Adverse Event Prediction in Geriatric Patients in the ED With Ultrasound
Conditions: Frailty, Adverse Event
Sponsor: University Medical Center Groningen

 
 
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Adverse event prediction in Geriatric patients in the ED with Ultrasound 
 
AGEDU 
 
Research register number: 202100945 
 
(non-WMO study protocol to obtain data/biomaterials 
from the Acutelines biobank) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Date of protocol: 
24-11-2021 
Version number: 
1.3 
List of abbreviations and relevant definitions  
ED  
Emergency Department  
 
UMCG 
University Medical Centre of Groningen 
APOP 
Acutely Presenting Older Patient 
MRI 
Magnetic resonance imaging 
CT 
Computed Tomography 
Qcsa 
Cross-sectional area 
CFS9 
Clinical Frailty Scale 
METC  
 
Medical research ethics committee (MREC); in Dutch: medisch ethische toetsing 
commissie (METC)  
 
Sponsor  
  
 
The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical company, academic hospital, scientific 
organisation or investigator. A party that provides funding for a study but does not 
commission it is not regarded as the sponsor, but referred to as a subsidising party.  
 
WMO  
Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-wetenschappelijk 
Onderzoek met Mensen) 
LOS 
Length of stay 
ITU 
Intensive therapy unit  
eCRF 
Electronic consent form  
REDCap 
Research electronic Data Capture 
 
 

 
 
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CONTENT 
 
List of abbreviations and relevant definitions ......................................................................................... 2 
1. STUDY ORGANIZATION ..................................................................................................................... 4 
2. PROTOCOL SIGNATURE SHEET .......................................................................................................... 5 
3. ABSTRACT (max. 250 words) ............................................................................................................... 6 
4. BACKGROUND .................................................................................................................................... 7 
5. METHOD .............................................................................................................................................. 9 
5.1 Description study design ................................................................................................................. 9 
5.2 Design ............................................................................................................................................ 9 
5.3 Population ...................................................................................................................................... 9 
5.4 Recruitment and informed consent/objection ............................................................................... 10 
5.5 Research Data Management Plan (RDMP)..................................................................................... 11 
5.6 Management of biomaterials ........................................................................................................ 12 
5.7 Burden, Risks & Benefits................................................................................................................ 13 
5.8 Incidental findings ......................................................................................................................... 13 
5.9 Data analysis ................................................................................................................................. 13 
5.10 Participant information after the study ........................................................................................ 14 
5.11 Research revenue ........................................................................................................................ 14 
6. Acutelines agreements ........................................................................................................................ 15 
6.1 Acutelines budget for acquisition, storage and transfer ..................................................................... 15 
7. REFERENCES ....................................................................................................................................... 16 
8. APPENDICES....................................................................................................................................... 18 
8.1 Required text for manuscript ............................................................................................................ 18 
 
 
 

 
 
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1. STUDY ORGANIZATION 
 
Study title 
Acutelines: Adverse event prediction in Geriatric patients in the ED with 
Ultrasound (research register number 202100945) 
Planned start date 
01-01-2022 
Estimated completion date 
01-10-2022 
Project leader (UMCG) 
Dr. E. ter Avest, Emergency physician 
University Hospital Groningen, University of Groningen 
Department of Emergency Medicine 
Email: e.ter.avest@umcg.nl 
 
(Principal) investigator UMCG 
S.L. Haak, AIOS Emergency Medicine  
Emergency Department  
Email: s.l.haak@umcg.nl 
Phone: 06-46771836 
Researcher(s) UMCG 
L. Giezen, AIOS Emergency Medicine 
Dr. E. ter Avest, Emergency Medicne  
Dr. H.R. Bouma, acute internal medicine  
Prof. Dr. B.C. van Munster, geriatrician internal medicine 
Prof. Dr. JC ter Maaten, acute internal medicine  
Corresponding researcher UMCG 
S.L. Haak, AIOS Emergency Medicine  
Emergency Medicine Department  
Email: s.l.haak@umcg.nl 
Phone: 06-46771836 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
UMCG (Acutelines)  
Financial support/subsidising party  
Geldstroom:  
 
NA 
Collaboration with non-profit 
Laboratory / research sites (in- and 
outside UMCG) 
NA 
Collaboration with commercial 
parties / companies (in- and outside 
UMCG) 
NA 
Name bio- or databank and 
bankmanager 
Acutelines (research register number 201900635) 
Center for Acute Care UMCG 
Email: acutelines@umcg.nl 
Phone: 68943 
 
Manager: prof.dr. B.C. van Munster, internal medicine 
Project leader: dr. H.R. Bouma, internal medicine 
 
☒ approved by the Board of Directors UMCG 
☐ not approved by the Board of Directors UMCG 
Name previous study ('FAIR data')  
Acutelines   
 
 
 

 
 
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2. PROTOCOL SIGNATURE SHEET 
 
The undersigned (Principal) investigator and head of department UMCG confirm that the study and its procedures 
will comply with the present study protocol and the nWMO Kaderreglement UMCG, and in addition agree with the 
Acutelines regulations for further use of data and biomaterials as stated in the current document. Without ethical 
approval the data/biomaterials will not be used for other (research) purposes (e.g. 'FAIR data').  
 
Name 
Signature 
Date 
(Principal) investigator UMCG: 
 
 
 
 
S.L. Haak, AIOS Emergency Medicine  
21-01-2022 
Head of the department UMCG: 
 
 
 
 
Prof. Dr. JC ter Maaten, acute internal 
medicine physician 
21-01-2022 
Bank manager Acutelines 
 
 
 
 
 
Prof.dr. B.C. van Munster  
21-01-2022 
Steering group Acutelines 
 
 
 
Dr. H.R. Bouma 
21-01-2022 
 
 
 

 
 
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3. ABSTRACT (max. 250 words) 
 
 
Background  
Older people visit the ED more frequently then younger people and have a higher risk of functional 
decline, ED revisit or death. Several screening tools (such as VMS and APOP) have been developed to 
identify patients at the highest risk of adverse outcomes. Almost all require adequate communication 
with the patient, which is not always possible, for example when elderly patients present with a 
delirium. Point of Care Ultrasonography (POCUS) may be a valuable alternative screening tool in 
these instances.   
 
 
Main research question 
To identify whether POCUS measurement of the rectus femoris muscle cross-sectional area (Qcsa)  
can be used as an alternative screening tool to predict functional decline, ED revisit or death in 
elderly patients in the ED. 
 
 
Design (including population, confounders/outcomes) 
This is a single centre prospective trial. Patients >70 years and older presenting in the ED of the 
UMCG hospital who are participating in the Acutelines bio-databank are eligible for inclusion. 68 
patients will be included. Data will be extracted from the Acutelines bio-databank. A trained 
physician will perform ultrasound measurements in a standardized way. 
 
Expected results 
The aim of this study is to evaluate whether ultrasound measurements of the Qcsa can be utilized to 
identify older patients who are at risk for functional decline, ED revisit or death.  
 
 
 

 
 
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4. BACKGROUND 
 
 
Introduction and rationale 
Older patients visit the emergency department (ED) more frequently in comparison to younger 
adults [1,2]. Admittance to the ED is associated with risk of negative health outcomes such as 
functional decline and mortality (the ultimate form of functional decline) [2,3]. This is partly 
explained by non-specific disease presentation or the presence of frailty, comorbidities or cognitive 
disorders, which complicates their ED presentation, diagnosis and management [4-6]. It is important 
to identify older patients with frailty, who are at the highest risk for negative outcomes, in order to 
be able to take appropriate measures during hospitalization (e.g. fall prevention, physiotherapy, 
geriatric consultation). Recently it became mandatory to screen all elderly ED patients for frailty as 
stated by the Health and Youth Care Inspectorate in the Netherlands.  
Several geriatric screening tools have been developed to identify frail geriatric patients in the ED [7]. 
The Acutely Presenting Older Patient (APOP) tool has already been implemented in several Dutch 
hospitals [8]. This is a validated instrument to predict risk for functional decline and mortality in older 
patients within three months of presentation in the ED [8, 9]. Like most of the existing screening 
tools the APOP relies on adequate communication with the patient (or the patients’ caregiver). 
Unfortunately, not infrequently communication with the patient is impaired in the ED due to trauma, 
confusion, sickness or pre-existent dementia.  
An alternative screening tool, based on measurement of sarcopenia with POCUS may provide 
valuable information in these instances. Sarcopenia is a syndrome characterized by progressive and 
generalized loss of skeletal muscle mass and strength with a risk of adverse outcomes such as 
physical disability, poor quality of life and death [10]. Sarcopenia and frailty are two separate 
conditions, but they overlap especially in the physical aspects of frailty [11]. Therefore, measuring 
sarcopenia might help in predicting frailty. MRI and CT are regarded as the gold standard to measure 
muscle mass but they are inconvenient and impossible to perform in everyday clinical practice, 
especially in the ED [10].  
POCUS has been shown to be a promising technique to measure skeletal muscle mass [12]. It is non-
invasive, can be performed at the bedside and has an excellent intra-class correlation coefficient for 
intra- and inter-observer agreement. [13, 14] Recent studies in a subgroup of hospitalized patients 
have shown that Qcsa measurements can predict readmission and mortality [15, 16]. ED data 
however are scarce: Shah et al found in a subset of elderly trauma patients that ultrasound 
measurements of biceps and quadriceps had modest concordance with the Clinical Frailty Scale 
(CFS9) [17], whereas Benton et al demonstrated that ultrasound measurements of sarcopenia in 
older non-trauma patients were (to a variable extend) associated with frailty, falls and subsequent 
hospitalizations [18].  
As POCUS measurement of Qcsa is independent of patient effort and functional or cognitive 
impairment, it has the potential to be a valuable (alternative) screening tool for functional decline 

 
 
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and mortality in older patients in the ED. However, until now, no data have been published about the 
relation between Qcsa and functional outcome for patients presenting in the ED. 
The aim of this study is to evaluate whether ultrasound measurements of the Qcsa in the ED may be 
utilized to identify older patients who are at risk for functional decline, ED revisit or death. Our study 
hypothesis is that Qcsa measurements can predict functional decline, ED revisit or death of older ED 
patients.  
 
Research question 
Primary objective 
To evaluate: 
 
The relation between POCUS measurements of the Qcsa in patients >70 presenting in the ED 
and ED revisit or death within three months and functional decline within twelve months of 
their ED visit. Functional decline in this respect is defined as at least one point increase in 
the Katz ADL-6 survey score or new institutionalization (higher level of assisted living) within 
twelve months after ED visit. 
 
Secondary objectives 
To evaluate:  
 
To compare the ability of the Qcsa ultrasound to predict functional decline, ED revisit or 
death in older patients in the ED to the APOP questionnaire (gold standard). 
 
To compare the added value of Qcsa ultrasound to the APOP questionnaire in the prediction 
of functional decline, ED revisit or death in older patients in the ED. 
 
To evaluate the relation between Qcsa ultrasound and physical activity (as scored by KATZ 
ADL-6 questionnaire). 
 
 
 

 
 
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5. METHOD 
 
5.1 Description study design 
This is a single centre prospective trial conducted in the ED of the UMCG. Data (including APOP, 
KATZ-ADL) will be collected from elderly patients presenting in the ED, and ultrasound 
measurements of the Qcsa will be obtained at the same time after consent is obtained for 
participation in the Acutelines bio-databank. Functional decline, ED revisit and mortality will be 
evaluated after three and twelve months as per Acutelines protocol. 
5.2 Design 
5.2.1 Mono- or multicenter study 
Mono-center study, use of data/biomaterials from 
Acutelines (de novo biobank) 
 
5.2.2 Retrospective study (available data/ biomaterials 
only) or prospective study (data/ biomaterials from 
[some] participants will be collected in the future).  
Retrospective study: 
yes/no 
 
Prospective study: 
YES (Acutelines) 
 
Note: while Acutelines is a prospective data/biomaterial collection, additional data may be collected 
retrospectively.  
5.2.3 Cross-sectional or follow-up study 
Cross-sectional study: 
yes/no 
Follow-up study 
yes/no 
All patients are screened in the ED. ED revisit and mortality will be evaluated after three months and 
functional decline after twelve months. 
5.2.4 Quantitative or qualitative study (click both if 
mixed-method) 
Quantitative study 
yes/no 
Qualitative study 
yes/no 
This is a quantitative study based on Qcsa measurement and screening tool data.  
5.2.4 Pilot study 
yes/no 
 
 
5.3 Population 
5.3.1 Inclusion and exclusion criteria 
Inclusion criteria:  
In order to be eligible to participate in this study, a subject must meet all of the following criteria:  
 
Age (>70 years)  
 
Presenting to the ED of the UMCG for one of the following specialties: internal medicine, 
nephrology, geriatric medicine, oncology, hematology, lung medicine, gastrointestinal/liver 
medicine, or emergency medicine (non-trauma). 
 
Consent obtained for participation in the Acutelines bio-databank 
Exclusion criteria:  
 
Unable to obtain ultrasound image of rectus femoris (e.g. amputation, edema)  
 
Paresis or paralysis of one or both legs 
5.3.2 Number of participants 
 
Target total number of participants: 68 
 
Target number of UMCG participants: 68 
5.3.3 Study subjects (tick all that apply) 
 
Healthy volunteers 
 
Patients 
NO 
YES 
5.3.4 Subject classification (tick all that apply) 
 
 
Participants ≥ 16 years 
 
Children between 12 and 16 years (if applicable, written informed consent will be obtained 
YES  
NO 

 
 
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from child and both parents - if both have authority, or guardian [or parents/guardian only if 
incapacitated child]) 
 
Children < 12 years (if applicable, written informed consent will be obtained from both 
parents - if both have authority, or guardian) 
 
 
NO 
 
NO 
5.3.5 Incapacitated adults 
 
Participants are incapacitated/ decisionally incompetent adults (if applicable, written informed 
consent will be obtained from legal representative) 
YES  
 
 
5.4 Recruitment and informed consent/objection 
5.4.1 
Retrospective study (tick all that apply) 
☒ Not applicable (see section 5.2.2) 
☐ Data will be copied from (electronic) patient records (e.g. ‘EPD UMCG’) 
☒ Data/biomaterials will be obtained from an already existing internal or external (UMCG/non-UMCG) 
bio- or databank (see Section 1. Study organization). Data/biomaterials will be obtained from the 'de 
novo' biobank Acutelines. 
☐ Data/biomaterials will be obtained from a previous study ('FAIR data' - internal/external; see Section 1. 
Study organization).  
5.4.3 Objection (Registry)  
in case one or more participants will not be asked informed consent, the objection registry will 
be checked for these participants and the data from those who objected will be excluded from 
the analyses. 
NA 
 
 
All participants will be asked informed consent (Acutelines). The objection registry will be checked prior 
to the study to see if patients have withdrawn consent between enrollment and start of the study.  
5.4.4 Informed consent (IC): access to identifiable participant data 
 
in case one or more study team members will have access to direct/indirect identifiable 
participant data, informed consent will be/has been obtained for this access. 
YES 
5.4.5 IC: Collaboration with commercial parties 
 
In case of collaboration with commercial/profit organizations, informed consent will be/has been 
obtained for this type of collaboration 
YES 
5.4.6 IC: Linking with other registries 
 
In case the data will be linked with other registries, informed consent will be/has been obtained 
for this linkage(s) 
YES 
5.4.7 IC: Incidental findings 
 
In case there is a risk of incidental findings, informed consent will be/has been obtained to return 
findings to the participant 
YES 
Participants are asked (written, consent form) whether they would like to be informed about incidental 
findings. 
5.4.8 IC: FAIR Data 
 
In case data collected for the present study will be shared for future studies, informed consent 
will be obtained for this 
YES 
5.4.9 IC: other aspects  
NA 
5.4.10 Withdrawal 
 
Can participants withdraw informed consent before publication and will all data/ 
biomaterials of that participant be destroyed 
 
Does the participant information letter contain information on how to withdraw 
NO  
 
YES 
If data or biomaterials have already been used, it cannot be destroyed anymore as stated in the consent 
form. 
 

 
 
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5.5 Research Data Management Plan (RDMP) 
In this study the data will be collected, processed, and archived in accordance with the General Data Protection 
Regulation (GDPR) and the FAIR (Findable, Accessible, Interoperable, Reusable) principles under the responsibility of 
the Principal Investigator. A research data management plan (RDMP) has been drawn up to describe the further 
operational details and procedures.  
☒  the RDMP section below is completed 
☐ a separate RDMP document will be attached to this protocol (appendix) 
5.5.1 Data collection 
 
Only essential baseline characteristics and data required to answer the research question(s) 
will be collected (retrieved from Acutelines) 
YES/NO 
Primary outcome: 
Ultrasound measurement images of the rectus femoris muscle cross-sectional area and data 
about ED revisit or death within three months and functional decline (Katz ADL-6 survey score or 
new institutionalization) within twelve months of their ED visit. 
Secondary and other outcomes: 
Data from the APOP questionnaire.  
 
Tooling (eg. software and procedures) used for collecting, processing, analysing, and storing 
data will be compliant with the UMCG policy and Standard Operating Procedures in the 
UMCG Research Toolbox. 
YES/NO 
 
5.5.2 Anonymization and pseudonymization 
 
Data will be anonymised during data collection (i.e. data cannot be linked back to the 
participant) 
NO 
(only partially) 
To allow follow-up of participants through surveys and importing data from the electronic health 
records or external sources, data cannot be anonymised upon collection in Acutelines, but have to 
be stored pseudonymized.  
 
Data will be pseudonymized by use of a code list stored in the electronic patient file (EPD) 
during data collection. 
YES 
 
 
Indirect and direct identifiable information collected will be minimized and only collected 
for the purpose of this study 
YES 
 
 
Direct identifiable information (e.g. contact details, code list/encryption key/subject 
identification log) will be stored separately from pseudonymized data in the electronic 
patient files (EPD), while the email address is stored in RedCap (field marked and protected 
as "identifier"). 
YES 
 
5.5.3 Data access (during the study) 
 
Direct identifiable information can only be accessed by the Principal Investigator and study 
delegates after authorization by the Principal Investigator. 
YES 
 
 
Pseudonymized/anonymized data can only be accessed by the Principal Investigator and 
study delegates after authorization by the Principal Investigator. 
YES 
 
 
Data roles, responsibilities, access and authorization - during the study and after study 
completion - will be managed and documented (e.g. in the RDMP, on study delegation log). 
YES 
 
5.5.4 Data sharing (during and after study completion) 
 
In case data (and biomaterials) will leave the UMCG, will you contact the loket Contract Research 
to arrange the proper contracts? (Loket_Contract_Research@umcg.nl) 
NA/YES/NO 
 
In case data (and biomaterials) will leave the UMCG, will you contact the Acutelines steering 
group and manager to arrange the proper contracts? (acutelines@umcg.nl) 
NA/YES/NO 
 
5.5.5 Data storage (during and after study completion) 
 
Digital data will be archived on the UMCG network complying with strict UMCG security 
YES 

 
 
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and back-up policy. 
 
Paper source data and study files will be archived within the UMCG facilities. 
YES 
 
Source data, study files and digital data will be stored 15 years after the study is completed. 
YES 
5.5.6 Data re-use and access after completion of the present study (‘FAIR data’) 
 
 
Data will become available and shared for re-use and participants will be asked informed 
consent for this ('FAIR data') 
YES 
 
Acutelines stimulates re-use and access of data (“FAIR data”), which is the primary aim of Acutelines 
and for which participants are asked informed consent. 
 
Data will be made findable by including the description of the study (and type of data (i.e. 
metadata) in the UMCG FAIR data catalogue and other discipline specific catalogue(s). 
 
 YES 
 
Data and biomaterials are findable through the website (acutelines.umcg.nl), where a data dictionary 
can be found and a link to the Groningen data catalogue. 
 
Review procedure, conditions and agreements for re-use of data and access to data by other 
researchers will be drawn up. 
YES 
These are described in the Acutelines Biobank reglement 
 
For this study a discipline specific metadata standard will be chosen (i.e. to increase 
interoperability and re-use). 
YES 
<if no, explain> 
 
All new data derived in this study will be returned to Acutelines to enrich the dataset (i.e. to 
increase interoperability and re-use). 
YES/NO 
 
 
5.6 Management of biomaterials 
Will biomaterials be collected, processed, analyzed and/or stored for the purpose of this study 
YES 
Data and biomaterials are collected as part of Acutelines (de novo biobank) 
 
5.6.1 Retrospective study (see sections 1, 5.2.2, and 5.4.1) 
If biomaterials will be used from a secondary/further use biobank that has not been approved by 
the Board of Directors of the UMCG, how will be prohibited that biomaterials necessary for 
future diagnostic/treatment purposes will be used in the present study. 
NA 
5.6.2 Biomaterials collection 
 
Only biomaterials required to answer the research question(s) will be collected 
NO 
 
What biomaterials will be collected 
Plasma (EDTA, Li-Heparin, citrate), buffy coat (EDTA), wholeblood RNA (PAXGene), serum, urine, feces 
 
How will the biomaterials be collected and processed 
Biomaterials are collected and processed according to the procedures as described by Acutelines.  
5.6.3 Pseudonymization and access to biomaterials 
 
Does the storage unit of the biomaterials comprise information that the participant 
(in)directly identifies, other than the participant's number and / or the sample number. 
NO 
 
Biomaterials can only be accessed by the Principal Investigator and study delegates after 
authorization by the Principal Investigator 
YES 
5.6.4 Sharing of biomaterials (during and after study completion) 
In case biomaterials (and data) will leave the UMCG, will you contact the loket Contract 
Research to arrange the proper contracts? (Loket_Contract_Research@umcg.nl) 
NA/yes/no 
 
5.6.5 Biomaterials storage (during and after study completion) 
 
Where and how will the biomaterials be stored 
Biomaterials are collected and stored by Acutelines in the Central Freezer facility UMCG. 
 
Biomaterials will be stored 15 years after the study is completed 
NA 
Biomaterials are collected and stored by Acutelines, for at least 15 years. 

 
 
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 
What will be done with the remaining biomaterials after study completion (eg. destroyed, returned to 
biobank/previous study, stored)  
Biomaterials are only collected as part of Acutelines, no extra biomaterials will be collected. 
5.6.6 Biomaterials re-use and access after completion of the present study 
Note: Acutelines stimulates re-use and access of data (“FAIR data”), which is the primary aim of 
Acutelines and for which participants are asked informed consent. Data and biomaterials are 
findable through the website (acutelines.umcg.nl), where a data dictionary can be found and a 
link to the Groningen data catalogue. 
NA 
☒ 
 
 
 
5.7 Burden, Risks & Benefits  
 
If participants are patients: Can be deviated from the standard care / diagnostic procedures 
(e.g. can medical treatment be postponed or limited) 
NA/yes/no 
Note: burden is minor, data and biomaterials are collected as part of Acutelines. 
 
 
Will the participants risk any injuries and/or other discomfort 
when they participate in the proposed study 
Yes, minimal 
risk/burden 
 
☐ 
Yes, more than 
minimal 
risk/burden 
☐ 
No 
 
 
☒ 
Note: data and biomaterials are collected as part of Acutelines 
 
Participant benefits/reward/incentives: not applicable. 
 
5.8 Incidental findings 
 
 
 
Is there a risk of incidental findings?  
Yes, minimal 
risk 
☒ 
Yes, ≥ 
substantial risk 
☐ 
No 
 
☐ 
 
If yes, 
o 
In case of incidental findings  resulting from the POCUS ultrasound, patients will be referred to 
radiology at the time of the procedure for formal ultrasonography of their leg, and findings will be fed 
back to the treating physician  
o 
The patient will be informed of the need of a formal ultrasonography in case of incidental findings 
 
 
5.9 Data analysis 
 
Justification of sample size (e.g. power analysis) 
The sample size is calculated based on functional decline and mortality in elderly visiting the ED. We 
defined functional decline as at least one point increase in the Katz ADL-6 survey score or new 
institutionalization (higher level of assisted living) within twelve months after ED visit. Prior research 
in the Netherlands found 9,5% of patients aged ≥70 year died within three months after ED visit and 
30,6% experienced functional decline or mortality at 90-day follow-up [8]. With an assumed 
prevalence of the composed endpoint of 30%, 54 patients are needed to be able to confirm a 
diagnostic test accuracy with a sensitivity and specificity of >0.8 each for a predefined Qcsa cut-off 
value with a power of 90% and an alfa error of 0.05. To allow for loss of follow-up, 25% more patients 
will be recruited, resulting in a sample size of 68 patients. 
 
Statistical analysis 
Continuous variables are expressed as mean (95% CI) when normally distributed and median with 
interquartile range when not normally distributed. Categorical data are presented as absolute 

 
 
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numbers and percentages.  
 
There is a difference in muscle mass between man and woman. The ultrasound measured Qcsa will 
therefore be adjusted for sex by multiplying female Qcsa with the coefficient 1.484 (male=1) prior to 
analysis [15]. Diagnostic accuracy of QCSA will be presented as sensitivity and specificity of the 
optimum Qcsa cut-off point to separate cases (primary endpoint reached after three or twelve 
months) from non-cases. This optimum cut-off point is calculated as the maximum sum of sensitivity 
+ (1-specificity) using ROC statistics (under the condition of equal costs of misqualification). 
 
A logistic regression model will be used to evaluate whether individual Qcsa predicts functional 
decline, ED revisit or death. Age, comorbidity, Katz ADL-6, known dementia are defined as clinically 
relevant covariates and will be included in the regression model.. The predictive ability of the 
multivariable risk prediction models (e.g. Qcsa prediction model vs APOP prediction model) will be 
compared. χ2 values will be calculated for each prediction model.  
 
A 2-sided P-value <0.05 will be considered statistically significant. Missing data are reported in the 
results section according to the STROBE 2015 guideline. All statistical analyses will be performed 
using R or SPSS 26.0 software. 
 
5.10 Participant information after the study 
Will participants be informed about the study results 
YES 
 
Acutelines aims to inform (former) participants, general public and health care professionals through 
their media channels (i.e. website, social media; LinkedIn and Twitter). Participants are informed about 
these media channels in the patient information brochure and via a “thank-you-for-participating-email”. 
 
5.11 Research revenue 
In case the study will result in revenues (e.g. as a result of the use of data/biomaterials or 
successful licensing of intellectual property or manufactured products), will you contact the loket 
Contract Research to arrange the proper contracts? 
YES 
 
Reveneus resulting from use of data/biomaterials or successful licensing of IP or manufactured products 
will be re-invested in the Acutelines biobank, in case no other agreements are made. 
 
 
 

 
 
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6. Acutelines agreements 
Return of investments 
 
 
Return of investment in kind, as follows: Acutelines will be mentioned in all published 
work compromising this trial. 
YES/NO 
 
Return of investment in cash according to the specified budget (6.1) 
NO 
<if both of the above are no, explain> 
Output 
 
 
Sharing scientific output in the form of (a) co-authorship(s) for Dr. H.R. Bouma, Dr. E. 
ter Avest, Prof Dr J.C. ter Maaten and Prof Dr B van Munster 
YES/NO 
 
Sharing intellectual property with Dr. H.R. Bouma for which further contracts will be 
signed prior to the initiation of the project 
NO 
 
The required text for manuscripts (8.1) will be included in all publications arising from 
data or biomaterials derived from Acutelines 
YES 
 
Any publication (a.o. [non]scientific manuscript, conference proceeding, presentation 
at conference, laid press, social media) arising from data or biomaterials derived from 
Acutelines will be send to acutelines@umcg.nl to obtain permission prior to publication 
YES 
Promoting outreach of results 
 
 
Lay-person summary for website (text [100-150 words], infographic [A5, color] or 
animation [< 2 min.] in Dutch and English 
YES 
 
Lay-person summary for Twitter in Dutch and English 
YES 
6.1 Acutelines budget for acquisition, storage and transfer 
Note: this is a required section prior to submitting the protocol. Obtain this information by sending the 
protocol to acutelines@umcg.nl to ask the steering committee to complete the budget below.  
 
Description 
Number 
Cost 
Total 
Data acquisition/storage 
68 
€ 0 
€ 0 
Biomaterial acquisition/storage 
68 
€ 0 
€ 0 
Preparation and transfer of data  
68 
€ 0 
€ 0 
Preparation and transfer of biomaterials 
68 
€ 0 
€ 0 
Total 
 
 
€ 0 
Costs are covered by participation costs of participating departments in the acutelines 
biobank 
 
 

 
 
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7. REFERENCES 
1. Samaras N, Chevalley T, Samaras D, Gold G. Older patients in the emergency department: a 
review. Ann Emerg Med. 2010;56(3):261–9. 
 
2. Aminzadeh F, Dalziel WB. Older adults in the emergency department: a systematic review of 
patterns of use, adverse outcomes, and effectiveness of interventions. Ann Emerg Med. 
2002;39(3):238–47. 
 
3. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 
2013;381(9868):752–62. 
 
4. Salvi F, Morichi V, Grilli A, Giorgi R, De Tommaso G, Dessi-Fulgheri P. The elderly in the emergency 
department: a critical review of problems and solutions. Intern Emerg Med 2007; 2: 292–301. 
 
5. Samaras N, Chevalley T, Samaras D, Gold G. Older patients in the emergency department: a  
review. Ann Emerg Med 2010; 56: 261–9. 
 
6. Nickel C, Bellou A, Conroy S, eds. Geriatric Emergency Medicine. Switzerland: Springer 
International Publishing, 2018. 
 
7. Carpenter CR, Shelton E, Fowler S, et al. Risk factors and screening instruments to predict adverse 
outcomes for undifferentiated older emergency department patients: a systematic review and meta‐
analysis. Acad Emerg Med. 2015; 22: 1‐ 21. 
 
8. Gelder J, Lucke JA, de Groot B, et al. Predicting adverse health outcomes in older emergency 
department patients: the APOP study. Neth J Med. 2016; 74:342-52. 11.  
 
9. Gelder J, Lucke JA, Blomaard LC, et al. Optimization of the APOP screener to predict functional 
decline or mortality in older emergency department patients: Cross-validation in four prospective 
cohorts. Exp Gerontol. 2018; 110:253-9. 
 
10. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, Martin FC, Michel JP, 
Rolland Y, Schneider SM, Topinková E, Vandewoude M, Zamboni M; European Working Group on 
Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: Report of 
the European Working Group on Sarcopenia in Older People. Age Ageing. 2010 Jul;39(4):412-23. doi: 
10.1093/ageing/afq034. Epub 2010 Apr 13. PMID: 20392703; PMCID: PMC2886201. 
 
11. Dodds R, Sayer AA. Sarcopenia and frailty: new challenges for clinical practice. Clin Med (Lond). 
2016;16(5):455-458. doi:10.7861/clinmedicine.16-5-455 
 
12. Ticinesi A, Meschi T, Narici MV, Lauretani F, Maggio M. Muscle Ultrasound and Sarcopenia in 
Older Individuals: A Clinical Perspective. J Am Med Dir Assoc. 2017 Apr 1;18(4):290-300. doi: 
10.1016/j.jamda.2016.11.013. Epub 2017 Feb 13. PMID: 28202349. 
 
13. Whitson MR, Mayo PH. Ultrasonography in the emergency department. Crit Care. 2016 Aug 
15;20(1):227. doi: 10.1186/s13054-016-1399-x. PMID: 27523885; PMCID: PMC4983783. 
 
14. Hadda V, Kumar R, Hussain T, Khan MA, Madan K, Mohan A, Khilnani GC, Guleria R. Reliability of 
ultrasonographic arm muscle thickness measurement by various levels of health care providers in 

 
 
Acutelines non-WMO study protocol, version 1 (23-09-2020) | page 17 of 19 
 
 
ICU. Clin Nutr ESPEN. 2018 Apr;24:78-81. doi: 10.1016/j.clnesp.2018.01.009. Epub 2018 Feb 17. 
PMID: 29576368. 
 
15. Greening NJ, Harvey-Dunstan TC, Chaplin EJ, Vincent EE, Morgan MD, Singh SJ, Steiner MC. 
Bedside assessment of quadriceps muscle by ultrasound after admission for acute exacerbations of 
chronic respiratory disease. Am J Respir Crit Care Med. 2015 Oct 1;192(7):810-6. doi: 
10.1164/rccm.201503-0535OC. PMID: 26068143; PMCID: PMC4613897. 
 
16. Mueller N, Murthy S, Tainter CR, Lee J, Riddell K, Fintelmann FJ, Grabitz SD, Timm FP, Levi B, 
Kurth T, Eikermann M. Can Sarcopenia Quantified by Ultrasound of the Rectus Femoris Muscle 
Predict Adverse Outcome of Surgical Intensive Care Unit Patients as well as Frailty? A Prospective, 
Observational Cohort Study. Ann Surg. 2016 Dec;264(6):1116-1124. doi: 
10.1097/SLA.0000000000001546. PMID: 26655919; PMCID: PMC4907876. 
 
17. Shah SP, Penn K, Kaplan SJ, Vrablik M, Jablonowski K, Pham TN, Reed MJ. Comparison of bedside 
screening methods for frailty assessment in older adult trauma patients in the emergency 
department. Am J Emerg Med. 2019 Jan;37(1):12-18. doi: 10.1016/j.ajem.2018.04.028. Epub 2018 
Apr 14. PMID: 29728285. 
 
18. Benton E, Liteplo AS, Shokoohi H, Loesche MA, Yacoub S, Thatphet P, Wongtangman T, Liu SW. A 
pilot study examining the use of ultrasound to measure sarcopenia, frailty and fall in older patients. 
Am J Emerg Med. 2020 Aug 7; S0735-6757(20)30676-8. doi: 10.1016/j.ajem.2020.07.081. Epub ahead 
of print. PMID: 33041131. 
 

 
 
Acutelines non-WMO study protocol, version 1 (23-09-2020) | page 18 of 19 
 
 
8. APPENDICES  
8.1 Required text for manuscript 
 
“Data/ samples were obtained  from the Acutelines data-, image and biobank [reference 3]. 
Acutelines is a prospective biobank including patients with a broad spectrum of acute conditions, 
aiming to facilitate interdisciplinary research on etiology and development of acute diseases with the 
aid of systematically collected biomaterials and medical data over various timepoints, both during 
the course of the patient’s disease and after recovery. A deferred consent procedure (by proxy) is in 
place to allow the collection of data and biomaterials prior to obtaining written consent. Clinical 
data, imaging data and biomaterials (i.e. blood, urine, feces, hair) are collected for patients 
presenting to the Emergency Department (ED) with a broad range of acute disease presentations. 
Bedside monitoring data (i.e. electrophysiological waveforms, vital parameters) are automatically 
captured and stored, and information from other data sources (such as the electronic health records 
of the hospital-, emergency medical services- and the general practitioner, the municipal registration, 
health insurance companies and the pharmacy) is securely imported. Follow up data are collected for 
all included patients during the first 72-hours of their hospitalization and 3-months, 1-year, 2-years 
and 5 years after their ED visit.” 
"Biomaterials were collected if the participant had an orange or red triage-color, or was admitted because of sepsis, 
pneumonia or shock. Sepsis was defined based on the physician's suspicion, sepsis-2 or sepsis-3 criteria. Pneumonia 
was defined based on radiological evidence of pneumonia combined with the physician's suspicion of a pneumonia. 
Shock was defined as hypotension (systolic blood prsure < 90 mmHg or a decrease of > 40 mmHg compared to pre-
existent) in combination with tachycardia (heart rate > 100 beats/minute).  
Study data were collected and managed using REDCap electronic data capture tools hosted at [YOUR 
INSTITUTION].1,2 REDCap (Research Electronic Data Capture) is a secure, web-based software platform designed 
to support data capture for research studies, providing 1) an intuitive interface for validated data capture; 2) audit 
trails for tracking data manipulation and export procedures; 3) automated export procedures for seamless data 
downloads to common statistical packages; and 4) procedures for data integration and interoperability with external 
sources." 
 
References 
1. PA Harris, R Taylor, R Thielke, J Payne, N Gonzalez, JG. Conde, Research electronic data capture (REDCap) – A 
metadata-driven methodology and workflow process for providing translational research informatics support, J 
Biomed Inform. 2009 Apr;42(2):377-81. 
2. PA Harris, R Taylor, BL Minor, V Elliott, M Fernandez, L O’Neal, L McLeod, G Delacqua, F Delacqua, J Kirby, SN 
Duda, REDCap Consortium, The REDCap consortium: Building an international community of software partners, J 
Biomed Inform. 2019 May 9 [doi: 10.1016/j.jbi.2019.103208] 

 
 
Acutelines non-WMO study protocol, version 1 (23-09-2020) | page 19 of 19 
 
 
3. E ter Avest, BC van Munster, RJ van Wijk, S Tent, S ter Horst, TT Hu, LE van Heijst, FS van der Veer, FE van 
Beuniungen, JC ter Maaten, HR Bouma.. Acutelines : a large de novo data-, image- and biobank aimingto improve 
early recognition and outcomes of scute diseases. BMJ Open 2021 ;11(7) :e047349