12 weeks of CSTEX or to Standard of Care plus Education (SOC-ED). Native Disease (cystic fibrosis versus non–cystic fibrosis) and sex (male versus female) will be used as stratification variables. The CSTEX protocol will have 2 integrated components: the CST component will systematically train patients in the use of coping skills for stress reduction (eg, training in relaxation, imagery, cognitive restructuring, etc) and promote key transplant-specific health behaviors (eg, monitoring of pulmonary function, medical adherence, etc). The EX component of the intervention will progressively increase participants exercise and promote daily PA through motivational interviewing (MI) strategies used previously.61 Patients in the SOC-ED condition also will receive 12 weekly sessions that will provide support and enhanced post-transplant education. The primary endpoints will be a global measure of distress and 6MWD to quantify functional capacity. Secondary outcomes will include measures of frailty, PA, sleep and health behaviors, and medical outcomes (ie, CLAD), the latter of which will be documented by annual medical record review for up to 4 years (median >2 y).
The study sample will consist of 150 recent (<1 y) lung transplant recipients from a single center. All patients who have undergone a lung transplant within the past year will be contacted by e-mail and invited to participate in the trial.
Men or women aged 18 years or older; single or bilateral first lung transplant recipient; discharged from the hospital for a minimum of 6 weeks; completed post-transplant PR within the past year; and on a stable medication regimen.
Illness such as malignancies that are associated with a life-expectancy of <12 months; current pregnancy; inability to read or to provide informed consent (eg, due to dementia); multiorgan transplant recipient or repeat lung transplant.
CST Combined With Home-Based Exercise
The CSTEX intervention will consist of 12 weekly sessions, delivered remotely, and conducted by respiratory therapists knowledgeable about lung transplantation and trained in MI, cognitive behavior therapy, and exercise therapy (Table 1). Remote or distance therapy refers to the use of telemedicine or e-health approaches to treating patients outside the conventional in-person office-based visit. The CSTEX intervention will be delivered over the telephone in patients’ home environment. Remote therapy decreases the burden associated with in-person appointments, eliminates travel expenses for patients living in rural areas, and permits outreach to individuals who may be less receptive to traditional mental health services. The theoretical underpinnings of the CSTEX intervention reflect prior work grounded in social cognitive theory,73-76 self-management strategies,77-83 and MI techniques61,77 that have been adapted for post lung transplant recipients to address our proximal goals of (1) increasing functional capacity and (2) reducing psychological distress. The CSTEX intervention will use MI principles, using client-centered, collaborative engagement with reflective listening, validation, and elicitation of change talk.78,79,84 Consistent with social cognitive theory,74,75 initial sessions are designed to target daily exercise and focus on improving exercise self-efficacy by providing a rationale for exercise, instruction and goal setting (ie, exercise prescription), identification and management of barriers to exercise, and assessment and reinforcement of exercise participation from real-time Fitbit monitoring. Fitbit data will be used to guide individually tailored goals, calibrated to maximize early success and adoption of exercise. Fitbit data will be reviewed during each session and any issues will be addressed before addressing the scheduled topic area. As participants demonstrate self-mastery of exercise-related behavioral goals, the intervention focus will shift to emphasize elements of self-management theory.81,85-87 Coping skills to aid in the management of distress include training in relaxation techniques, cognitive restructuring, and problem solving.
The standard home-based exercise prescription for post-transplant patients is identical to the current recommendations for adults and includes frequency, intensity, and duration—30 minutes of moderate-vigorous intensity aerobic exercise (eg, walking), 3–5 d/wk for at least 150 minutes each week, flexibililty exercises, and muscle-strengthening activities that involve all major muscle groups 2 or more days a week.88 This is an aspirational goal that may not be realistic for all participants, so that exercise prescriptions will be individualized based on their baseline PA levels, 6MWD, and resting heart rate (HR). For most participants, the aerobic exercise prescription will consist of 30 minutes of aerobic exercise at least 3 d/wk at an intensity of 4–6/10 (“sort of hard” to “hard”) on the Modified Borg Rating of Perceived Exertion Scale, corresponding to a HR >60% max.
Use of Fitbit Technology
Participants will be provided with a Fitbit Inspire HR (Fitbit Group Health, San Francisco, CA) fitness wristband activity and HR monitor. They will be asked to wear the Fitbit daily during the 12-week intervention, from rising in the morning until bedtime, when they will recharge the device overnight. Participants will be instructed to perform the data-sync process at least once daily. While this commercially available device lacks the precision of the Actigraph GT9X Link, the more user-friendly Fitbit will provide reasonable estimates of bouts of moderate to vigorous PA (MVPA) and overall daily PA. Importantly, it has been shown to successfully strengthen PA interventions,89 encourage the use of theory-driven self-regulation skills,90 and will serve to increase participant motivation by providing feedback and enhancing participants’ accountability. The interventionists will be able to monitor participants’ daily MVPA exercise (of bouts >10 min) and PA remotely through the Fitbit Dashboard portal and will incorporate this information in their weekly sessions; participants also will have access to the Dashboard so they will be able to self-monitor their performance.
Training and Supervision of Respiratory Therapists
The training protocol integrates skills practice with real-time constructive feedback. The training of the respiratory therapists will be trained and supervised by experienced clinical psychologists (D.C.M. and F.J.K.). Interventionists will summarize the progress of therapy during weekly supervision sessions and specific problems will be addressed. In addition, clinical competence and adherence will be monitored by weekly review of contact logs and by regular review of audio-taped intervention sessions. Similarly, the SOC-ED sessions delivered by the health educators will be audiorecorded for review by our medical team to confirm that the intervention adheres to the manualized protocol.
Standard of Care and Education Comparison Group
Patients in the standard of care and lung transplant education condition (SOC-ED) will receive their standard medical care and, in addition, will receive twelve 30 minutes weekly calls for support and enhanced education about transplantation. During these calls, patients will be given detailed educational information about post-transplant care, the importance of medication adherence, and maintenance of PA (see Table 1 for list of educational topics). Participants randomized to the SOC-ED intervention also will be provided with a Fitbit to self-monitor their PA. Health educators will deliver the education module and assist patients with self-management but they will not instruct patients in coping strategies or provide PA feedback. Previous study has shown that self-management interventions alone may improve self-care, but do not reduce distress or improve survival.68
Assessments will include the 6-Minute Walk Test (6MWT), PA using actigraphy, pulmonary function, and a psychometric and behavioral battery consisting of a global measure of distress including stress, depression, anxiety, and anger; transplant QoL, frailty, coping, and self-efficacy. The psychological measures will be administered at 3 time points: baseline, 12 weeks, and 1-year follow-up. Participants will receive a link to complete the questionnaires online through Research Electronic Data Capture (REDCap). REDCap is a secure, web-based application designed to support data capture. At each time point, study participants receive a link to complete the questionnaires online. Through this web-based application, study staff are able to monitor the participants progress, send reminders to complete the questionnaires as needed, as well as verify when the questionnaire battery is complete. Because medical adherence is a critical aspect of patient management and ultimately clinical outcomes, both general medical adherence and medication adherence will be assessed. Specifically, adherence to medical regimen will be assessed using the Health Habits Survey.91,92 The Health Habits Survey is a self-report measure of behavioral compliance that uses an ordinal response format to determine post-transplant adherence such as taking medications in general and primary immunosuppressants, attending clinic appointments, performing home spirometry, and abstaining from tobacco use and limiting alcohol consumption. Following convention,91 responses for each element will be adjudicated based on the minimum level acceptable according to programmatic guidelines set forth by our study pulmonologists. To estimate overall adherence, elements are summed for a total score (range 0–10).
Because medication adherence is critical to the success of solid organ transplantation, we will rely on biologic markers of medication adherence. In addition to our self-report assessment of medication adherence, we will validate participants’ self-reported adherence levels using blood assays. Blood assay markers for tacrolimus (FK) and cyclosporine (CsA) are performed at each clinic visit using a therapeutic range for each drug based on clinical guidelines (eg, CsA: 100–150 ng/mL and FK: 5–10 ng/mL for most patients). Consistent with previously established methods,93,94 trough blood level results will be combined using the nontherapeutic blood assay variability of FK and CsA, in which the percentage of subtherapeutic or supratherapeutic FK/CsA assays are calculated by dividing the number of assays outside individually determined, recommended levels divided by the total number of FK/CsA assessments taken. Blood levels assessed >3 months following transplant will be used for baseline assessments, to allow for individual variability in initial metabolic adaptation to postoperative medication changes.
The primary endpoints for INSPIRE-III include (1) psychological distress and (2) functional capacity (6MWD).
- Psychological distress: The global measure of distress will consist of a combined score from 5 separate instruments, which have been found to (a) capture different aspects of distress, (b) predict clinical events, and (c) be modifiable with treatment.95
- Depression will be measured using the Beck Depression Inventory (BDI-II). The BDI-II is a 21-item self-report inventory of depression that assesses the current degree of depression through items pertaining to affective, cognitive, motivational, and physiologic areas of depressive symptomatology.96
- General distress will be measured using the General Health Questionnaire (GHQ). The GHQ is a 60-item screening questionnaire for nonpsychotic psychiatric disorders. It assesses somatic symptoms, anxiety, social dysfunction, and depression.97 The GHQ has been shown to be modifiable with treatment and predictive of adverse events.98,99
- Perceived stress will be measured by the Perceived Stress Scale (PSS). The PSS consists of 10 items that are evaluated on a 5-point Likert scale.100 The items on the PSS tap the degree to which individuals feel that events in their lives are unpredictable and uncontrollable.
- Anxiety will be measured by the State Trait Anxiety Inventory-State (20-item) version of the STAI.101 The STAI was developed as a tool for investigating anxiety in normal (nonpsychiatric) adults, but has been used in assessing anxiety in neuropsychiatric, medical, and surgical patients.
- Patient-Reported Outcomes Measurement Information System (PROMIS) Anger will be used to assess anger, which may be an important aspect of distress.102 The 8-item PROMIS Anger scale assesses several dimensions of anger with higher scores indicating greater anger.
- Functional capacity: Functional capacity will be quantified as the distance walked on the 6MWT.23,103 This procedure is a commonly performed test of functional capacity and is a functional measure of disease severity in patients with moderate to severe respiratory impairment and is a reliable and sensitive index of change in functional ability following treatment that is prognostic of clinical outcomes.104 The 6MWT is a self-paced, timed test of the total distance that a patient is able to walk in 6 minutes.
We will have several secondary endpoints, including a measure of CLAD-free survival (CLAD and all-cause mortality). Patients’ medical records will be reviewed semiannually and within 3 weeks following the anniversary of their baseline study assessments. Events will be adjudicated by our pulmonologists using standard criteria for CLAD.105 Data with regards to survival, retransplant, and CLAD are routinely obtained as part of regular clinic follow-up. Records of outside hospitalizations will be incorporated into the electronic record and information from a range of sources to populate a centrally managed Redcap database (https://redcap.duke.edu/redcap/).
PA will serve as another secondary endpoint and will be assessed using the Actigraph GT9X Link (Actigraph Corp., Pensacola, FL). The GT9X is a small, lightweight, rechargeable device that uses a 3-axis accelerometer, with motion sampled at a frequency of 30–100 Hz. It will be worn on the wrist, with time-of-day display active (but activity data display inaccessible) for 24 hours per day, over 7 consecutive days prerandomization, and again for 7 days postintervention. The total weekly minutes of MVPA will be the primary GT9X-based outcome measure, with secondary outcome measures including average daily cumulative step count and average daily energy expenditure (kcal/d), derived using the Actigraph Actilife software.106,107
The actigraph also will be used to assess sleep quality, derived from the wrist-worn GT9X actigraphy data obtained during the nighttime sleep periods over the 7-day preintervention/postintervention PA assessment protocol described above. The sleep parameters of primary interest will be average daily sleep duration (calculated by subtracting all periods of wakefulness from the time spent in bed) and sleep efficiency (defined as the ratio of total sleep time divided by time spent in bed).108-110 Additional measures will include sleep fragmentation index (a measure of the restlessness of sleep, defined as the sum of 2 percentages: the percentage of the sleep period spent moving, and the percentage of the number of immobile phases that were ≤1 min long). Scoring of actigraphy sleep data will follow the guidelines set forth by the Society of Behavioral Sleep Medicine.111 In addition to these objective measures of sleep quality, we also will assess subjective sleep times and quality over the 7 days of actigraphy monitoring, using the Consensus Sleep Diary Core.112 The Pittsburgh Sleep Quality Index, a widely used and reliable measure of global sleep quality,113 also will be administered prerandomization and postintervention.
The Lung Transplant Quality of Life Survey114,115 is a 60-item survey that measures 10 transplant-specific QoL domains including physical symptoms, functioning, emotional well-being, and health perceptions.116
Frailty will be assessed by the Fried Frailty Index including self-reported exhaustion, weak grip strength, slow walking speed, and low PA, and unintentional weight loss.117
The COPE Inventory,118 a measure of functional and dysfunctional coping styles, will be used to assess coping. Self-efficacy for emotional distress will be obtained from the 10-item General Self-efficacy scale.119
All analyses will follow the intention-to-treat principle, including all patients who were randomized. Patterns of missing data will be characterized using Rubin’s120 criteria and managed accordingly using Harrell’s multiple imputation (mult.impute) procedure in R. Intention-to-treat analysis will be supplemented with an examination of the treatment effect among completers using Rubin’s Complier Average Causal Effect model.121 The primary hypotheses (ie, that the CSTEX intervention will be superior to SOC-ED in reducing distress and improving functional capacity) will utilize the “gatekeeper” approach,122 which has been shown to maintain the experiment-wise error rate while maximizing power when testing multiple endpoints. This type of methodology has been widely advocated in RCTs involving medical populations123-131 as a parsimonious strategy to control type-I error within the first (ie, “gatekeeper”) step, because a favorable result on any individual component observed by chance is unlikely to be overly influential to the composite as a whole. Because the type-I error is minimized at this stage of analysis, the familywise error rate can then be propagated to the second analysis stage, examining individual components. In contrast, error correction to individual components of the composite measure often over-controls for type-I error when the purpose is explanatory. To mitigate type-I error with multiple outcomes, we will partition the conventional α = 0.05 to test treatment effects on global distress and functional capacity each at α = 0.025. Thus, for our examination of changes in global distress, an experiment-wise P value of 0.025 will be used to assess significance. If this test fails to be rejected at P ≤ 0.025, then tests of individual components are not interpreted. However, if improvements in global distress are found, examination of changes in individual components of distress are carried out in a secondary, explanatory step.132 Consistent with contemporary recommendations,133-138 secondary outcomes will be considered as potentially supportive and therefore examined at the α = 0.05 for each domain.
The effect of treatment on global distress will be assessed using the procedure recommended by O’Brien139 as a way to control for type 1 error with multiple endpoints across related domains. The general approach is to combine the multiple endpoints into a global score within a domain of interest. Before combining outcomes, each scale is transformed into ranks, which are then averaged. The global distress score will be comprised of the BDI-II, GHQ, PSS, STAI-S, and PROMIS Anger. Changes in global distress following treatment will be assessed using general linear modeling framework with treatment assignment (CSTEX versus SOC-ED) as a between-subjects factor, and pretreatment global distress, age, native disease, gender, type of transplant (bilateral versus unilateral), primary graft dysfunction, donor age, and total number of days hospitalized following transplant as covariates. Following the statistical principles section from the International Conference on Harmonization,140 we have selected the covariates for the primary models a priori, but we also will conduct auxiliary sensitivity analyses that evaluate whether potential group imbalances might have biased the treatment effect estimate. These analyses will be performed using conventional testing for confounding.141 A parallel approach will be used to examine changes in 6MWD using the same covariates and pretreatment 6MWD in lieu of global distress. Secondary outcomes will be examined using the same analytic strategy, with separate models for each outcome and a correction for multiple testing using Benjamini and Hochberg’s142 false discovery rate. Secondary outcomes will include PA during daily life, QoL, sleep quality, frailty, coping, and self-efficacy.
As an exploratory aim, CSTEX will be compared with SOC-ED on CLAD-free survival. Special consideration will be given to the high mortality (55% at 5 y) and frequency of CLAD (45% at 4 y)143 among lung transplant recipients. A clustered event approach will be used following the Wei-Lin-Weissfeld methodology,144,145 a recurrent time-to-event modeling approach in which multiple clinical outcomes can be aggregated into a unified criterion. We have previously used this approach,61 as the Wei-Lin-Weissfeld has been shown to improve power by up to 50% to detect group differences among clinical populations with high event rates.145 Specifically, separate Cox proportional hazards models will be aggregated into a composite outcome of (1) diagnosis of CLAD and (2) retransplantation or death. Patients who have not died or who have not been hospitalized will be managed as censored as of the time of last contact. This model will utilize the same covariates as above. In addition to examining the standard regression assumptions, assumptions specific to the Cox model will be assessed using techniques suggested by Schoenfeld.146 We will use Harrell’s Design and Hmisc libraries147 in the R software package (http://cran.r-project.org) to conduct these analyses.
Additional exploratory analyses will examine factors that may have mediated any observed treatment improvements in distress, functional capacity, or CLAD-free survival. Specifically, improvements in PA, medical adherence, and reduced distress will be examined as possible mediators of treatment-related improvements following the bootstrap procedures described by MacKinnon148 using the mediation package available in R for time-to-event outcomes149 and the PROCESS MACRO in SAS for continuous outcomes.150 We also will consider the persistence of benefit by examining the treatment effects at the 1-year follow-up using a repeated measures, mixed model approach (PROC MIXED in SAS).
With respect to changes in global distress, we estimated power using a correlation of 0.53 between covariates and the outcome,48 an initial sample size of 150 participants, attrition of 15%, and an α of 0.025. Based on these assumptions, we will have 80% power to detect a small-to-moderate treatment size difference (d = 0.44). For changes in functional capacity and PA, we should have 80% power to detect even small differences in 6MWD (d = 0.21) and total daily actigraphy steps (d = 0.32). As an exploratory aim, we also will examine the impact of CSTEX on clinical outcomes. Power for our exploratory clinical event models was estimated assuming a conservative event rate of 75% in the SOC-ED control group, 42 months for patient accrual, a median follow-up of 30 months, and a minimum follow-up time of 6 months. At an α of 0.05, and 75 patients per group, we will have 80% power to detect a 64% event rate reduction.
INSPIRE-III is a RCT that, if shown to be effective in improving functional capacity and QoL and potentially improving clinical outcomes, the CSTEX intervention could be adopted in the routine management of post-transplant recipients. The trial is unique in that few studies have examined the impact of behavioral interventions in post-transplant patients,151,152 and to our knowledge, none have done so among lung transplant recipients, despite the high prevalence of post-transplant psychological distress and its prognostic relationship with adverse clinical outcomes. Previous studies have focused on pretransplant psychological functioning, which is only weakly associated with post-transplant levels of distress and are not prognostic of poor clinical outcomes after surgery. In addition, by focusing on pretransplant candidates, studies have not accounted for clinically relevant, post-transplant medical factors and fail to target psychological factors at a time when behavioral aspects of care (eg, medical adherence, PA) are critical for optimal longer-term outcomes. Our examination of intervention effects on post-transplant clinical events is unique in that we will be targeting psychological distress and physical inactivity at a critical time for improving behavioral aspects of care.153 Our examination of long-term CLAD-free survival is also innovative in that we will test the premise that improving both psychological and physical well-being will lead to reduced lung transplant complications, admissions, improved medication compliance, and improved long-term CLAD-free survival.
We believe that the timing of the intervention is an important design feature insofar as the intervention will be delivered at a critical time in which patients, who are medically stable, have been transitioned from the security of an outpatient transplant PR program to their own home environment. This transition period is when patients are more likely to discontinue their exercise routines25 and often experience increased distress.16,45 As such, this transition period represents a window of opportunity in which patients may be especially receptive to behavioral interventions.154 Once patients leave the PR center and return home, they may be apprehensive about exercising on their own without supervision. CST teaches individuals to become aware of and change cognitions that contribute to anticipatory anxiety and avoidance of activity. Although previous trials have examined the impact of intervening among waitlisted lung candidates,52,155 no studies have targeted this important transition period, when patients need to maintain important health behaviors such as daily exercise and medication adherence, and are most vulnerable to depression, distress, and adverse medical events.
Previous studies have relied on the use of mental health professionals to deliver CST, which is often impractical and costly. Moreover, mental health professionals often are not familiar with the unique needs of transplant patients. Respiratory therapists, with specific knowledge and experience working with this patient population, are especially attuned to the issues these patients encounter on a daily basis. INSPIRE-III will engage respiratory therapists to deliver the CSTEX intervention, providing a translatable framework for “real-world” implementation of the intervention. Further, INSPIRE-III utilizes accelerometry assessment tools with Bluetooth capability and cloud-based data access, providing therapists with data-driven feedback on participants’ daily exercise and activity levels that will be incorporated in the weekly CSTEX therapy sessions. If successful, results of the INSPIRE-III could serve as a model for extending care of post lung transplant recipients by remotely delivering training in coping skills and exercise to promote enhanced psychosocial functioning, reduced distress, improved functional capacity, and potentially better clinical outcomes.
We want to express our thanks to the members of our Safety Monitoring Committee: Diane Catellier, PhD (chair), Krisa Ingle, PhD, Cindy M. Lawrence MSN, and Matthew Pipeling, MD, for their guidance and oversight of this study. We also thank Catherine Wu, MA, for her assistance in the preparation of this manuscript.
1. Christie JD, Edwards LB, Kucheryavaya AY, et al.; International Society of Heart and Lung TransplantationThe Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012.J Heart Lung Transplant2012311073–1086
2. The International Society for Heart and Lung TransplantationRegistries slides. [ISHLT Web site].2017Available at https://ishltregistries.org/registries/slides.asp
. Accessed April 26, 2017.
3. Yusen RD, Christie JD, Edwards LB, et al.; International Society for Heart and Lung TransplantationThe Registry of the International Society for Heart and Lung Transplantation: thirtieth adult lung and heart-lung transplant report–2013; focus theme: age.J Heart Lung Transplant201332965–978
4. Valapour M, Paulson K, Smith JM, et al. OPTN/SRTR 2011 annual data report: lung.Am J Transplant201313Suppl 1149–177
5. Alrawashdeh M, Zomak R, Dew MA, et al. Pattern and predictors of hospital readmission during the first year after lung transplantation.Am J Transplant2017171325–1333
6. Lushaj E, Julliard W, Akhter S, et al. Timing and frequency of unplanned readmissions after lung transplantation impact long-term survival.Ann Thorac Surg2016102378–384
7. Munro PE, Holland AE, Bailey M, et al. Pulmonary rehabilitation following lung transplantation.Transplant Proc200941292–295
8. Izoe Y, Harada T, Kohzuki M. Rehabilitation in patients undergoing lung transplantation (LTx).Pulm Res Respir Med Open J2017SES57–S62
9. Singer JP, Katz PP, Soong A, et al. Effect of lung transplantation on health-related quality of life in the era of the lung allocation score: a U.S. prospective cohort study.Am J Transplant2017171334–1345
10. Fusar-Poli P, Lazzaretti M, Ceruti M, et al. Depression after lung transplantation: causes and treatment.Lung200718555–65
11. Reinsma GD, ten Hacken NH, Grevink RG, et al. Limiting factors of exercise performance 1 year after lung transplantation.J Heart Lung Transplant2006251310–1316
12. Trulock EP. Lung transplantation.Am J Respir Crit Care Med1997155789–818
13. Finlen Copeland CA, Vock DM, Pieper K, et al. Impact of lung transplantation on recipient quality of life: a serial, prospective, multicenter analysis through the first posttransplant year.Chest2013143744–750
14. Dew MA, DiMartini AF, DeVito Dabbs AJ, et al. Onset and risk factors for anxiety and depression during the first 2 years after lung transplantation.Gen Hosp Psychiatry201234127–138
15. Seiler A, Klaghofer R, Ture M, et al. A systematic review of health-related quality of life and psychological outcomes after lung transplantation.J Heart Lung Transplant201635195–202
16. Dew MA, DiMartini AF. Psychological disorders and distress after adult cardiothoracic transplantation.J Cardiovasc Nurs2005205 SupplS51–S66
17. Gries CJ, Rue TC, Heagerty PJ, et al. Development of a predictive model for long-term survival after lung transplantation and implications for the lung allocation score.J Heart Lung Transplant201029731–738
18. Sweet SC, Shah AS. Lung transplantation–looking beyond 1-year survival.Am J Transplant2014142199–2200
19. Blumenthal JA, Smith PJ, Durheim M, et al. Biobehavioral prognostic factors in chronic obstructive pulmonary disease: results from the INSPIRE-II trial.Psychosom Med201678153–162
20. Durheim MT, Smith PJ, Babyak MA, et al. Six-minute-walk distance and accelerometry predict outcomes in chronic obstructive pulmonary disease independent of Global Initiative for Chronic Obstructive Lung Disease 2011 Group.Ann Am Thorac Soc201512349–356
21. Rogal SS, Dew MA, Fontes P, et al. Early treatment of depressive symptoms and long-term survival after liver transplantation.Am J Transplant201313928–935
22. Martinu T, Babyak MA, O’Connell CF, et al.; INSPIRE InvestigatorsBaseline 6-min walk distance predicts survival in lung transplant candidates.Am J Transplant200881498–1505
23. Castleberry AW, Englum BR, Snyder LD, et al. The utility of preoperative six-minute-walk distance in lung transplantation.Am J Respir Crit Care Med2015192843–852
24. Waschki B, Kirsten A, Holz O, et al. Physical activity is the strongest predictor of all-cause mortality in patients with COPD: a prospective cohort study.Chest2011140331–342
25. Langer D, Gosselink R, Pitta F, et al. Physical activity in daily life 1 year after lung transplantation.J Heart Lung Transplant200928572–578
26. Lederer DJ, Arcasoy SM, Wilt JS, et al. Six-minute-walk distance predicts waiting list survival in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med2006174659–664
27. Hallstrand TS, Boitano LJ, Johnson WC, et al. The timed walk test as a measure of severity and survival in idiopathic pulmonary fibrosis.Eur Respir J20052596–103
28. Wensel R, Opitz CF, Anker SD, et al. Assessment of survival in patients with primary pulmonary hypertension: importance of cardiopulmonary exercise testing.Circulation2002106319–324
29. Nixon PA, Orenstein DM, Kelsey SF, et al. The prognostic value of exercise testing in patients with cystic fibrosis.N Engl J Med19923271785–1788
30. Didsbury M, McGee RG, Tong A, et al. Exercise training in solid organ transplant recipients: a systematic review and meta-analysis.Transplantation201395679–687
31. Wickerson L, Mathur S, Brooks D. Exercise training after lung transplantation: a systematic review.J Heart Lung Transplant201029497–503
32. Wickerson L, Mathur S, Singer LG, et al. Physical activity levels early after lung transplantation.Phys Ther201595517–525
33. Mosconi G, Roi GS, Nanni Costa A, et al. [Physical activity and renal transplantation].G Ital Nefrol201128174–187
34. Romano G, Lorenzon E, Montanaro D. Effects of exercise in renal transplant recipients.World J Transplant2012246–50
35. Huppmann P, Sczepanski B, Boensch M, et al. Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease.Eur Respir J201342444–453
36. Jastrzebski D, Ochman M, Ziora D, et al. Pulmonary rehabilitation in patients referred for lung transplantation.Adv Exp Med Biol201375519–25
37. Dowman L, McDonald CF, Hill C, et al. The benefits of exercise training in interstitial lung disease: protocol for a multicentre randomised controlled trial.BMC Pulm Med2013138
38. Smith PJ, Frankel CW, Bacon DR, et al. Depressive symptoms, physical activity, and clinical events: the ADAPT prospective pilot study.Clin Transplant201933e13710
39. Smith PJ, Byrd R, Lusby M, et al. Depressive symptoms, exercise capacity, and clinical outcomes after lung transplantation.Psychosom Med201880403–409
40. Langer D, Burtin C, Schepers L, et al. Exercise training after lung transplantation improves participation in daily activity: a randomized controlled trial.Am J Transplant2012121584–1592
41. Limbos MM, Joyce DP, Chan CK, et al. Psychological functioning and quality of life in lung transplant candidates and recipients.Chest2000118408–416
42. Pinson CW, Feurer ID, Payne JL, et al. Health-related quality of life after different types of solid organ transplantation.Ann Surg2000232597–607
43. Rosenberger EM, DiMartini AF, DeVito Dabbs AJ, et al. Psychiatric predictors of long-term transplant-related outcomes in lung transplant recipients.Transplantation2016100239–247
44. Smith PJ, Blumenthal JA, Carney RM, et al. Neurobehavioral functioning and survival following lung transplantation.Chest2014145604–611
45. Smith PJ, Blumenthal JA, Trulock EP, et al. Psychosocial predictors of mortality following lung transplantation.Am J Transplant201616271–277
46. Smith PJ, Blumenthal JA, Snyder LD, et al. Depressive symptoms and early mortality following lung transplantation: a pilot study.Clin Transplant201731e12874
47. DiMartini A, Dew MA, Chaiffetz D, et al. Early trajectories of depressive symptoms after liver transplantation for alcoholic liver disease predicts long-term survival.Am J Transplant2011111287–1295
48. Blumenthal JA, Emery CF, Smith PJ, et al. The effects of a telehealth coping skills intervention on outcomes in chronic obstructive pulmonary disease: primary results from the INSPIRE-II study.Psychosom Med201476581–592
49. Emery CF, Schein RL, Hauck ER, et al. Psychological and cognitive outcomes of a randomized trial of exercise among patients with chronic obstructive pulmonary disease.Health Psychol199817232–240
50. de Godoy DV, de Godoy RF. A randomized controlled trial of the effect of psychotherapy on anxiety and depression in chronic obstructive pulmonary disease.Arch Phys Med Rehabil2003841154–1157
51. Kunik ME, Braun U, Stanley MA, et al. One session cognitive behavioural therapy for elderly patients with chronic obstructive pulmonary disease.Psychol Med200131717–723
52. Blumenthal JA, Babyak MA, Keefe FJ, et al. Telephone-based coping skills training for patients awaiting lung transplantation.J Consult Clin Psychol200674535–544
53. Silveira H, Moraes H, Oliveira N, et al. Physical exercise and clinically depressed patients: a systematic review and meta-analysis.Neuropsychobiology20136761–68
54. Rethorst CD, Wipfli BM, Landers DM. The antidepressive effects of exercise: a meta-analysis of randomized trials.Sports Med200939491–511
55. Mead GE, Morley W, Campbell P, et al. Exercise for depression.Cochrane Database Syst Rev20082009CD004366
56. Blumenthal JA, Babyak MA, Doraiswamy PM, et al. Exercise and pharmacotherapy in the treatment of major depressive disorder.Psychosom Med200769587–596
57. Blumenthal JA, Babyak MA, Moore KA, et al. Effects of exercise training on older patients with major depression.Arch Intern Med19991592349–2356
58. Blumenthal JA, Sherwood A, Babyak MA, et al. Exercise and pharmacological treatment of depressive symptoms in patients with coronary heart disease: results from the UPBEAT (understanding the prognostic benefits of exercise and antidepressant therapy) study.J Am Coll Cardiol2012601053–1063
59. Gary RA, Dunbar SB, Higgins MK, et al. Combined exercise and cognitive behavioral therapy improves outcomes in patients with heart failure.J Psychosom Res201069119–131
60. Blumenthal JA, Babyak MA, O’Connor C, et al. Effects of exercise training on depressive symptoms in patients with chronic heart failure: the HF-ACTION randomized trial.JAMA2012308465–474
61. Sherwood A, Blumenthal JA, Koch GG, et al. Effects of coping skills training on quality of life, disease biomarkers, and clinical outcomes in patients with heart failure: a randomized clinical trial.Circ Heart Fail201710e003410
62. Emery CF, Shermer RL, Hauck ER, et al. Cognitive and psychological outcomes of exercise in a 1-year follow-up study of patients with chronic obstructive pulmonary disease.Health Psychol200322598–604
63. Sherwood A, Blumenthal JA, Smith PJ, et al. Effects of exercise and sertraline on measures of coronary heart disease risk in patients with major depression: results from the SMILE-II randomized clinical trial.Psychosom Med201678602–609
64. Blumenthal JA, Sherwood A, Babyak M, et al. Mental stress and coronary disease. The smart-heart study.N C Med J19996095–99
65. Blumenthal JA, Sherwood A, Babyak MA, et al. Effects of exercise and stress management training on markers of cardiovascular risk in patients with ischemic heart disease: a randomized controlled trial.JAMA20052931626–1634
66. Lin X, Zhang X, Guo J, et al. Effects of exercise training on cardiorespiratory fitness and biomarkers of cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials.J Am Heart Assoc20154e002014
67. Langer D. Rehabilitation in patients before and after lung transplantation.Respiration201589353–362
68. DeVito Dabbs A, Song MK, Myers BA, et al. A randomized controlled trial of a mobile health intervention to promote self-management after lung transplantation.Am J Transplant2016162172–2180
69. Rosenberger EM, DeVito Dabbs AJ, DiMartini AF, et al. Long-term follow-up of a randomized controlled trial evaluating a mobile health intervention for self-management in lung transplant recipients.Am J Transplant2017171286–1293
70. Bennell KL, Ahamed Y, Jull G, et al. Physical therapist-delivered pain coping skills training and exercise for knee osteoarthritis: randomized controlled trial.Arthritis Care Res (Hoboken)201668590–602
71. Somers TJ, Kelleher SA, Westbrook KW, et al. A small randomized controlled pilot trial comparing mobile and traditional pain coping skills training protocols for cancer patients with pain.Pain Res Treat201620162473629
72. Keefe FJ, Shelby RA, Somers TJ, et al. Effects of coping skills training and sertraline in patients with non-cardiac chest pain: a randomized controlled study.Pain2011152730–741
73. Bennell KL, Rini C, Keefe F, et al. Effects of adding an internet-based pain coping skills training protocol to a standardized education and exercise program for people with persistent hip pain (HOPE trial): randomized controlled trial protocol.Phys Ther2015951408–1422
74. Bandura A. Self-Efficacy: The Exercise of Control1997New York, NYW.H. Freeman and Company
75. Bandura A. Social Foundations of Thought and Action: A Social Cognitive Theory1986Englewood Cliffs, NJPrentice-Hall
76. Blonstein AC, Lv N, Camargo CA, et al. Acceptability and feasibility of the ‘DASH for asthma’ intervention in a randomized controlled trial pilot study.Public Health Nutr2016192049–2059
77. Keefe FJ, Lefebvre JC, Kerns RD, et al. Understanding the adoption of arthritis self-management: stages of change profiles among arthritis patients.Pain200087303–313
78. Rollnick SM, Miller WR, Butler CC. Motivational Interviewing in Health Care: Helping Patients Change Behavior2008New York, NYGuilford Press
79. Miller WR, Rollnick S. Motivational Interviewing: Helping People Change2012New York, NYGuilford Press
80. Knittle K, De Gucht V, Hurkmans E, et al. Explaining physical activity maintenance after a theory-based intervention among patients with rheumatoid arthritis: process evaluation of a randomized controlled trial.Arthritis Care Res (Hoboken)201668203–210
81. Bond DS, Vithiananthan S, Thomas JG, et al. Bari-active: a randomized controlled trial of a preoperative intervention to increase physical activity in bariatric surgery patients.Surg Obes Relat Dis201511169–177
82. Bond DS, Thomas JG, King WC, et al. Exercise improves quality of life in bariatric surgery candidates: results from the bari-active trial.Obesity (Silver Spring)201523536–542
83. Sakakibara BM, Lear SA, Barr SI, et al. Development of a chronic disease management program for stroke survivors using intervention mapping: the stroke coach.Arch Phys Med Rehabil2017981195–1202
84. Miller WR, Rollnick S. Motivational Interviewing: Preparing People for Change1991New York, NYGuilford Press
85. Kahlert D, Unyi-Reicherz A, Stratton G, et al. PREVIEW behavior modification intervention toolbox (PREMIT): a study protocol for a psychological element of a multicenter project.Front Psychol201671136
86. Wadden TA, West DS, Delahanty L, et al. Look AHEAD Research Group. The Look AHEAD study: a description of the lifestyle intervention and the evidence supporting it.Obesity (Silver Spring, Md)200614737–752
87. Richardson J, Loyola-Sanchez A, Sinclair S, et al. Self-management interventions for chronic disease: a systematic scoping review.Clin Rehabil2014281067–1077
88. American College of Sports MedicineACSM’s Guidelines for Exercise Testing and Prescription201710th edPhiladelphia, PALippincott Williams & Wilkins
89. Cadmus-Bertram LA, Marcus BH, Patterson RE, et al. Randomized trial of a fitbit-based physical activity intervention for women.Am J Prev Med201549414–418
90. Michie S, Abraham C, Whittington C, et al. Effective techniques in healthy eating and physical activity interventions: a meta-regression.Health Psychol200928690–701
91. DeVito Dabbs A, Dew MA, Myers B, et al. Evaluation of a hand-held, computer-based intervention to promote early self-care behaviors after lung transplant.Clin Transplant200923537–545
92. Dew MA, Kormos RL, Roth LH, et al. Early post-transplant medical compliance and mental health predict physical morbidity and mortality one to three years after heart transplantation.J Heart Lung Transplant199918549–562
93. Flippin MS, Canter CE, Balzer DT. Increased morbidity and high variability of cyclosporine levels in pediatric heart transplant recipients.J Heart Lung Transplant200019343–349
94. Schäfer-Keller P, Steiger J, Bock A, et al. Diagnostic accuracy of measurement methods to assess non-adherence to immunosuppressive drugs in kidney transplant recipients.Am J Transplant20088616–626
95. Blumenthal JA, Sherwood A, Smith PJ, et al. Enhancing cardiac rehabilitation with stress management training: a randomized, clinical efficacy trial.Circulation20161331341–1350
96. Beck AT, Steer RA, Brown GK. Beck Depression Inventory Manual1996San Antonio, TXThe Psychological Corporation
97. Goldberg D. The Detection of Psychiatric Illness by Questionnaire1972London, UKOxford University Press
98. Frasure-Smith N. In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men.Am J Cardiol199167121–127
99. Stansfeld SA, Fuhrer R, Shipley MJ, et al. Psychological distress as a risk factor for coronary heart disease in the Whitehall II Study.Int J Epidemiol200231248–255
100. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress.J Health Soc Behav198324385–396
101. Spielberger CE, Gorsuch RL. Manual for the State-Trait Anxiety Inventory1970Palo Alto, CAConsulting Psychologists Press
102. Cella D, Riley W, Stone A, et al.; PROMIS Cooperative GroupThe patient-reported outcomes measurement information system (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008.J Clin Epidemiol2010631179–1194
103. Castleberry AW, Englum BR, Snyder LD, et al. Utility of six-minute walk distance in predicting outcomes after lung transplant: a nationwide survival analysis.J Heart Lung Transpl201332S147
104. ATS Committee on Proficiency Standards for Clinical Pulmonary Function LaboratoriesATS statement: guidelines for the six-minute walk test.Am J Respir Crit Care Med2002166111–117
105. DerHovanessian A, Todd JL, Zhang A, et al. Validation and refinement of chronic lung allograft dysfunction phenotypes in bilateral and single lung recipients.Ann Am Thorac Soc201613627–635
106. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart Association.Med Sci Sports Exerc2007391423–1434
107. Heil DP, Brage S, Rothney MP. Modeling physical activity outcomes from wearable monitors.Med Sci Sports Exerc2012441 Suppl 1S50–S60
108. Marino M, Li Y, Rueschman MN, et al. Measuring sleep: accuracy, sensitivity, and specificity of wrist actigraphy compared to polysomnography.Sleep2013361747–1755
109. Ancoli-Israel S, Cole R, Alessi C, et al. The role of actigraphy in the study of sleep and circadian rhythms.Sleep200326342–392
110. Sadeh A, Acebo C. The role of actigraphy in sleep medicine.Sleep Med Rev20026113–124
111. Ancoli-Israel S, Martin JL, Blackwell T, et al. The SBSM guide to actigraphy monitoring: clinical and research applications.Behav Sleep Med201513(Suppl 1)S4–S38
112. Carney CE, Buysse DJ, Ancoli-Israel S, et al. The consensus sleep diary: standardizing prospective sleep self-monitoring.Sleep201235287–302
113. Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research.Psychiatry Res198928193–213
114. Hailey D, Roine R, Ohinmaa A. The effectiveness of telemental health applications: a review.Can J Psychiatry200853769–778
115. Bee PE, Bower P, Lovell K, et al. Psychotherapy mediated by remote communication technologies: a meta-analytic review.BMC Psychiatry2008860
116. Singer JP, Soong A, Chen J, et al. Development and preliminary validation of the lung transplant quality of life (LT-QOL) survey.Am J Respir Crit Care Med20191991008–1019
117. Fried LP, Tangen CM, Walston J, et al.; Cardiovascular Health Study Collaborative Research GroupFrailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci200156M146–M156
118. Carver CS, Scheier MF, Weintraub JK. Assessing coping strategies: a theoretically based approach.J Pers Soc Psychol198956267–283
119. Luszczynska A, Scholz U, Schwarzer R. The general self-efficacy scale: multicultural validation studies.J Psychol2005139439–457
120. Little RJ, Rubin DB. Statistical Analysis with Missing Data1987New York, NYJ. WIley & Sons
121. Little RJ, Yau LHY. Statistical techniques for analyzing data from prevention trials: treatment of no-shows using Rubin’s causal model.Psychol Methods June19983147–159
122. Dmitrienko A, Offen WW, Westfall PH. Gatekeeping strategies for clinical trials that do not require all primary effects to be significant.Stat Med2003222387–2400
123. Tilley BC, Marler J, Geller NL, et al. Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial.Stroke1996272136–2142
124. Anderson JL, Muhlestein JB, Carlquist J, et al. Randomized secondary prevention trial of azithromycin in patients with coronary artery disease and serological evidence for chlamydia pneumoniae infection: the azithromycin in coronary artery disease: elimination of myocardial infection with chlamydia (ACADEMIC) study.Circulation1999991540–1547
125. Macle L, Khairy P, Weerasooriya R, et al.; ADVICE trial investigatorsAdenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial.Lancet2015386672–679
126. Engel J Jr, McDermott MP, Wiebe S, et al.; Early Randomized Surgical Epilepsy Trial (ERSET) Study GroupEarly surgical therapy for drug-resistant temporal lobe epilepsy: a randomized trial.JAMA2012307922–930
127. Gheorghiade M, Konstam MA, Burnett JC Jr, et al.; Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) InvestigatorsShort-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: the EVEREST clinical status trials.JAMA20072971332–1343
128. Zafonte RD, Bagiella E, Ansel BM, et al. Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: citicoline brain injury treatment trial (COBRIT).JAMA20123081993–2000
129. Hollenberg NK, Williams GH, Anderson R, et al. Symptoms and the distress they cause: comparison of an aldosterone antagonist and a calcium channel blocking agent in patients with systolic hypertension.Arch Intern Med20031631543–1548
130. Poole CJ, Earl HM, Hiller L, et al.; NEAT Investigators and the SCTBGEpirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer.N Engl J Med20063551851–1862
131. Chesnut RM, Temkin N, Carney N, et al.; Global Neurotrauma Research GroupA trial of intracranial-pressure monitoring in traumatic brain injury.N Engl J Med20123672471–2481
132. Koch GG, Gansky SA. Statistical considerations for multiplicity in confirmatory protocols.Drug Inf J199630523–533
133. Dmitrienko A, Tamhane AC, Wiens BL. General multistage gatekeeping procedures.Biom J200850667–677
134. Dmitrienko A, Tamhane AC. Gatekeeping procedures with clinical trial applications.Pharm Stat20076171–180
135. Westfall P, Krishen A. Optimally weighted, fixed sequence and gatekeeper multiple testing procedures.J Stat Plan Infer20019925–40
136. Comelli M, Klersy C. Different methods to analyze clinical experiments with multiple endpoints: a comparison of real data.J Biopharm Stat19966115–125
137. Pocock SJ, Stone GW. The primary outcome is positive - is that good enough?N Engl J Med2016375971–979
138. Pocock SJ, Stone GW. The primary outcome fails - what next?N Engl J Med2016375861–870
139. O’Brien PC. Procedures for comparing samples with multiple endpoints.Biometrics1984401079–1087
140. International Conference on HarmonisationStatistical principles in clinical trials (E9).1997Available at http://www.ich.org/LOB/media/MEDIA485.pdf
. Accessed April 26, 2017.
141. Berger V. Selection Bias and Covariate Imbalances in Randomized Clinical Trials2005Hoboken, NJWiley
142. Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing.J R Stat Soc Series B Methodol199557289–300
143. Faust HE, Golden JA, Rajalingam R, et al. Short lung transplant donor telomere length is associated with decreased CLAD-free survival.Thorax2017721052–1054
144. Wei LJ, Lin DY, Weissfeld L. Regression analysis of multivariate incomplete failure time data by modeling marginal distributions.J Am Stat Assoc1989841065–1073
145. Saville BR, Herring AH, Koch GG. A robust method for comparing two treatments in a confirmatory clinical trial via multivariate time-to-event methods that jointly incorporate information from longitudinal and time-to-event data.Stat Med20102975–85
146. Schoenfeld D. Partial residuals for the proportional hazards regression model.Biometrika198269239–241
147. Harrell FE. Regression Modeling Strategies: With Applications to Linear Modeling, Logistic Regression, and Survival Analysis2001New York, NYSpringer
148. MacKinnon DP, Lockwood CM, Hoffman JM, et al. A comparison of methods to test mediation and other intervening variable effects.Psychol Methods2002783–104
149. Tingley D, Yamamoto T, Keele L, et al. Mediation: R Package for causal mediation analysis.J Stat Software2014591–38
150. Hayes AF, Rockwood NJ. Regression-based statistical mediation and moderation analysis in clinical research: observations, recommendations, and implementation.Behav Res Ther20179839–57
151. Conway A, Sheridan J, Maddicks-Law J, et al. Pilot testing a model of psychological care for heart transplant recipients.BMC Nurs20161562
152. Laudenslager ML, Simoneau TL, Kilbourn K, et al. A randomized control trial of a psychosocial intervention for caregivers of allogeneic hematopoietic stem cell transplant patients: effects on distress.Bone Marrow Transplant2015501110–1118
153. Cupples S, Dew MA, Grady KL, et al. Psychosocial Outcomes Workgroup of the Nursing and Social Sciences Council of the International Society for Heart and Lung Transplantation. Report of the Psychosocial Outcomes Workgroup of the Nursing and Social Sciences Council of the International Society for Heart and Lung Transplantation: present status of research on psychosocial outcomes in cardiothoracic transplantation: review and recommendations for the field.J Heart Lung Transplant200625716–725
154. McBride CM, Emmons KM, Lipkus IM. Understanding the potential of teachable moments: the case of smoking cessation.Health Educ Res200318156–170
155. Rodrigue JR, Mandelbrot DA, Pavlakis M. A psychological intervention to improve quality of life and reduce psychological distress in adults awaiting kidney transplantation.Nephrol Dial Transplant201126709–715