This study is reported following the Strengthening of Reporting in Observational studies in Epidemiology (STROBE) guidance .
The Intensive Care Outcomes Network study (ICON) was a UK multicentre prospective cohort study assessing heath related quality of life (HRQoL) and caseness of anxiety, depression and PTSD, by postal questionnaire, following at least 24 h treatment on an ICU. Caseness is the degree to which the accepted standardised diagnostic criteria for a given condition are applicable to a given patient. A questionnaire study assesses the self-reported symptom burden consistent with a specific disorder but cannot be considered diagnostic. The trial was registered ISRCTN69112866 (assigned 2 May 2006) and the study protocol has been published . This study was conducted in three consecutive phases (summarised in Additional file 1). Ethical approval for phases 1 and 2 was granted by Oxfordshire Research Ethics Committee B (REC 06/Q1605/17). Ethical approval for phase 3 was granted by National Research Ethics Service – South Central Berkshire (REC 11/SC/0172). The ICON study had Section 60 of the Health and Social Care Act 2001 (subsequently Section 251 of the National Health Service (NHS) Act 2006) approval (PIAG 2–05(e)/2006). This granted permission to record details of all admissions meeting the inclusion criteria at participating ICUs.
Phases 1 and 2 took place in the same 26 UK ICUs (1 university hospital, 6 university-affiliated hospitals and 19 district general hospitals) and postal questionnaires were sent at 3, 12 and 24 months following discharge form ICU. Phase 1 recruited from November 2006 to May 2008 and recruited 9582 patients. Phase 2 recruited from May 2008 to October 2010 and recruited 18,490 patients as part of an RCT to study the effect of different questionnaire burden on response rate, the results of which have been published .
Phase 3 took place between May 2012 and May 2013 in 31 UK ICUs (10 university hospital, 3 university-affiliated hospitals and 18 district general hospitals), and of these 18 recruiting centres are common with phases 1 and 2. Phase 3 recruited 2876 patients, with postal questionnaires administered at 3 and 12 months post ICU discharge. Questionnaire burden was identical to phase 1. Where possible patients were approached by a research nurse prior to their discharge from hospital. Patients were followed up by telephone if they later failed to respond to a postal questionnaire.
We extracted data from all three phases of the ICON study database, with the exception of group A from the second phase, as this group did not receive psychological instruments by design [15, 16]. Each phase had identical inclusion and exclusion criteria.
Eligible patients received level 3 care on an ICU (as defined by the Intensive Care Society, London ), for at least 24 h and were 16 years or older at ICU admission. We excluded patients not registered with a general practitioner or of no fixed abode (factors anticipated to prevent follow up in the study). We also excluded patients taking part in another questionnaire follow-up study run by the same research office and in phase 3, those patients who withdrew consent prior to discharge from hospital (as we could not legitimately track their mortality even to hospital discharge). In addition, we excluded those patients who could not be matched to the Intensive Care National Audit & Research Centre (ICNARC) Case Mix Programme database and patients who were not captured by the ICON study during their incident admission to ICU during their hospital stay (as we were timing questionnaire response from their first exposure to ICU). Patients could withdraw their consent at any point during any phase of the study (by contacting the study office or by returning the survey blank). This resulted in their personal identifying data being purged from the study database, anonymising their record at that point. We did not contact patients following a specific request by their GP.
Patients received a letter introducing the study at ICU discharge. The letter explained that they might receive mail from the study team and provided contact details for the study office. Eligible patients received postal questionnaires at 3 and 12 months following discharge from ICU. Each mailing included the HADS (14 questions, 7 depression and 7 anxiety, each scored ordinally 0–3), the Post Traumatic Stress Disorder Check List – Civilian version (PCL-C – 17 questions score ordinally 1–5) and other health related quality of life instruments (see Additional file 1). When there was no response to the first mailing, this was followed by a second postal copy 14 days later. In phases 1 and 2 no response after the second mailing was considered a loss to follow up. In phase 3, an additional attempt was made to call the patient.
A cut-off score ≥ 8 for either HADS anxiety or depression scales defined caseness of the respective condition . We applied HADS boundaries for mild, moderate and severe symptoms to those exhibiting caseness . A PCL-C score ≥ 45 defined PTSD caseness .
Data sources and measurement
We linked participant records with the ICNARC Case Mix Programme  to obtain admitting diagnoses, severity of illness scores and to capture previous admissions to ICU during their hospital stay. We checked survival and current registered address with the patient’s registered general practitioner (GP) and the National Health Service Summary Care Record  before posting each questionnaire pack.
With the exception of those who withdrew consent, we linked participants to the Medical Research Information Service (MRIS) run by NHS Digital. This provided linked mortality data and event notification from the Office of National Statistics (ONS).
In phase 1 and 2, clinical staff gave participants a letter explaining that they would receive ICON documentation in the post at the point of discharge from the ICU. In phase 3 a study nurse aimed to visit the patients between ICU and hospital discharge to introduce the ICON study, where a study nurse was available. Further information was provided and a second visit could be arranged to provide written consent if so wished. Patients could remove their consent at any time.
Study size was based on the total number of patients meeting inclusion criteria and admitted to the participating units inside the recruitment period.
For this analysis the primary outcome was the proportion of patients meeting predefined thresholds for caseness of anxiety and depression (using the HADS scale) and for PTSD (using PCL-C) at 3 and 12 months following discharge from ICU. Secondary outcome measures were survival at 3, 12 and 24 months following discharge from ICU, the proportion of individual patients transitioning these thresholds between time points and the correlation between PTSD, anxiety and depression.
Statistical analysis was undertaken using R Core v3.4.1 . We did not correct for multiple testing. Response was defined as return of a questionnaire with valid written consent. Each instrument was scored in accordance with the author’s instructions. Individual responses not meeting these instructions were considered invalid and excluded from further analysis. The proportions of patients meeting the criteria for caseness were calculated for each instrument at each time point. Those meeting the HADS thresholds were further subdivided by symptom severity (mild, moderate, severe).
Population demographics, responses to the individual psychological instruments and change analysis were presented in keeping with the pre-specified data collection plan for the ICON Study. Survival analysis was first performed using the Kaplan-Meier (KM) method. Patients were right censored when we could no longer track their mortality (lost to follow up). This occurred when patients explicitly withdrew their consent (excluding them from being enrolled with MRIS/ONS). Study phases and participants with and without caseness were compared using the log-rank test with p < 0.01.
We performed ad-hoc Cox proportional hazards modelling to study the effects of depression, anxiety and PTSD caseness on survival, adjusting for known confounders. We verified the assumption of proportional hazards prior to conducting the analysis. The study design meant that censoring of individual subjects did not occur as a result of the disease process. We identified age (as a continuous variable), sex (as a binary variable) and severity of illness Acute Physiology and Chronic Health Evaluation (APACHE) II score as a continuous variable ) as potential confounders from the literature [3, 13, 25]. The interpretation of a continuous variable is that for each additional unit increase in the continuous variable the hazard ratio increases by the value reported. The interpretation of a binary variable is the hazard ratio associated with male versus female (sex) or caseness versus no caseness for the other variables.
The effect of these variables on survival was confirmed using univariable Cox proportional hazard analysis. Four multivariable models were then constructed. All included the co-founders identified in the literature. Models 1–3 included each psychological disorder in isolation and model 4 included all three.