Supplementary Material
Development and External Validation of a Prediction Model for Quality of Life of Intensive Care Unit Survivors; a Multicenter Prospective Cohort Study
Table of Contents
Supplement 1: TRIPOD checklist
Supplement 2: Input variables for prediction modelling
Supplement 3: Baseline characteristics responders versus non-responders Supplement 4: Number of missing values per potential predictor
Supplement 5: Linear regression model including all 49 variables
Section/TopicItem Checklist Item Page Title and abstract
Title 1 D;V Identify the study as developing and/or validating a multivariable prediction model, the
target population, and the outcome to be predicted. 1
Abstract 2 D;V Provide a summary of objectives, study design, setting, participants, sample size,
predictors, outcome, statistical analysis, results, and conclusions. 3 Introduction
Background and objectives
3a D;V
Explain the medical context (including whether diagnostic or prognostic) and rationale for developing or validating the multivariable prediction model, including references to existing models.
4 3b D;V Specify the objectives, including whether the study describes the development or
validation of the model or both. 4
Methods Source of
data
4a D;V Describe the study design or source of data (e.g., randomized trial, cohort, or registry
data), separately for the development and validation data sets, if applicable. 5 4b D;V Specify the key study dates, including start of accrual; end of accrual; and, if applicable,
end of follow-up. 5
Participants
5a D;V Specify key elements of the study setting (e.g., primary care, secondary care, general
population) including number and location of centres. 5
5b D;V Describe eligibility criteria for participants. 5
5c D;V Give details of treatments received, if relevant.
Outcome 6a D;V Clearly define the outcome that is predicted by the prediction model, including how and
when assessed. 6
6b D;V Report any actions to blind assessment of the outcome to be predicted. 6 Predictors
7a D;V Clearly define all predictors used in developing or validating the multivariable prediction
model, including how and when they were measured. 7; S2
7b D;V Report any actions to blind assessment of predictors for the outcome and other
predictors. 7
Sample size 8 D;V Explain how the study size was arrived at.
Missing data 9 D;V Describe how missing data were handled (e.g., complete-case analysis, single
imputation, multiple imputation) with details of any imputation method. 7
Statistical analysis methods
10a D Describe how predictors were handled in the analyses. 8
10b D Specify type of model, all model-building procedures (including any predictor selection),
and method for internal validation. 8
10c V For validation, describe how the predictions were calculated. 8
10d D;V Specify all measures used to assess model performance and, if relevant, to compare
multiple models. 8
10e V Describe any model updating (e.g., recalibration) arising from the validation, if done. 8 Risk groups 11 D;V Provide details on how risk groups were created, if done.
Development
vs. validation 12 V For validation, identify any differences from the development data in setting, eligibility
criteria, outcome, and predictors. 6
Results
Participants
13a D;V
Describe the flow of participants through the study, including the number of participants with and without the outcome and, if applicable, a summary of the follow-up time. A diagram may be helpful.
Fig1
13b D;V
Describe the characteristics of the participants (basic demographics, clinical features, available predictors), including the number of participants with missing data for predictors and outcome.
9, Tab1, Fig 2, S3, S4 13c V For validation, show a comparison with the development data of the distribution of
important variables (demographics, predictors and outcome). Tab1, Fig2 Model
development
14a D Specify the number of participants and outcome events in each analysis. 9 14b D If done, report the unadjusted association between each candidate predictor and
outcome.
Model specification
15a D Present the full prediction model to allow predictions for individuals (i.e., all regression
coefficients, and model intercept or baseline survival at a given time point). 10, Tab2
15b D Explain how to the use the prediction model. 10, S6
Model
performance 16 D;V Report performance measures (with CIs) for the prediction model. 9-10
Model-
updating 17 V If done, report the results from any model updating (i.e., model specification, model
performance). 9-10
Discussion
Limitations 18 D;V Discuss any limitations of the study (such as nonrepresentative sample, few events per
predictor, missing data). 12
Interpretation
19a V For validation, discuss the results with reference to performance in the development
data, and any other validation data. 11
19b D;V Give an overall interpretation of the results, considering objectives, limitations, results
from similar studies, and other relevant evidence. 11-12
Implications 20 D;V Discuss the potential clinical use of the model and implications for future research. 12 Other information
Supplementary
information 21 D;V Provide information about the availability of supplementary resources, such as study
protocol, Web calculator, and data sets. S2-6
Funding 22 D;V Give the source of funding and the role of the funders for the present study. 2
Supplement 2 Input variables for prediction modelling
Variable Definition / categories / scale
Demographics
Age Years
Gender Male
Female
Body Mass Index (BMI) Kg/m2
Ethnicity Non-Dutch
Dutch
Living situation Alone or in healthcare facility
With someone else
Education level Low, defined as ≤ secondary school graduate
Middle
High, defined as postsecondary graduate
Income <1200 euro
1200-1700 euro 1700-2500 euro
>2500 euro Baseline questionnaires
Clinical Frailty Scale (CFS) 1 – 9
Checklist Individual Strength (CIS) 8 – 56
Baseline EQ-5D-5L index score -0.446 – 1
Hospital Anxiety and Depression Scale: anxiety 0 – 21 Hospital Anxiety and Depression Scale: depression 0 – 21 Cognitive Failures Questionnaire (CFQ) 0 – 100 Medical history / comorbidities
Chronic renal insufficiency (or chronic dialysis) Defined as serum creatinine >177 umol/L, which was already present before current hospital admission
Metastasized neoplasm or haematological malignancy Defined as presence of confirmed metastasis, stage IV cancer, malignant lymphoma, acute leukaemia, or multiple myeloma
Immunological insufficiency Defined as prolonged immunosuppressive therapy, corticosteroid use, active chemotherapy or radiotherapy in past year, or documented humoral or cellular deficiencies
Chronic Obstructive Pulmonary Disease (COPD) Defined as chronic (> 6 months) use of bronchodilators or steroids for chronic lung disease
Diabetes Defined as medication dependent diabetes
Other comorbidity Presence of one of the following (yes / no):
- Chronic cardiovascular insufficiency, defined as New York Heart Association class IV
- Respiratory insufficiency, defined as respiratory dependency or chronic lung disease resulting in severe movement restriction
- Cirrhosis, defined as documented portal hypertension or previous episodes of liver failure, coma or encephalopathy Two or more comorbidities Presence of two or more of the following:
Chronic renal insufficiency Diabetes
COPD
Immunological insufficiency
Metastasized or haematological malignancy Cardiovascular insufficiency
Respiratory insufficiency Cirrhosis
Admission reason and treatment
Admission type Medical (admission for a non-surgical reason)
Acute surgical (admission after unplanned surgery) Planned surgical (admission after planned surgery) Hospital length of stay prior to ICU admission Days
Confirmed infection Yes / no
Cardiopulmonary resuscitation Yes / no
Vaso-active medication within first 24 hours Yes / no Mechanical ventilation within first 24 hours Yes / no Vital parameters (in first 24 hours)
Minimum Glasgow Coma Scale (excluding sedation effects)
0 – 15
Minimum heartrate Beats / min
Maximum heartrate Beats / min
Minimum respiratory rate Respirations / min
Maximum respiratory rate Respirations / min
Minimum mean blood pressure mm Hg
Maximum mean blood pressure mm Hg
Minimum body temperature Degrees Celsius
Maximum body temperature Degrees Celsius
Urine output L / 24 hours
Laboratory values (in first 24 hours)
Minimum white blood cell count 1000 per mm3
Maximum white blood cell count 1000 per mm3
Minimum haematocrit level Ratio
Maximum haematocrit level Ratio
Minimum thrombocyte level 1.000.000.000 / L
Minimum creatinine level umol / L
Maximum creatinine level umol / L
Minimum glucose level mmol/L
Maximum glucose level mmol/L
Hypoalbuminemia Albumin level <20 g/L
Hyperbilirubinemia Bilirubin level >16 umol/L
Hypercapnia PaCO2 >45 mmHg
Hypoxemia PaO2 <75 mmHg
Acidosis pH <7.35
Scores
P/F ratio PaO2 / FiO2 <200
APACHE IV score 0 – 286
Supplement 3 Baseline characteristics responders versus non-responders. Values shown are N (%) for
categorical variables and median (25
th– 75
thpercentile) for continuous variables.
Responders (n = 1951)
Non-responders (n = 725)
p-value
Sex: Female 746 (38%) 309 (43%) 0.04
Age, years 64 (54 – 71) 62 (50 – 72) 0.03 Ethnicity: non-Dutch 157 (8.5%) 87 (13%) <0.001 Living situation: alone or in healthcare facility 344 (18%) 156 (22%) 0.02
Education level
- Low
- Middle - High
591 (31%) 848 (44%) 481 (25%)
291 (41%) 307 (43%) 114 (16%)
<0.001
Clinical Frailty Score 3 (2 – 4) 3 (2 – 4) <0.001 Quality of life at baseline (EQ5D) 0.80 (0.57 – 0.89) 0.74 (0.44 – 0.88) <0.001 Chronic Obstructive Pulmonary Disease 229 (12%) 103 (15%) 0.08
Diabetes 199 (11%) 96 (14%) 0.02
Chronic renal insufficiency 82 (4.3%) 31 (4.4%) >0.9 Admission type
- Medical - Acute surgical - Planned surgical
960 (51%) 306 (16%) 621 (33%)
375 (54%) 104 (15%) 219 (31%)
0.4
Confirmed infection 373 (20%) 141 (20%) 0.8
Minimum Glasgow Coma Scale 15 (15 – 15) 15 (15 – 15) 0.2 Mechanical ventilation in first 24 hours 998 (53%) 356 (51%) 0.4 Use of vasoactive medication in first 24 hours 939 (50%) 297 (42%) 0.001
APACHE IV score 51 (39 – 68) 50 (36 – 68) 0.2 ICU length of stay (days) 1.8 (0.9 – 3.8) 1.8 (0.9 – 4.0) 0.8
Supplement 4 Number of missing values per potential predictor in development dataset (n = 1057)
Number of missing values Percentage of missing values
Sex 0 0%
Age 0 0%
Body Mass Index (BMI) 3 0.3%
Ethnicity 46 4.4%
Living situation 6 0.6%
Education level 16 1.5%
Income* 129 12.2%
Clinical Frailty Score 1 0.1%
Checklist Individual Strength 0 0%
HADS anxiety 0 0%
HADS depression 0 0%
Cognitive Failure Questionnaire* 207 19.6%
Quality of life at baseline (EQ-5D-5L) 20 1.9%
Admission type 0 0%
Confirmed infection 0 0%
Cardiopulmonary resuscitation 0 0%
Chronic renal insufficiency 0 0%
COPD 0 0%
Diabetes 0 0%
Neoplasm 0 0%
Immunological insufficiency 0 0%
Other comorbidity 0 0%
Two or more comorbidities 0 0%
Hospital length of stay prior to ICU admission 61 5.8%
Minimum Glasgow Coma Scale 0 0%
Minimum heart rate 0 0%
Maximum heart rate 0 0%
Minimum respiratory rate 0 0%
Maximum respiratory rate 0 0%
Minimum mean blood pressure 0 0%
Maximum mean blood pressure 2 0.2%
Minimum body temperature 1 0.1%
Maximum body temperature 1 0.1%
Urine output 5 0.5%
Minimum white blood cell count 2 0.2%
Maximum white blood cell count 2 0.2%
Minimum haematocrit level 2 0.2%
Maximum haematocrit level 2 0.2%
Minimum thrombocyte level 2 0.2%
Minimum creatinine level 1 0.1%
Maximum creatinine level 1 0.1%
Minimum glucose level 0 0%
Maximum glucose level 0 0%
Albumin level 58 5.5%
Bilirubin level 51 4.8%
PaCO2 95 9.0%
PaO2 95 9.0%
pH 95 9.0%
P/F ratio 86 8.1%
Mechanical ventilation 0 0%
Vasoactive medication 0 0%
APACHE IV score 0 0%
* Excluded from further analysis due to >10% missing values at random
Supplement 5 Linear regression model including all 49 variables
Variable Coefficient (β) Standard error p-value
Intercept 1.43812 0.39944 0.00033
Sex: Female -0.01237 0.01474 0.40157
BMI -0.00215 0.00145 0.13760
Age -0.00071 0.00058 0.21732
Living situation: with someone else 0.02834 0.01806 0.11684
Education level: middle 0.02632 0.01665 0.11435
Education level: high 0.03264 0.01879 0.08274
Ethnicity: non-Dutch -0.02191 0.02511 0.38300
Clinical Frailty Score (CFS) -0.01369 0.00567 0.01592
Checklist Individual Strength (CIS) -0.00053 0.00064 0.41235
HADS anxiety -0.00901 0.00227 0.00008
HADS depression -0.00107 0.00251 0.66931
Admission type: acute surgery -0.02089 0.02135 0.32819
Admission type: planned surgery 0.05024 0.01932 0.00944
Confirmed infection -0.01398 0.02334 0.54935
Cardiopulmonary resuscitation 0.03846 0.04002 0.33682
Chronic renal insufficiency -0.02733 0.04275 0.52271
COPD 0.00265 0.02589 0.91840
Diabetes -0.00389 0.02781 0.88876
Neoplasm 0.00341 0.02406 0.88749
Immunological insufficiency -0.00068 0.02432 0.97755
Other comorbidity -0.04044 0.03855 0.29450
Two or more comorbidities 0.02277 0.03397 0.50280
Minimum heartrate -0.00051 0.00054 0.35108
Maximum heartrate 0.00039 0.00040 0.32877
Minimum respiratory rate -0.00239 0.00215 0.26664
Maximum respiratory rate 0.00115 0.00120 0.33802
Minimum mean blood pressure -0.00003 0.00068 0.96758
Maximum mean blood pressure -0.00036 0.00043 0.40736
Minimum temperature -0.00295 0.00941 0.75395
Maximum temperature -0.01885 0.01040 0.07014
Minimum Glasgow Coma Scale 0.01020 0.00344 0.00311
Urine output 0.00668 0.00723 0.35590
Minimum haematocrit level 0.00632 0.14247 0.96462
Maximum white blood cell count 0.00074 0.00038 0.04853
Minimum thrombocyte level 0.00014 0.00008 0.07670
Acidosis 0.02276 0.01729 0.18833
Hypoxemia 0.01482 0.01447 0.30576
Hypercapnia -0.03170 0.01909 0.09701
Abnormal P/F ratio -0.01042 0.01897 0.58278
Maximum creatinine level 0.00008 0.00010 0.38107
Minimum glucose level 0.00217 0.00485 0.65437
Maximum glucose level -0.00147 0.00177 0.40743
Hypoalbuminemia 0.02363 0.02346 0.31404
Hyperbilirubinemia -0.02247 0.01481 0.12938
Mechanical ventilation -0.02523 0.01721 0.14296
Vasoactive medication 0.00606 0.01569 0.69950
Hospital length of stay prior to ICU admission 0.00030 0.00139 0.83024
APACHE IV score 0.00018 0.00066 0.78459
EQ5D at baseline -0.83261 0.02987 <0.00001
