Tools for the Integrated Management of Childhood Illness: Evaluation of Pulse Oximetry and Clinical Decision Support Algorithms in Primary Care. Cross-country Quasi-experimental Pre-post Study, With Embedded Mixed Methods Studies, Cost and Modelled Cost-effectiveness in Kenya and Senegal
Conditions: Childhood Severe Illness, Pneumonia, Primary Health Care, Hypoxia, Referreal and Consultation, Decision Support Systems, Clinical, Oxymetry
Sponsor: Swiss Tropical & Public Health Institute

Protocol
TIMCI: Tools for the Integrated Management of Childhood Illness
Evaluation of pulse oximetry and clinical decision support algorithms in
primary care
Cross-country Quasi-experimental Pre-post Study, With Embedded
Mixed Methods Studies, Cost and Modelled Cost-effectiveness in Kenya
and Senegal
NCT: NCT05065320
Date: 5th April 2023

Tools for the Integrated Management of Childhood Illness
Evaluation of pulse oximetry and clinical decision support algorithms in primary care
Longitudinal observational study, with embedded mixed methods studies, cost and modelled
cost-effectiveness in Kenya and Senegal
Version / date
Description
Prepared by
Kenya& Senegal specific protocol
Versions 0.1.1 to 0.1.5
Draft versions (internal only)
Version 0.1.6, 1st Apr 2020
Protocol
shared
with
PATH
for
independent Scientific Merit Review
submission
Version 0.1.8 20th May 2020      Protocol shared with PATH in response
to independent Scientific Merit Review
Version 0.1.9, 3rd June 2020
Protocol shared with PATH in response
to independent Scientific Merit Review
(with track changes)
Version 0.2.0, 3rd June 2020
Protocol approved by independent
Scientific Merit Review (without track
changes)
Version 0.2.1, 3rd July 2020
Protocol shared with PATH, updating
setting & sample size for Myanmar
(with track changes)
Version 0.2.2, 3rd July 2020
Protocol approved by independent
Scientific Merit Review (without track
changes)
Version 0.2.3, 6th August 2020
Protocol shared with WHO ERC in
response to Secretariat Memorandum
Version 0.2.4, 19th     November Protocol shared with WHO ERC in
2020
response to review letter
Version 0.2.4.1, 8th December Removal of Myanmar from Protocol,
2021
shared with WHO ERC for renewal
Version 0.2.5, 5th April 2023
Submission for WHO ERC for extension
and minor design modifications
Swiss TPH, PATH,
UoW, KGMU, UoN,
Burnett, UCAD, IHI
Swiss TPH
Swiss TPH, PATH,
UoW, UoN,
Burnet, UCAD,
Swiss TPH
Swiss TPH
Swiss TPH
Swiss TPH
Swiss TPH, PATH
Swiss TPH, PATH,
UoW, UoN,
Burnet, UCAD,
Swiss TPH
Swiss TPH
The information contained in this document is confidential. It is intended solely for the Investigators, potential
Investigators, consultants, or applicable Independent Ethics Committees and Regulatory Authorities. It is
understood that this information will not be disclosed to others without prior written authorization from the
Sponsor, except where required by applicable local laws.

Contents
Abbreviations...................................................................................................................................................................................5
1       Summary.................................................................................................................................................................................7
2       General information.........................................................................................................................................................12
2.1        Trial registration......................................................................................................................................................12
2.2        WHO Trial Registration Data Set......................................................................................................................12
2.3        Funding.......................................................................................................................................................................12
2.4        Roles & responsibilities........................................................................................................................................12
2.4.1     Protocol development: Swiss TPH..............................................................................................................14
2.4.2     Project and research governance................................................................................................................15
3       Background & rationale.................................................................................................................................................18
3.1        Rationale for pulse oximetry..............................................................................................................................18
3.2        Rationale for clinical decision support algorithm......................................................................................20
3.3        The TIMCI project...................................................................................................................................................21
4       Goal & objectives..............................................................................................................................................................22
5       Study design.......................................................................................................................................................................24
5.1        Pilot phase.................................................................................................................................................................25
5.2        Quasi-experimental pre-post study ................................................................................................................25
5.3        Service provision assessment ............................................................................................................................26
5.4        Facility-based process mapping and time-flow study.............................................................................26
5.5        Healthcare providers’ acceptability and perceptions of the intervention........................................27
5.6        Caregiver perceptions of the intervention and health-seeking behaviour......................................27
5.7        Stakeholder perceptions and project data review ...................................................................................28
5.8        Cost and modelled cost-effectiveness study...............................................................................................29
6       Participants, interventions, and outcomes..............................................................................................................30
6.1        Study setting.............................................................................................................................................................30
6.1.1     Kenya......................................................................................................................................................................30
6.1.2     Senegal..................................................................................................................................................................31
6.2        Eligibility criteria......................................................................................................................................................31
6.2.1     Quasi-experimental pre-post study and pilot........................................................................................31
6.2.2     Other mixed methods studies......................................................................................................................32
6.2.3     Cost and modelled cost-effectiveness study..........................................................................................33
6.3        Interventions.............................................................................................................................................................33
6.4        Outcomes...................................................................................................................................................................37
6.4.1     Quasi-experimental pre-post study...........................................................................................................37
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6.4.2     Other mixed methods studies......................................................................................................................39
6.4.3     Cost and modelled cost-effectiveness study..........................................................................................39
6.5        Participant timeline................................................................................................................................................40
6.5.1     Quasi-experimental pre-post study...........................................................................................................40
6.5.2     Other mixed methods studies......................................................................................................................44
6.5.3     Cost and modelled cost-effectiveness study..........................................................................................45
6.6        Sample size ...............................................................................................................................................................46
6.6.1     Quasi-experimental pre-post study...........................................................................................................46
6.6.2     Mixed methods studies...................................................................................................................................47
6.6.3     Cost and modelled cost-effectiveness study..........................................................................................49
6.7        Recruitment...............................................................................................................................................................49
7       Data collection, management and analysis............................................................................................................51
7.1        Data collection methods......................................................................................................................................52
7.1.1     Quasi-experimental pre-post study...........................................................................................................52
7.1.2     Routine data........................................................................................................................................................53
7.1.3     Other mixed methods studies......................................................................................................................54
7.1.4     Cost and modelled cost-effectiveness study..........................................................................................56
7.2        Data management..................................................................................................................................................59
7.2.1     Data flow, storage and transfer ...................................................................................................................59
7.2.2     Data entry, handling and validation...........................................................................................................61
7.2.3     Data privacy protection...................................................................................................................................63
7.2.4     Data quality assurance and control............................................................................................................64
7.3        Statistical methods.................................................................................................................................................65
7.3.1     Quasi-experimental pre-post study...........................................................................................................65
7.3.2     Routine data........................................................................................................................................................66
7.3.3     Other mixed methods studies......................................................................................................................66
7.3.4     Cost and modelled cost-effectiveness study..........................................................................................67
8       Monitoring...........................................................................................................................................................................68
9       Ethics and dissemination ...............................................................................................................................................69
9.1        Research ethics approval.....................................................................................................................................69
9.1.1     Regulatory status of the intervention........................................................................................................69
9.2        Protocol amendments ..........................................................................................................................................70
9.3        Consent or assent...................................................................................................................................................70
9.3.1     Quasi-experimental pre-post study...........................................................................................................70
9.3.2     Other mixed methods studies......................................................................................................................70
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9.3.3     Cost and modelled cost-effectiveness study..........................................................................................71
9.4        Confidentiality..........................................................................................................................................................71
9.4.1     Quasi-experimental pre-post study...........................................................................................................71
9.4.2     Other mixed methods studies......................................................................................................................71
9.4.3     Linking between quasi-experimental pre-post study and mixed methods studies................72
9.4.4     Cost and modelled cost-effectiveness study..........................................................................................72
9.5        Risks and benefits to participants....................................................................................................................72
9.6        Access to data..........................................................................................................................................................73
9.7        Dissemination policy.............................................................................................................................................73
10     References ...........................................................................................................................................................................75
11     Appendices..........................................................................................................................................................................81
11.1      Informed consent forms appended to the protocol ................................................................................81
11.2      Study instruments appended to the protocol.............................................................................................81
11.3      Budget and collaboration appended to the protocol..............................................................................81
11.4      TIMCI Preliminary Theory of Change..............................................................................................................82
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Abbreviations
(co)-PI
(e)CRF
CDSA
CE
CG
CHC
CS
CSO
DALY
DB
DHIS
DMC
DMP
EDC
ePOCT
ERC
FGD
GPS
HC
HCP
HMIS
HP
HQ
IAG
ICC
ICD-10
ID
IDI
IHI
IMCI
IQR
KGMU
KII
LMIC
M&E
MedAL-C
MedAL-R
MedDRA
MEP
MIS
MOH
PHC
PII
RA
RHC
SAP
SNOMED CT
(co)-Principal Investigator
(electronic) Case Report Form
Clinical Decision Support Algorithm
Conformité Européenne
Caregiver
Community Health Centre
Case Studies
Civil Society Organization
Disablity-Adjusted Life Years
Database
District Health Information System
Data Monitoring Committee
Data Management Plan
Electronic Data Capture
electronic Point of Care Tool
Ethical Review Committee
Focus Group Discussion
Global Positioning System
Health Centre
Health Care Provider
Health Management Information System
Health Post
Headquarters
International Advisory Group
Intracluster Correlation Coefficient
International Statistical Classification of Diseases and Related Health Problems
Identification
In-Depth Interview
Ifakara Health Institute
Integrated Management of Childhood Ilnesses
Interquartile Range
King George's Medical University
Key Informant Interview
Low- and middle-income countries
Monitoring and Evaluation
Medical Algorithm – Creator
Medical Algorithm – Reader
Medical Dictionary for Regulatory Activities
Monitoring and Evaluation Plan
Management Information System
Ministry Of Health
Primary Healthcare Center
Personal Identifiable Information
Research Assistant
Rural Health Center
Statistical Analysis Plan
Systemized Nomenclature of Medicine - Clinical Terms
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SOP
SPA
SRA
Swiss TPH
TIMCI
ToC
UCAD
UoN
US FDA
VPN
WHO
Standard Operating Procedure
Service Provision Assessment
Stringent Regulatory Authority
Swiss Tropical and Public Health Institute
Tools for integrated management of childhood illness
Theory of Change
Université Cheikh Anta Diop de Dakar
University of Nairobi
United States Food and Drug Administration
Virtual Private Network
World Health Organisation
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1 Summary
Background / rationale
Achieving global targets for child mortality reduction in low- and middle-income countries
(LMICs) requires significant improvements in the detection and management of severely ill
children. Existing guidelines are inconsistently implemented by healthcare providers and, as
they are based on clinical signs, are inadequate for the detection of hypoxaemia, a strong
predictor of mortality.
The overall goal of the Tools for the Management of Childhood Illness (TIMCI) project is to
reduce morbidity and mortality in sick children attending primary care facilities, while
supporting the rational and efficient use of diagnostics and medicines by healthcare providers.
The evaluation component of the project seeks to generate evidence on the health impact,
operational priorities, cost and modelled cost-effectiveness of introducing pulse oximetry,
embedded into a Clinical Decision Support Algorithm (CDSA), at primary care level in LMICs,
for children 0 – 59 months of age, to facilitate national and international decision-making on
scale-up.
Study design
Health impact will be assessed through a quasi-experimental pre-post study, comparing clinical
care of children attending primary care facilities in a pre-intervention period with those
attending facilities following introduction of the intervention. The intervention package will be
piloted and refined in parallel with the pre-intervention study period.
This will be complemented by embedded mixed methods sub-studies to evaluate key
components of quality of care and gain a deeper understanding of the implementation
processes, mechanisms and context following a realist approach. These studies include
modified Service Provision Assessments (SPAs), a facility-based process mapping and time-
flow study, qualitative studies with caregivers, healthcare providers and key stakeholders, a
survey sent to selected key stakeholders, a desk-based project document and monitoring and
evaluation (M&E) review, and a cost and modelled cost-effectiveness study.
Study setting
The study setting encompasses facility-based primary care level in Kenya (Kakamega, Kitui and
Uasin Gishu), and Senegal (Thiès). Caregivers often attend different types of facilities to meet
their primary care needs; the study setting therefore includes a diverse range of facilities
providing primary care services, including outpatient settings within larger health centres in
addition to the more traditionally-labelled primary care facilities. This includes Level 2
(dispensaries) and Level 3 (health-centres / sub-county hospitals) in Kenya, and health posts in
Senegal.
Key Eligibility Criteria
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Consenting government-designated healthcare facilities providing outpatient curative primary
care services for children 0 – 59 months of age will be included. Facilities will be excluded if
they use pulse oximetry as a routine part of outpatient consultations of children prior to the
start of the intervention.
Children 0 – 59 months, for whom caregivers provide consent, will be eligible if attending any
study facility with an illness, excluding those admitted as inpatients within the facility, or
attending for a consultation related to trauma only.
Caregivers of enrolled children, and healthcare providers at study sites involved in the care of
children 0 – 59 months of age, and stakeholders involved in or affected by the intervention,
will be eligible for inclusion in the applicable studies.
Interventions
The TIMCI project will introduce pulse oximetry, incorporated into a CDSA, into primary care
facilities, supported by targeted training and embedded into monitoring, supportive
supervision and maintenance systems.
The pulse oximeters provided in the study will be UNICEF-approved handheld pulse oximeters
with paediatric and neonatal probes. The criteria for pulse oximetry use, on which healthcare
providers will be trained, are:
x
All children under 2 months of age
x
Children 2 – 59 months of age presenting with cough / difficulty breathing
x
Children 2 – 59 months of age with Integrated Management of Childhood Illness (IMCI)
signs of moderate / severe disease (IMCI ‘yellow’ or ‘red’ classification)
Healthcare providers will be advised to use a cut-off of SpO2 <90% for referral, unless
specific national guidance states otherwise (for example in Senegal, where it is likely that a
<92% SpO2 cut-off may be instituted). Different SpO2 cut-offs for referral for sites at high
altitude will be finalised with the International Advisory Group (IAG) and Ministries of Health
(MoHs).
The above guidance will be incorporated into a tablet-based CDSA, which guides healthcare
providers through medical consultations with an algorithm called electronic point-of-care tool
(ePoct+). The clinical algorithm will be adapted to reflect national guidelines for the
management of children 0 – 59 months of age in primary care (based on IMCI and additional
relevant case management guidelines), and will be validated through consultation of
international and national experts in each country.
Outcomes
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Two primary outcomes will be assessed between the pre-intervention and the last
intervention period of the pre-poststudy:
x
Proportion of children referred by a primary care healthcare provider to a higher level
of care (either to a hospital or to an inpatient part of a larger primary healthcare
facility) at Day 0 consultation
x
Proportion of children prescribed an antibiotic at Day 0 primary care consultation
Important secondary outcomes include:
x
Proportion of children with a severe complication (death or secondary hospitalisation)
by Day 7
x
Proportion of children admitted to hospital within 24 hours of the Day 0 primary care
consultation and as a result of a referral (used as a proxy for ‘appropriate referral’)
x
Proportion of children who completed referral, as reported at Day 7 follow-up
x
Proportion of children cured (defined as caregiver reported recovery from illness) at
Day 7 follow-up
x
Proportion of children with hypoxaemia (according to differing cut-offs) with severe
complication
Sub-group analyses will include age (under 2 months, 2 – 12 months, 13 – 59 months), sex,
and clinical presentation (with cough / difficulty breathing, fever, other). Exploratory
interrupted time series analysis across the 5 quarters of the pre-post study will be conducted,
along with other exploratory analyses of individual and health system factors associated with
health and patient-centred outcomes.
Mixed methods sub-studies will mostly be exploratory, to evaluate quality of care outcomes
and explore perceptions, values, attitudes and beliefs. Process evaluation criteria will be
evaluated according to the Medical Research Council criteria.
Cost and modelled cost-effectiveness will assess:
x
Full implementation cost of the intervention per focal country (cost to health system as
well as direct costs paid by the household to the health system)
x
Cost per child assessed using pulse oximetry devices and CDSA per country compared
to without these supports.
x
Modelled cost per DALY averted attributed to the introduction of pulse oximetry and
CDSAs
Sample size
The sample size for the pre-post study is calculated separately for each country, based on
comparison between pre- and post-intervention periods. In order to detect a difference in
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referral from primary care from 3% to at least 4.5%, with 80% power, we initially estimated a
sample size in each country as follows:
x
Kenya – 17 facilities, recruiting an average of 690 children per facility in each period,
equating to 11,730 children per period
x
Senegal – 18 facilities, recruiting an average of 510 children per facility in each period,
equating to 9,180 children per period
For the antibiotic prescription primary outcome, this would enable a minimum detectable
reduction of 18% in both Kenya and Senegal.
Following lower than anticipated recruitment in the pre-intervention period, sample size
calculation was revised. As a result, two additional facilities were added per country and the
pre-intervention period was extended from an initially anticipated 3 months to a 6 – 8 month
period. A decision was also taken to target a post-intervention sample size of at least the same as
the pre-intervention sample size, as well as a minimum duration of 9 months post-
intervention to allow for stabilisation over time and some seasonal overlap of pre- and post-
intervention periods.
Service provision assessments and process mapping will be conducted in 8 – 10 study facilities
per country, stratified by rural / urban location and facility type. At each facility at each time
point, 10 – 30 children per facility will be included, resulting in an estimated sample size of 800 –
1000 clinical observations, time-flow observations and exit interviews per country over the
study period.
Final sample size for qualitative studies will be determined by reaching thematic saturation. For
those countries choosing to conduct qualitative data collection pre-intervention an estimated
10-20 IDIs with caregivers and health care providers and 10-20 KIIs with stakeholders will be
conducted. Per country, an estimated total of 35-45 in-depth interviews (IDIs), 6 – 8 walking
interviews and 6 focus group discussions (FGDs) will be conducted with caregivers, spread
across the period of implementation. Similarly, 35 – 45 IDIs and 6 FGDs will be conducted with
healthcare providers, and approximately 45 key informant interviews with stakeholders.
Ethics Review
Following independent scientific merit review, the protocol will be submitted to all relevant
research ethics committees / institutional review boards in each country and the WHO ethical
review committee.
Estimated study timeline
Pending all relevant ethical approvals, first enrolment is anticipated to be in Q2 2021, with
completion of data collection in Q1 2023.
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Depending on the evolution of the Covid-19 pandemic, we will keep implementation,
research processes and timelines under review and inform the necessary bodies and
institutions accordingly of any changes.
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2 General information
2.1 Trial registration
The trial is registered on clinicaltrials.gov, with the main register ID: NCT05065320.
2.2 WHO Trial Registration Data Set
To be uploaded once approved
2.3 Funding
The TIMCI project and associated research described in this protocol are funded by UNITAID.
PATH (Seattle) is the primary recipient of the funds and manages the project, with distribution of
funds for project implementation to PATH Country offices. All research partners are sub-
contracted by and accountable to PATH. PATH is responsible for all procurement related to
implementation (including medical supplies and consumables). Pulse oximeters used within
the study will be procured through UNICEF.
2.4 Roles & responsibilities
PATH headquarters (Seattle) lead the project, including strategic direction and decision-
making, project oversight and compliance, global communications, risk monitoring and
mitigation, quality/change management, as well as serving as liaison with UNITAID, the
International Advisory Group and other relevant global partners, such as WHO and UNICEF.
Additional details on project governance are described below. PATH retain overall
responsibility for the project, but have sub-contracted (Fig. 1): Swiss TPH to coordinate
research design and analysis, which includes collaboration with UniSanté, who lead the design
and development of the clinical decision support algorithm; University of Waterloo (UoW) to
conduct cost-effectiveness analysis; and the following research partners leading country
research activities: King George’s Medical University (KGMU, India); University of Nairobi (UoN,
Kenya); Université Cheikh Anta Diop de Dakar (UCAD, Senegal); and Ifakara Health Institute
(IHI, Tanzania). As this protocol relates only to research activities in Kenya and Senegal, other
country research leads will not be further detailed in this document.
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Fig. 1. TIMCI project partners
PATH is the Sponsor of the research but is delegating certain responsibilities to Swiss TPH and
country research partners, outlined in Tab. 1. Through that delegation, Swiss TPH in
collaboration with the research partners in each country will be responsible for the initiation,
and management of the research. Each of the three study countries has a separate tri-partite
agreement between the country research partner, PATH and Swiss TPH. Within this agreement,
Swiss TPH has the lead in development and design of the research. The respective in-country
research partner will be responsible for the adaption of the design to the country specific
context, in close collaboration with Swiss TPH and PATH.
Tab. 1. TIMCI Sponsor & research responsibilities
PATH
Investigator selection
Lead
Medical expertise
Review
Research design
Review
Submission to WHO ethical review
Lead
Submission to country ethical review
Review
Preparation of study sites
Review
Research management
Research conduct
Data collection
Quality assurance & control
Review
Data analysis (country specific)
Data analysis (cross-country)
Dissemination
Review
Compensation
Review
Financing
Lead
Swiss TPH
Lead
Lead
Review
Review
Participates
Lead
Participates
Participates
Lead
Participates
Lead
Lead
Lead
Research Partners
Participates
Participates
Review
Lead
Lead
Participates
Lead
Lead
Lead
Lead
Participates
Lead
Participates
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Swiss TPH
Unisanté
UoW
2.4.1 Protocol development: Swiss TPH
Swiss TPH leads the study design and protocol development in close collaboration with all
other partners. The University of Waterloo leads the development and conduct of the cost-
effectiveness component of the research, in close collaboration with Swiss TPH, PATH and the
country research partners. The pre-post study with mixed methods sub-studies and cost-
effectiveness research will be conducted in two countries, Kenya and Senegal. In each country,
Swiss TPH and PATH collaborate with research institutions, all of which have extensive
experience in implementing and conducting large-scale projects in their respective study
settings. PATH central contributes to the protocol development, ensuring alignment of the
proposed research with the intervention and the training packages, which are led by PATH. In
both study countries, the local PATH interlink with the research partners Tab. 2 outlines the
investigators and contributors to the protocol.
Tab. 2. TIMCI investigators and contributors for Kenya and Senegal study
Name
Prof. Kaspar Wyss
Prof. Valérie d’Acremont
Dr. Fenella Beynon
Dr. Hélène Langet
Dr. Leah F. Bohle
Dr. Fabian Schär
Dr. Tracy Glass
Silvia Cicconi
Dr. Gillian Levine
Dr. Kristina Keitel
Dr. Elisabeth Reus
Dr. Vânia Oliveira
Anja Orschulko
Role
Co-PI
Co-PI
Clinical
Research
Scientist, Co-I
Data Manager, Co-I
Social Scientist, Co-I
Project Manager, Co-I
Biostatistician
Biostatistician
Clinical Researcher
Senior
Clinical
Scientist
Clinical Operations
Clinical Operations
Social Scientist
Input
Oversight & overall responsibility for research design
for Swiss TPH
Oversight & overall responsibility for research design
for Swiss TPH
Quantitative study design and analysis, clinical input
for algorithm
Study design, data management oversight, technical
input for algorithm, link CDSA into research design
Qualitative study design & analysis
Study design, Ethics approval, timelines and link with
research partners
Input into study design, data management and
analysis
Input into study design, data management and
analysis
Development of clinical content for young infants;
input into study design; qualitative study design and
analysis for young infants; data analysis
Input in development of clinical content for algorithm,
input on study design
Development of monitoring plan, ethics input
Monitoring of study conduct
Qualitative study design & analysis
Vincent Faivre
Alan Vonlanthen
Deputy head of IT
department
Project Manager
Software development
UniSanté Project Management, IT department
Prof. Susan Horton
Dr. Nnachebe Michael
Onah
Cost-effectiveness PI
Cost-effectiveness
Co-I
Oversight and analysis of cost-effectiveness study
Design and conduct of cost-effectiveness study in
collaboration with country research partners
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UoN
UCAD
PATH
Prof. James Machoki
M’Imunya
Mr. Francis Njiri John
National PI
Project Coordinator
Overall administrative and scientific lead for Kenya
Data collection & Management, Ethics approval,
timelines and link with partners
Dr.     Rose
Jepchumba
Kosgei
Clinical Epidemiology
Lead
Clinical Expertise, Study design, Research
Implementation
Dr.
Anthony
Runo
Gichangi
Dr. Mercy Mugo
Biostatistician
Cost-Effectiveness
Lead
Data Management, statistical analysis and
dissemination
Design and conduct of cost-effectiveness study
Dr. Mariah Ngutu
Prof. Ousmane Ndiaye
Prof. Papa Moctar Faye
Dr. Aliou Thiongane
Dr. Marième Sougou
Dr. Jean Augustin Tine
Mr. Mike Ruffo
Ms. Mira Emmanuel-
Fabula
Dr. Helen Storey
Dr. Manjari Quintanar
Solares
Ms Tara Herrick
Mr Zachary Clemence
Ms Tanya Lalwani
Dr. Andolo Miheso
Dr. Dan Otieno
Dr. Maymouna Ba
Operations Research
Lead
National PI
Research Coordinator
/ Clinical Researcher
Clinical Researcher
–Qualitative Research
Lead
Consultant -
Biostatistician
TIMCI Project Director
TIMCI Project
Manager
Senior Research
Officer
Senior Program
Officer
Senior Market
Analytics Officer
Market Dynamics
Senior Associate
Senior Program
Officer
PATH-Kenya
PATH-Kenya
PATH-Senegal
Design, conduct and analysis for the Mixed-methods
studies including Observational, Qualitative and
Time-flow studies
Overall lead for Senegal
Data collection & Management, Ethics approval,
timelines and link with partners
Clinical
Expertise,
Study
design,
Research
Implementation
Design, conduct and analysis for the Mixed-methods
studies including Observational, Qualitative and Time-
flow studies
Data Management and statistical analysis
Oversight & overall responsibility for TIMCI
Global Project Management PATH
Lead research PATH on Output 2
Training Lead
Cost-Effectiveness Lead
Implementation development
Monitoring & Evaluation Lead
PATH-Tanzania Country Representative
TIMCI Country Lead
TIMCI Country Lead
2.4.2 Project and research governance
The TIMCI project has several different working groups for governance of implementation and
research activities, described in Tab 3 below. As shown in Fig. 2, the research governance for
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the pre-post study is shared with the RCT (conducted in India and Tanzania) through a Research
Steering Committee (RSC). The RSC is chaired by an independent expert, and will include two
sub-groups, which act as management groups, one for the RCT and one for the pre-post study.
The Management groups will facilitate the day-to-day running of the RCT and escalate issues to
the RSC. Thematic Working Groups will consist of thematic experts from all study countries.
Tab 3. TIMCI project and research governance
Project Governance
Group
International Advisory
Group
Country
Implementation
Working Groups
Global Implementation
Team
Consortium Executive
Board
Country-Level Technical
Working Groups
Manufacturers Advisory
Group
Research Governance
Research Steering
Committee
Subgroup one: RCT
management group
Subgroup two: LS
management group
Thematic Working
Groups
Membership
Unitaid*, ALIMA, WHO, UNICEF, USAID, experts
in paediatrics and IMCI, CHAI
*Unitaid is an observer in this group
PATH in-country project lead, leaders of Swiss
TPH and research/implementation partners for
research activities, key implementation and/or
management staff, MOH representatives
PATH country- and HQ-based leadership, Swiss
TPH, Country Implementation Working Group
leaders
PATH and Swiss TPH executive-level leaders,
Program Director, Senior Project Manager
Depends upon country; link with most
applicable existing group, such as a child
health TWGs. Key influencers with MOH, policy,
operations
Influential organizations involved with product
development for pulse oximetry, multimodal
devices, O2, and possibly clinical or
procurement functions
Independent external chair, with
representation from Swiss TPH, and research
partners
Swiss TPH, KGMU, IHI
Swiss TPH, UoNand UCAD
Thematic experts Swiss TPH, UoN, UCAD, and
IHI, KGMU
Function
Strategy and guidance focused; shared
with ALIMA – recipient of parallel
UNITAID award
Project management focused at
country level; ensures close country-
level collaboration across multiple
organizations and implementation
partners; important link to MOH.
Pan-country strategic and
management function; forum to build
relationships between countries, share
learnings, and ensure alignment.
Strategic advisory and dispute-
resolution committee for PATH and
Swiss TPH.
Existing working groups that will
provide essential review and oversight
in each country; builds and maintains
linkages with country operators.
Inform development of TPP, design
manufacturer incentive programs, and
ensure alignment with market forces.
Regular review of research progress in
all five countries with particular focus
on trial and pre-post study
Internal working group for
management of RCT study activities
Internal working group for
management of LS study activities
Exchange on content-specific topics
across all research partners
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Fig. 2. TIMCI governance overview
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3 Background & rationale
Despite progress in reducing child mortality in the last few decades, an estimated 5.3 million
children under five years of age died of preventable causes in 2018.1 If we are to achieve the
Sustainable Development Goal 3.2 by 2030, all countries must reduce under-five mortality to at
least as low as 25 per 1,000 live births and neonatal mortality to at least as low as 12 per 1,000
live births.2 Strengthening systems to identify and appropriately treat sick children,
alongside health prevention and promotion activities, is critical to achieving this goal.
The Integrated Management of Childhood Illness (IMCI) guidelines, launched in 1995 and now
adopted by over 100 countries, responded to the need to systematise the implementation of
evidence-based health interventions for children under five in primary care and the
community.3 The case management component provides a simple, structured approach to
assessment, classification and treatment of the sick child, with a particular focus on severe
illness.4
Yet despite the intention of IMCI to have high sensitivity for detection of severe disease, many
studies have demonstrated poor identification and management of severely ill children due to
both non-adherence by health workers5–9 and intrinsic problems of guidelines based on clinical
signs alone10–14. The Tools for the Integrated Management of Childhood Illness (TIMCI) project
seeks to address these issues by introducing clinical decision support algorithms and pulse
oximetry to strengthen guideline implementation and accuracy in order to improve quality of
care and reduce morbidity & mortality.
3.1 Rationale for pulse oximetry
Hypoxaemia, a reduction in blood oxygenation, has a myriad of causes in children – both
respiratory and non-respiratory, but regardless of the cause, is strongly associated with
mortality.15 A meta-analysis of 13 studies on 13,928 children found a 5.5 fold increased risk of
death among children with acute lower respiratory infection (ALRI) with oxygen saturation
(SpO2) below 90%.15     The association of hypoxaemia with mortality in non-respiratory
conditions is less extensively documented, but a recent large study in Nigeria found adjusted
odds of death in hypoxaemic children to be 7.1 in ALRI, and range from 5.9 to 6.6 in the next
most common causes of hypoxaemia (malaria, acute febrile encephalopathy, sepsis, seizures).16
The prevalence of hypoxaemia is estimated to be around 13% among children with WHO
defined suspected pneumonia.17 Prevalence is also high among sick neonates (18 – 23%),
malaria (3 – 17%), meningitis (3 – 15%) and malnutrition (2 – 8%).ibid Studies have further
demonstrated the importance of hypoxaemia in children with asthma, sepsis, malaria, sickle
cell disease, tetanus and a variety of neonatal illnesses.16,18–22 However, the relative contribution
of different diseases to the burden of hypoxaemia is highly variable in different settings17, and
likely to reflect the local burden of disease. For example, in the aforementioned study of 23,926
hospitalised children in Nigeria, among all children (28 days – 14 years) with hypoxaemia, 37%
had ALRI, 33% malaria, 32% acute febrile encephalopathy, 27% sepsis and 18% seizures. In
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countries facing a lower burden of malaria, such as India (2.2% of under 5 deaths are attributed
to malaria, compared to 13.2% in Nigeria), whilst systematic data on hypoxaemia burden is not
available, this distribution is likely to be rather different.23
Given the prevalence of hypoxaemia and its role in mortality, a number of studies have sought to
evaluate the predictive power of clinical signs to detect hypoxaemia and guide oxygen
therapy. But no single sign or combination of signs has reliably been found to detect
hypoxaemia with adequate sensitivity or specificity.24 Using clinical signs alone thus leads to a
failure to identify all children who need oxygen and unnecessary administration of oxygen
(which is often in scarce supply) for children who do not need it.24
Pulse oximeters provide a non-invasive, accurate and easy to use method of evaluating
hypoxaemia. A number of observational studies at hospital level have shown significant
reductions in child mortality, referrals and triage time following the introduction of pulse
oximetry and associated interventions.13,25,26 Furthermore, a recent modelling study estimated
that implementing pulse oximetry could avert up to 148,000 deaths per year of children under-5
in fifteen high-burden pneumonia countries, far more than the potential deaths averted by
IMCI alone.27 In addition to the potential impact on child morbidity and mortality, there are
potential resource savings through the reduction in unnecessary oxygen use – up to two thirds of
children eligible for oxygen based on WHO criteria are not hypoxic.14
Whilst most data and guidance relating to pulse oximetry pertains to hospital settings, there is
emerging evidence on the benefit in primary care. In Malawi, provision of pulse oximetry to
rural health centres and community health workers resulted in increased referral rates among
children with WHO-defined severe pneumonia.13 They also found that pulse oximetry enabled
the identification of hypoxaemic children who otherwise would have been categorised as
having non-severe pneumonia. Whilst their study was implemented before the 2014
modification to WHO IMCI guidelines, retrospectively applying the criteria to their dataset
revealed that 69% of hypoxaemic children would not have been categorised as requiring
referral. Pulse oximetry therefore provides the opportunity to improve the sensitivity of IMCI
guidelines for severe disease. Implementation of pulse oximetry could also be a strategy to
rule-out severe disease and therefore reduce unnecessary hospital referrals and admissions,
though the exact oxygen saturation cut-off requires further validation.28
This potential to improve the detection and referral of children with severe disease has led to
strengthened interest in the potential to rollout pulse oximetry to primary care. However,
before significant investment is made in this area, it is critical to understand what health impact
pulse oximetry has, for which children in which contexts, and with what consequences – such as
over-referral to already stretched hospital resources. Impact is likely to depend on a number of
factors, including burden of hypoxaemia in primary care, choice of criteria for pulse oximetry use
(to optimise detection of hypoxaemic children whilst avoiding false positives and over-
burdening clinic staff) and pre-existing quality of care.
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3.2 Rationale for clinical decision support algorithm
Whilst the introduction of pulse oximetry can improve the identification of sick children in
primary care, it does not provide a comprehensive approach to improve adherence to
evidence-based guidelines. Observational studies have indicated that IMCI-trained healthcare
providers only correctly classify children according to IMCI guidelines 33 – 87% of the time.5
This lack of correct classification likely stems from incomplete assessments. Pooled data from
the Service Provision Assessment surveys in Namibia, Kenya, Tanzania and Uganda found
health workers conducted a complete danger signs assessment in less than 33% of 6856
children assessed.6 In Malawi, fewer than 1% of children had an assessment including all 16
elements of the history and examination.9 In the same study, respiratory rate was only checked in
16% of children presenting with cough or difficulty breathing.
Failure to assess key signs can result in under-classification of severity and inadequate
management of children with severe disease, leading to a higher mortality risk. For example, in
the above study in Malawi, clinical officers did not refer 41% of children with severe / very
severe pneumonia, and requested oxygen for only 23% of those that met criteria.9 Similarly, in a
study in South Africa, only 47% of children with severe disease were correctly identified by a
health worker.7
Even when health workers do recognise severe disease, they do not necessarily treat and refer
according to guidelines. In a study in Tanzania, only 38% of children with severe disease were
referred by IMCI-trained health workers, despite 95% having been recognised as having severe
pneumonia, severe malaria or both.8 The authors surveyed health workers and found that 91%
believed that referral was not a necessary component of management for certain severe
conditions.
Electronic clinical decision support algorithms (CDSAs) provide an electronic step-by-step
guide through a clinical consultation for healthcare providers, supporting the integrated
disease management approach promoted by WHO. Recent studies of two such tools, based on
IMCI and national guidelines, have demonstrated potential for significant improvements in
health outcomes and large reductions in unnecessary antimicrobial prescribing.29,30 The use of
one such tool by healthcare providers in consultations for all acutely unwell children was found to
improve cure rate at day 7 (97% compared to 92% in routine care) whilst reducing antibiotic
prescriptions from 84% to 15%.29 Another tool, ePOCT, used for children with fever and
integrating point of care diagnostic tests, reduced clinical failure rate to 2% (compared to 5% in
routine care) and antibiotic prescriptions to 11% (from 95%).31
The mechanisms by which CDSAs impact health worker practice may stem from the fact that
the electronic algorithms, by design, provide support in decision making for any combination of
clinical findings, whereas paper-based IMCI or national guidelines are, by necessity,
reductionist.10 In a mixed-methods exploration of the reasons for non-adherence to IMCI
guidelines by health workers, Lange and colleagues described “cognitive overload” as a
contributory factor to non-adherence.32 In such circumstances, support to the complex clinical
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decision making process with CDSAs can facilitate health workers to provide higher quality
care. This is likely to be particularly true in the case of introducing novel technology such as
pulse oximetry, which adds an additional level of complexity to the integrated clinical
assessment of children.
Implementing pulse oximetry embedded into a CDSA has the potential to improve the
detection of children with severe disease and improve the adherence of healthcare providers to
evidence-based, integrated disease management guidelines. We hypothesise that these
interventions will result in a reduction in adverse health outcomes through better treatment
and referral decisions, and an improvement in quality of care through the rational use of
essential medicines and improvements in the health worker and caregiver experience.
3.3 The TIMCI project
The Tools for Integrated Management of Childhood Illness (TIMCI) project builds on this
hypothesis to form part of the response to the need for better mechanisms to detect and
manage children with severe illness in LMICs. It is a 4 year UNITAID-funded project, focused on
the interventions of pulse oximetry and CDSAs in primary care, organised into four main
outputs: (1) introduction of pulse oximetry and CDSAs in four countries (India, Kenya, Senegal
and Tanzania); (2) evidence generation for pulse oximetry and CDSA introduction; (3) market
strengthening for adapted multi-modal devices; and (4) creating conditions for national and
global scale-up and sustainable use of these tools.
This protocol focuses on the evidence generation component of the TIMCI project in Kenya
and Senegal (a separate protocol has been developed for India and Tanzania to reflect a
different study design).
To our knowledge, no large scale studies have systematically evaluated the health impact, cost
and optimal implementation approaches of pulse oximetry, alone or embedded into a CDSA,
for children with a broad range of clinical diagnoses in primary care.
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4 Goal & objectives
The overall goal of the TIMCI project is to reduce morbidity and mortality in sick children
attending primary care facilities, while supporting the rational and efficient use of diagnostics
and medicines by healthcare providers. The evaluation component of the project in Kenya and
Senegal seeks to generate evidence on the health impact, operational priorities, cost and
modelled cost-effectiveness of introducing pulse oximetry, embedded into a CDSA, into
primary care in LMICs, for children 0 – 59 months of age, to facilitate national and international
decision-making on scale-up. Specific objectives, according to these themes, include:
Health and quality of care impact
To evaluate the impact on health and quality of care outcomes of sick children 0 – 59 months of
age of introducing pulse oximetry, embedded into a CDSA, for facility-based primary care,
compared to routine care, including on:
x
Referral and hospitalisations
x
Antimicrobial prescription
x
Adherence by primary healthcare providers to key components guidelines
To assess the prevalence of severe, moderate and mild hypoxaemia among sick children
attending primary care, and understand the association of different degrees of hypoxaemia
with adverse outcomes, according to socio-demographic and clinical features.
Implementation and process
x
To understand the facilitators and barriers to uptake, and acceptability of the
intervention and behaviour change by health care providers, caregivers and their
children, and a variety of stakeholders at community, health facility, national and
international levels
x
To evaluate characteristics of children, caregivers, healthcare providers and health
facilities associated with uptake and impact of the interventions
x
To understand how the interventions affect patient flow and patient-provider
interactions, including change in care processes, consultation time, and communication
between caregivers and healthcare providers
Cost and modelled cost-effectiveness
x
To determine the cost and estimate any cost savings and/or additional costs of
introducing pulse oximetry and CDSAs into primary health care
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x
To model cost-effectiveness of the interventions compared to routine care and other
interventions aimed at improving the management of severe illness in children 0 – 59
months of age
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5 Study design
Health impact will be assessed through a quasi-experimental pre-post study, comparing clinical
care of children attending primary care facilities in a pre-intervention (baseline period) with
those attending facilities following introduction of the intervention (intervention period). The
intervention package includes pulse oximetry embedded into a CDSA, with training,
supervision, monitoring and community engagement, further described in Section 6.3. This
intervention package will be piloted and refined in parallel to the pre-intervention period.
This assessment of the health impact of the intervention will be complemented by embedded
mixed methods sub-studies to evaluate other key components of quality of care33 and gain a
deeper understanding of the implementation mechanisms and context. These studies include
modified Service Provision Assessments (SPAs), a facility-based process mapping and time-
flow study, qualitative studies with caregivers, healthcare providers and key stakeholders, a
regular survey sent to selected key stakeholders, a desk-based document and monitoring and
evaluation (M&E) review, and an economic evaluation (Fig. 3, Tab. 8).
Fig. 3: Timeline of TIMCI research in Kenya and Senegal. Pre-post study: comparing clinical care of children in a pre-
intervention period (‘baseline’) with a post-intervention period (‘implementation’). Pilot – 2 to 4 facilities in parallel to baseline, to
refine the intervention. The pre-post study dataset will be collected in these facilities, along with SPA and process mapping,
caregiver IDIs and HCP IDIs. SPAs – cross-sectional assessments in 8-10 facilities comprising of observations of consultations of
sick children, exit interviews with caregivers, interviews with HCPs and facility assessments. Process-mapping and time-flow –
during baseline, early and late implementation. Qualitative studies with caregivers and with HCPs – at pilot facilities (IDIs only)
and across the implementation period to understand change over time. IDIs will also take place in the baseline/pre-intervention
period. Key stakeholders – KIIs during baseline / pilot, early and late implementation. All intervention facilities – PATH M&E
data, ePoct+ clinical consultation data, Health Management Information System data. Cost and modelled cost-effectiveness:
cost data will be collected prior to intervention and on start-up costs, and again during implementation with final data collection
to capture any missing information. Abbreviations: SPA – service provision assessments; IDIs – in-depth interviews; FGDs – focus
group discussions; KIIs – key informant interviews; HCPs – healthcare providers
The intervention will be implemented in approximately 60 health facilities providing primary
care services. Pre-post, mixed-method and costing studies will be conducted in only a sub-
sample of these facilities, with triangulation across studies to generate in-depth insights into
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implementation. Routine data from non-study facilities will be extracted for analysis of the
wider programme, including from the health management information system (HMIS),
anonymised routine clinical data from the CDSA, and PATH project data.
This mixed methods design draws on principles of realist evaluation (focusing on processes,
and mechanisms in their respective contexts leading to outcomes)34, the MRC guidance on
Process Evaluation for Complex Interventions35, the Theoretical Framework of Acceptability of
Health Care Interventions36, and the COM-B model of behaviour change37. It is further informed
by the project’s Theory of Change (ToC, appendix), developed in line with the approach taken by
de Silva and colleagues38 and the Centre for Theory of Change39. The ToC components will be
tested and revised to incorporate unanticipated pathways and assumptions and provide
feedback to strengthen the intervention.
5.1 Pilot phase
The pilot phase will occur over an estimated 3-month period in small number of facilities in
each country whilst the pre-intervention assessment is occurring in the pre-post study facilities.
It will serve to refine the intervention package if necessary, including the approach to training,
supervision, caregiver engagement and guidance on where to use the devices within the care
process. This refined package will then be implemented in the remaining facilities involved in
the TIMCI project.
The pre-post study dataset will be collected from these pilot facilities and will be used for
exploratory analysis in comparison with data from the main pre-post study. We will also collect
SPA, process mapping and time-flow data and qualitative data (from interviews with caregivers,
healthcare providers and key stakeholders; possibly informal group discussions, feedback from
post-training assessments by PATH). These studies will aid understanding of implementation
processes, mechanisms and context. Emphasis will be placed on exploring acceptability, and
barriers and facilitators to implementation to inform fine-tuning and adaptations of the
intervention.
Concurrently, we will pilot the research instruments and processes and refine if necessary,
including eligibility screening, participant information and consent, and data collection tools.
5.2 Quasi-experimental pre-post study
A quasi-experimental pre-post study, comparing clinical care of children attending primary
care facilities in a pre-intervention (baseline period) with those attending facilities following
introduction of the intervention (intervention period). The 6 – 8 month baseline period is
followed by a 9 – 12 month intervention period to allow for evaluation of change over time
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from introduction of intervention and for some seasonal overlap in pre- and post-intervention
periods.
5.3 Service provision assessment
This periodic assessment of service delivery will follow the approach of the Demographic and
Health Surveys (DHS) Program Service Provision Assessment (SPA) (facility assessment,
healthcare provider interview, sick child observation protocol and caregiver interview),40–42
modified to focus on child health, pulse oximetry and CDSA use and incorporate additional
quantitative and qualitative questions covering factors associated with child mortality and
health-seeking behaviour, as well as patient-centred outcomes including experience of care.
We will conduct cross-sectional surveys at a stratified sample of facilities at baseline and during
early and late intervention periods in order to assess differences over the course of
implementation and with varying burden of disease in different seasons. Stratification is based
on rural / urban location, facility type, and, where applicable, district and altitude. On the days of
the surveys, we will conduct an abbreviated facility assessment, administer a questionnaire to all
providers consulting children under five, and a modified ‘sick child’ observation and exit
interview on all eligible children attending the facility.
5.4 Facility-based process mapping and time-flow study
Prior to intervention, we will develop a basic process map defining the common steps in the
care pathway of sick children in primary care facilities in each country (adapted to facility type).
The map will be reviewed and refined through informal discussions with staff and non-
participant observation at a sample of facilities (including on whether specific processes have
been introduced or changed as a result of COVID-19). Time-flow data will be captured for
discrete steps in the care process through observation of a sample of children attending the
facility, from arrival through to consultation (including on use of the devices), to departure
from the facility. Non-participant observation will focus on understanding rationale for care
processes and when and why deviation from the standard pathway may occur.
This pre-intervention map will be adapted to incorporate pulse oximetry and CDSAs through
discussions with staff and observations in the pilot facilities to understand the impact of the
intervention on care processes (including on time) and on patient-provider interactions, and
inform refinement of the intervention strategy if necessary. After roll-out of the intervention,
this will be repeated both early and late in the intervention to understand changes in care
processes and time with the refined intervention package, and adaptations that may have
occurred as a result of provider preferences (or as a result of other changes to care processes
external to the TIMCI project). This will also generate information on whether the intervention
has been normalised into care processes over the longer-term in order to understand
sustainability and inform the package for scale. Time-flow data will also be used in the cost and
modelled cost-effectiveness study.
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5.5 Healthcare providerV·DFFHSWDEaLnOdLWpe\rceptions of the
intervention
We will conduct semi-structured in-depth interviews (IDIs) and possibly focus group
discussions (FGDs) with clinical vignettes with a purposive sample of healthcare providers
working in intervention facilities. IDIs (and informal group discussions) will be conducted at the
pilot facilities to inform intervention refinement. IDIs and possibly FGDs will be conducted over
the course of the intervention to understand changes in perception of the intervention over
time and reasons for early and late adoption. In Kenya and Senegal only, IDIs will also take
place pre-intervention for comparison. FGDs will be based around clinical vignettes to facilitate
discussion of experiences with the devices (including usability, practicality and design) and on
quality of care and acceptability of tools without causing unwanted disclosure, or bias due to
self-stigmatization or self-censorship. IDIs, which may include vignettes, will focus particularly
on the individual experience with the introduction of the intervention and over time; the
acceptability of the intervention; mechanisms, processes and contexts leading to behaviour
change and identifying barriers and facilitators for intervention success.
5.6 Caregiver perceptions of the intervention and health-seeking
behaviour
Semi-structured IDIs, walking interviews resulting in case studies (CS) and FGDs will be
conducted with a purposive sample of caregivers who have attended study facilities. IDIs and
FGDs will be carried out at the household and respective community level.
IDIs (and informal group discussions where required) will be carried out with caregivers
attending pilot facilities to inform intervention refinement. IDIs, walking interviews and FGDs
will be conducted with caregivers attending intervention facilities over the course of the
implementation period to understand changes in perception of the intervention over time and
behaviour change. In Kenya and Senegal only, IDIs will also take place pre-intervention for
comparison. The IDIs, walking interviews and FGDs will focus on aspects of the quality of care
and acceptability frameworks, as well as health-seeking behaviour and decision making,
incorporating a realist approach. Walking interviews will delve into greater detail on decision-
making on and experience of referral.
Classical FGDs will be paired with focus groups incorporating method acting (i.e. adaptation of
interactive performance) structured in a three-step approach including verbalized senses and
experiences, embodied images and performance, using photo- and or video-recording.
Method acting is particularly useful when conducting focus groups with participants who have
low health literacy or in groups where hierarchy between participants predominates, and can
enable empathetic associations, linking knowledge, attitudes and behaviour to personal lived
experience.
Walking interviews will be conducted with a purposive sample of caregivers having received
referral advice and after their visit at an intervention facility allowing for case studies. Walking
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interviews will use an explorative theme catalogue focusing on the care seeking pathway and
decision-making. When accompanying the caregiver, the pathway will be tracked by the data
collector (e.g. by using a mobile device and GPS data). Hand-written notes and GPS coordinates
from qualitative data collected will be used for mapping of care seeking pathways.
Participants with a particularly interesting or divergent view in focus group discussions with
health care providers or caregivers might be approached for follow-up IDIs.
Qualitative data collection is exploratory in nature; time points in data collection are
preliminary. Final time points will depend on the preliminary analysis of qualitative data and
findings throughout the data collection. Therefore the studies planned may require a closer
follow-up or data collection at additional time points (e.g. mid phase of the intervention).
5.7 Stakeholder perceptions and project data review
This will incorporate key-informant interviews (KIIs) with selected stakeholders at global,
national, subnational and local level with perspectives on implementation, policy and research.
Stakeholders will include those internal (i.e. project stakeholders, e.g. PATH) and external (i.e.
non-project stakeholders e.g. Ministry of Health, community, other organisations) to the
project, either directly involved in implementation or affected by implementation. This includes,
but may not be limited to: selected International Advisory Group members, Unitaid and WHO
representatives, PATH headquarters staff, national policy makers, members of district health
management teams, health facility managers, community leaders, national and local PATH
implementation staff and research staff. The KIIs will be conducted during the pilot phase, to
understand perspectives at the start of implementation, and during late intervention, to gain
reflections into implementation over time and to inform a package for scale. In Kenya and
Senegal only, KIIs will also be conducted in the pre-intervention phase to understand health
care provision prior to implementation.
These interviews will be complemented by electronic surveys of selected project informants
and a structured review of key documents including PATH project reports (including on
changes as a result of COVID-19), minutes and M&E data (e.g. on training evaluation or
maintenance and replacement of devices) for each country. It will primarily focus on the
processes, mechanisms and context (i.e. MRC process evaluation criteria) of implementation
including adaptations made.
In each country, PATH project data, along with routine Health Management Information
Systems (HMIS) data, and anonymised data from clinical consultations with the CDSA routinely
entered by healthcare providers will be assessed for all facilities and administrative regions
where the project is running (i.e. both study facilities and non-study facilities) to draw
inferences on the wider project implementation.
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5.8 Cost and modelled cost-effectiveness study
The economic evaluation will involve a cost analysis and modelled cost-effectiveness using
direct health system costs in which financial and economic costs will be assessed. The scope of
the costing will cover only intervention costs and not research-based costs, and will include
costs incurred by the health system as well as estimated direct costs paid out of pocket by the
households to the health system. It is important to note that this cost methodology is not
comprehensive. It does not include the indirect costs incurred by the consumer (patient) e.g.
the caregiver’s time or transport costs. Rather, it focuses exclusively on the provider’s direct
costs, whether borne by the health system or paid out of pocket by the patient’s household.
The approach that has been taken in applying this methodology has been to capture what is
thought to be the “most likely” cost scenario, on average. In identifying this “most likely” cost
scenario, effort will be made to supplement the analysis with a discussion about factors that
influence the level of costs (e.g. the number of trainees per training, or the frequency of
supervision) so as to provide a type of sensitivity analysis of the robustness of the estimates.
Cost scenarios will also guide possible future programme scale up. The cost resources for each
cost centre might differ across the three countries. For instance, at some facilities laboratory
tests or some treatments may not be available, and patients have to be referred elsewhere: we
will have to take account of these differences.
Research-based costs are excluded to enable the costing to provide guidance on future
replication and potential scale up of the intervention. Full and incremental costing involving an
activity-based and ingredient-based approach will be used. When available, effectiveness data
will be combined with the cost data and cost per DALY averted will be estimated as outlined in
7.3.3. The costing and modelled cost-effectiveness will use a 12-month time frame and a 3%
discount rate. Where applicable, discount rates will be adjusted to prevailing rates at country-
level.
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6 Participants, interventions, and outcomes
6.1 Study setting
Whilst the study is taking place in diverse health systems and communities in Africa and Asia,
outlined below, the common feature is the focus on facility-based primary care. Caregivers
often attend a diverse range of facilities to meet their primary care needs. The study setting
therefore includes a diverse range of facilities providing primary care services, including
outpatient settings within larger health centres in addition to the more traditionally-labelled
primary care facilities.
Fig. 4. Map overview of the countries that are involved in TIMCI. Countries conducting the pragmatic
cluster RCT (India and Tanzania) are displayed in red, while countries conducting the pre-post study
(Kenya and Senegal) are displayed in yellow.
6.1.1 Kenya
Setting
Health dispensaries (Level 2) and health centres/sub-county
hospitals (Level 3) in three counties of Kenya (Kakamega, Kitui and
Uasin Gishu). They have been selected due to the expected numbers
of children presenting in the health dispensaries and health
centres/sub-county hospitals, as well as absence of other
interventions. Kitui altitude averages 400-1800m (Kitui County CIPD,
2018), Kakamega county 1535m (Kakamega County CIPD, 2018) and
Uasin gishu from 2700 m – 1500m (Uasin Gishu CIPD, 2018).
Services & Staffing
Both health dispensaries and HCs have opening hours 8am-5pm.
The health dispensaries in the cities act like a health centre, with the
difference that the dispensary does not have in-patient facilities.
HCs are small hospitals with minimal facilities, yet they offer services
like the big hospitals. Health dispensaries are run by clinical officers.
HCs are run by at least one doctor, clinical officers and nurses.
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Referral system & O2 availability
Ambulances located in hospitals are usually called to refer
emergency cases. However, most stable patients are given referral
notes by the referring health facility and they organize their own
transport to the next level of care. Neither dispensaries nor HCs have
cylinder-based oxygen.
6.1.2 Senegal
Setting
Health posts (HPs) in the Thiès region.
Services & Staffing
Health posts are open between 8 am and 4 pm. They offer primary
health services like prenatal care, births, nutrition assessment,
immunization, care for sick babies etc. They are staffed with 4 to 5
health care providers on average. No inpatient care for children or
adults. No permanent staff for nights and weekends, but nurses may
be contacted if needed.
Referral system & O2 availability
The HPs refer to health centers and health centers refer to hospital
level 1, 2 or 3. From HPs, generally only non-medicalized ambulances
are available. Oxygen is available in most referral health centers but
still of limited use. Most HPs do not have oxygen yet. Pulse oximeters
are used in some health centers and not in HPs, except for sites
enrolled in the Oxygen Access project led by Air Liquide.
6.2 Eligibility criteria
6.2.1 Quasi-experimental pre-post study and pilot
Facility inclusion:
x
Consenting government-designated healthcare facilities within the selected
geographical areas of each country
x
Providing curative primary care services for children 0 – 59 months of age
x
Oxygen available or referral mechanism in place with oxygen available at a higher level
facility
x
Electricity available (from any source with continuous or intermittent supply)
Facility exclusion:
x
Attending to fewer than 20 sick children per month (based on the prior 12 month
average)
x
Already using pulse oximetry as a routine part of outpatient-based consultations of
children 0 – 59 months
x
Selected to be part of a major child health programmatic or research intervention
during the study period likely to significantly affect the primary outcome
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x
Inaccessible to the study team (e.g. due to weather conditions or security issues) for
significant parts of the year.
Individual child inclusion:
x
Children 0 – 59 months for whom caregivers provide consent
x
Consulting for an illness, or reported to be unwell when attending for a routine visit
(e.g. vaccination, growth or chronic disease monitoring)
Individual child exclusion:
x
Children in the immediate post-natal period or first day of life
x
Attending for a consultation related to trauma only (including new and follow-up
presentations for burns, injuries, wounds)
x
Admitted within an inpatient part of the facility (including neonates delivered at the
facility admitted with their mother)
x
Enrolled in the study within the preceding 28 days at any study facility
6.2.2 Other mixed methods studies
Facilities for the remaining studies will be sampled from the pre-post study facilities (and pilot
facilities for healthcare provider and caregiver IDIs). A stratified sample of facilities will be
selected for the SPA and process mapping and time flow study, with stratification factors
including location (rural/urban) and type of health facility (if applicable, regional differences
and altitude may also be taken into account). Sub-samples for qualitative studies with
healthcare providers and caregivers will be sampled from SPA facilities to allow for
triangulation of data between studies, but may also be sampled from non-SPA facilities to
avoid research fatigue or amplification of the Hawthorne effect.
Individual children and caregivers will be eligible for inclusion in the SPA observed consultation
and exit interviews if they are eligible for the pre-post and attend a study facility selected for
the SPA during a period when it is being conducted (5 time points, for 3-10 days as outlined in
6.6.2) (. Caregivers will be eligible for inclusion in IDIs and FGDs if their child has been
enrolled in the pre-post study.
Individual healthcare providers will be eligible for the SPA interview if they are present on the
day(s) of assessment and are involved in the care of children 0 – 59 months at that facility.
Healthcare providers for IDIs and FGDs will be eligible if they provide care for children 0 – 59
months at any study facility.
Individual stakeholder eligibility: policy, implementation or research stakeholders at a national
or international level with expertise in child health and / or the devices introduced; local and
sub-national stakeholders either internal or external to the project, directly involved in any
aspect of implementation or affected by the intervention.
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6.2.3 Cost and modelled cost-effectiveness study
Medical and non-medical personnel from study facilities and the government-designated
hospitals to which they refer will be approached for costing data as described in section 6.6.3.
6.3 Interventions
The intervention package included in the TIMCI project is comprised of introduction of pulse
oximetry, incorporated into a CDSA, supported by targeted training. This will be embedded
into monitoring and supportive supervision systems, and link with existing systems to provide
device maintenance and replacement parts. Community engagement will complement the
facility-based intervention, to promote health-seeking behaviour and compliance with referral
advice.
Pulse oximetry
UNICEF-approved handheld pulse oximeters (Acare, AH-MX)43 will be provided, along with a
package of supplies that includes a carry case, spare set of rechargeable batteries, battery
charger, and six reusable probes (two each of adult, paediatric and neonatal sizes). Handheld
devices were selected as they are portable, and thus better suited for point-of-care use in PHC
settings, and more affordable than benchtop devices. Handheld devices are also more
appropriate for children and neonates than fingertip devices, which are typically not designed
for these populations.
The criteria for pulse oximetry use, agreed with the International Advisory Group and Ministries
of Health:
x
All children under 2 months of age
x
Children 2 – 59 months of age presenting with cough / difficulty breathing
x
Children 2 – 59 months of age with IMCI signs of moderate / severe disease (IMCI
‘yellow’ or ‘red’ classification)
These criteria aim to identify children with the highest likelihood of having hypoxaemia whilst
avoid unnecessary referrals of children with a low likelihood of having hypoxaemia and a false
positive result, as well as avoiding over-burdening healthcare providers or contributing to clinic
delays.
Young infants represent a small proportion of all clinic attendees44, but with a relatively high
prevalence of hypoxaemia and risk of severe disease and mortality.1,7,16 Children with cough or
difficulty breathing represent around 40 – 70% of children attending primary care. Children
with WHO-defined suspected pneumonia (around 15 – 30% of clinic attendees)7,44,45 are more
likely to be hypoxaemic than those with cough / cold, but respiratory rate, one of the key
differentiating signs is often not measured.16,45,46 All children with cough / difficulty breathing
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are therefore chosen to avoid missing children inappropriately classified as not having
suspected pneumonia.
Lastly, children presenting with signs of moderate or severe disease are included to ensure
detection of children with illnesses such as sepsis, meningitis, malaria, malnutrition, diarrhoea,
anaemia that may also present with hypoxaemia.16,17 Children with mild disease – such as
diarrhoea with no evidence of dehydration, fever with no evidence of malaria, meningitis /
encephalitis, or complicatedmeasles – are very unlikely to have hypoxaemia and pulse oximetry
use will therefore not be advised in this group.
In certain circumstances, there may be a deviation from these criteria for operational reasons.
Such circumstances will be agreed with local decision-makers, but, for example, may include
the use of pulse oximetry during a triage step in large, high volume facilities. In such
circumstances, preference may be given to using pulse oximetry on all sick children. In the
event that this occurs, children found to have low oxygen saturation will be triaged for
immediate assessment by a clinician, who may repeat the pulse oximetry measurement if
needed.
In Kenya, the Ministry of Health opted to recommend pulse oximetry be usedin the assessment
of all sick children under five years of age.
Healthcare providers will be advised to use a cut-off of SpO2 <90% for referral in Kenya, and
SpO2 <92% in Senegal in line with national guidance.47 The message to refer children with
other signs will be reinforced. Different SpO2 cut-offs for referral for sites at high altitude will
be finalised with the IAG and MoHs, given that the normal range for SpO2 varies with altitude,
but this is unlikely to affect cut-offs below 2500m.48
Healthcare providers will be advised to only take one measurement for children with severe or
moderate disease and will be advised not to attempt to obtain a reading for more than 5
minutes (most readings are obtainable within this time)13,49,50. However, if a child with no
other sign of moderate or severe disease (i.e. IMCI ‘green’ category) is found to have SpO2
<90% (or altitude-specific cut-off), healthcare providers will be advised to repeat the reading.
In cases of conflicting readings (i.e. one <90% and one ≥90%, or altitude-specific cut-off), a
third reading will be advised as confirmatory.
The above guidance will be incorporated into the CDSA, described in detail below.
Clinical Decision Support Algorithm
In addition to pulse oximetry, healthcare providers in the pulse oximeter plus Clinical Decision
Support Algorithm (CDSA) will be guided throughout their medical consultations by an
algorithm called ePoct+ and developed by Swiss TPH in collaboration with Unisanté/Wavemind
(Lausanne, Switzerland).
Healthcare providers will use ePoct+ for the assessment, diagnosis and management of all sick
children 0 – 59 months of age (i.e. only excluding those coming for routine immunisation /
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growth check visits who are not reported to be unwell). In case a child comes back to the facility
during the same disease episode, ePoct+ can be used to manage the child in the same way as
during the baseline visit, as the algorithm takes into account duration of symptoms and
previous treatments provided.
MedAL-R, the front-end application developed by Unisanté/Wavemind to implement ePoct+ is
available for Android tablet or PC. The application can be deployed in health facilities in a
standalone mode or a multi-device mode to facilitate the collaboration of several healthcare
providers and storage of information in the patient’s medical records. In the context of this
study, MedAL-R will be deployed on tablets. The choice of a standalone / multi-device setting
depends on discussions with the country MoHs.
The clinical algorithm will be adapted to reflect national guidelines for the management of
children 0-59 months of age in primary care (based on IMCI and additional relevant case
management guidelines for children 0 – 59 months). An expert group will be established and
consulted in each country using a Delphi method approach and / or nominal group technique to
validate the clinical algorithm.
The adaptation of ePoct+ will be done using MedAL-C, the back-end software developed by
Unisanté/Wavemind to manage, reference, modify and deploy the different versions of the
clinical algorithm into MedAL-R. MedAL-C allows an interactive visualization of the clinical
algorithm and therefore clinicians without any IT programming skills can modify the decision
trees to release a new version of the clinical algorithm. Recommendations on use of additional
point of care laboratory and diagnostic test use, such as malaria or haemoglobin, will be
incorporated into the algorithm if routinely available at the targeted health facilities. Before the
start of the study, ePoct+ will be reviewed and validated by national key experts in child health.
The clinical algorithm will not be updated for the duration of the study, except for technical
reason (patches).
Training
PATH, with input from other collaborators, will develop the pulse oximetry and CDSA curricula,
adapting existing materials (such as Lifebox training materials) to IMCI context using WHO and
national guidelines, specifically including examples of pneumonia and possible serious
bacterial infection. Materials will be pilot tested at PATH HQ, and the next iteration will be
reviewed by the technical working group in each country. The feedback from countries will be
incorporated into the final English version of the pulse oximetry training materials and job aids.
Materials will then be translated into local languages as applicable and back translated to
ensure accuracy. Training materials and job aids will be printed and distributed to all TIMCI
health facilities in draft form for the pilot phase and pending finalization after the pilot phase.
In collaboration with respective Ministries of Health (MOHs), PATH will conduct training of
healthcare providers in the use of pulse oximetry and use of CDSA. To avoid creating a parallel
program and improve sustainability, PATH will work with each MOH to integrate with existing
training programs. WHO has updated their IMCI guidelines recently to include changes in
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pneumonia management and offering outpatient treatment of possible serious bacterial
infection in young infants when referral is not feasible. Per WHO curricula, the trainings for
these updates include clinical sessions with visits to health facilities to see real life patients,
which is out of the scope of the TIMCI project. To expedite the updated IMCI training process,
PATH may provide financial support to ensure that these trainings are conducted in TIMCI
areas if necessary. PATH in partnership with the MOH in each country will agree on which day of
the IMCI training the pulse oximetry and CDSA modules will be included. Trainings will be
conducted using a “train the trainers” approach, leveraging the experience of MOH IMCI
trainers. Moreover, supervisors will also be included in training sessions to equip them for their
supportive supervision role.
The pulse oximetry training session will be interactive, in line with adult learning principles, and
with sessions that allow hands-on practice using the device. At the end of the training session,
a post-training written test and one observation of the use of the pulse oximetry per participant
will be used to determine immediate acquisition of knowledge and skill. If incorrect answers or
limited skills were observed, the trainer will reinforce the correct concepts and provide
supportive guidance and encouragement to correct use of the device. At the end of the CDSA
training session, a post-training practical test based on a set of pre-recorded cases will be used
to determine immediate acquisition of knowledge and skills. Competency evaluation will be
extended post-course by asking trainees to perform a certain number of consultations while
using the CDSA and including a minimum number of classical IMCI conditions.
In the case of staff turnover in TIMCI facilities detected during monitoring visits, PATH in
consultation with the MOH will elaborate a plan for training such new staff either at the facility or
a in a group session elsewhere, depending on circumstances at the time.
Supervision
As per training, PATH will work with each MOH to integrate pulse oximetry and CDSA use into
existing supervision mechanisms where possible. Supportive supervision for CDSA may
additionally include personalized feedback directly informed by data recorded in the device.
Intensive mentoring / supervision will be conducted following training, and then will be
gradually tapered and fully transferred to government mechanisms.
Community and caregiver engagement
PATH will build on existing relationships with local civil society organisations (CSOs) and
networks active in the child health space, and relevant Ministry of Health community initiatives
(such as community healthcare provider networks), establishing new collaborations as needed.
PATH will work closely with these CSOs and Ministries of Health to integrate information on
the intervention, and content aimed at encouraging care seeking and following referral
recommendations into their ongoing child health activities.
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Additional information materials on pulse oximetry and CDSAs will be provided at intervention
facilities, including multi-media materials or public health nurse talks, depending on
preferences within each country.
6.4 Outcomes
6.4.1 Quasi-experimental pre-post study
Two primary outcomes will be assessed between the pre-intervention and post- intervention
period:
x
Proportion of children referred by a primary care healthcare provider to a higher level of
care (either to a hospital or to an inpatient part of a larger primary healthcare facility) at
Day 0 consultation
x
Proportion of children prescribed an antibiotic at Day 0 primary care consultation
These two outcomes are selected to reflect the intended impact on referral of children with
severe disease (pulse oximetry and CDSA) and antimicrobial stewardship (CDSA). Severe
complication outcomes are included in secondary outcomes rather than primary as, given the
pre-post nature of the study, change in mortality / morbidity outcomes could be influenced by
other events occurring between the baseline and post-intervention comparison phase.
Secondary outcomes:
x
Proportion of children with a severe complication (death or secondary hospitalisation)
by Day 7
o Secondary hospitalisation refers to any delayed hospitalisation (occurring at any
point greater than 24 hours after Day 0 consultation) and any hospitalisation
occurring without referral. The denominator is all enrolled children
x
Proportion of children admitted to hospital within 24 hours of the Day 0 primary care
consultation and as a result of a referral
o This is used as a proxy for ‘appropriate referral’ of children, as those with severe
disease should generally be admitted to hospital. The denominator for this
outcome is also all children enrolled in the study, rather than only referred
children. This is because the proportion of referred children that are admitted
may be high in routine care, in the context of an inappropriately low referral
rate. The aim of the intervention is therefore to increase the overall referral rate
of children with severe disease. Hospital admission is chosen as the proxy of
severe disease rather than using primary care classification of severe disease, as
there are inadequacies in the classification of severe disease in routine practice
x
Proportion of children who completed referral as reported at day 7 follow-up
x
Proportion of children cured (defined as caregiver reported recovery from illness) at
Day 7 follow-up
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Sub-groups for analysis of primary and secondary outcomes:
x
Age (under 2 months, 2 – 12 months, 13 – 59 months)
x
Sex
x
Presentation with cough / difficulty breathing
Other outcomes of interest – hypoxaemia
x
Proportion of children with severe (SpO2 <90%), moderate (SpO2 90 – 91%) and mild
hypoxaemia (SpO2 92 – 93%), adjusted for sites at high altitude
x
Proportion of children with hypoxaemia (according to differing cut-offs) with severe
complication
x
Proportion of children with severe hypoxaemia not meeting any other clinical criteria
for severe disease
x
Proportion of children referred with hypoxaemia who receive oxygen at hospital
Other outcomes of interest – referral and follow-up
x
Proportion of children with non-severe disease referred to a higher level of care on Day
0
x
Average length of stay (in days) of children admitted to hospital
x
Proportion of children attending scheduled follow-up at the same facility by Day 7
x
Proportion of children presenting for unscheduled follow-up to any health facility by
Day 7
Other outcomes of interest – antimicrobial prescription
x
Proportion of children prescribed a diagnosis-appropriate antibiotic
x
Proportion of febrile children tested for malaria at Day 0
x
Proportion of malaria positive children prescribed an antimalarial
x
Proportion of malaria negative children prescribed an antimalarial
x
Proportion of untested children prescribed an antimalarial
Other exploratory analyses:
x
Additional sociodemographic characteristics: urban / rural location, distance from
health facility, key household indicators such as maternal age and education
x
Additional complaint / symptom categories (fever, diarrhoea and other) and time since
onset of symptoms
x
Alternative hypoxaemia cut-offs
x
Healthcare provider severity classification
x
Facility and health system factors – type of facility, healthcare provider qualification and
previous training
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x
Time point (pre, early, late) and pilot site data
6.4.2 Other mixed methods studies
These studies will mostly be exploratory, particularly the qualitative studies, which seek to
understand perceptions, values, attitudes and beliefs. Process evaluation criteria will be
evaluated according to the MRC criteria.35
Service provision assessments, at baseline, early and late intervention implementation, will
assess: adherence to IMCI (or national guidelines) and device guidelines (during intervention
phase), including proportion of: caregivers asked about all three danger signs; caregivers asked
about all main symptoms; children with cough or difficulty breathing in whom a respiratory
rate is counted for a minute and (where applicable) in whom a pulse oximetry reading is
attempted, conducted correctly, obtained at first attempt or at repeated attempts; and
proportion of children in whom CDSA is used and recommendations are adhered to.
Furthermore, correctness of classification and treatment (as far as is possible with available
information), and other indices of quality of care will be assessed. Facility and healthcare
provider factors associated with health and quality of care impact and intervention uptake will be
assessed.
Facility-based process maps and associated non-participant observational data will be
described and compared between baseline and early and late intervention periods. Time (in
minutes) will be compared (pre, early and late intervention) for total in clinic; in consultation;
and on use of devices, and any other relevant single steps of the care process. Comparison will be
made using mean (if parametric) or median (if non-parametric).
Qualitative enquiry with healthcare providers and caregivers will primarily focus on service
provision, the participant response to the intervention and acceptability of devices, with
exploration of change in perceptions, attitudes and behaviour over time. With caregivers, we
will also explore experience of care and care-seeking behaviour through IDIs and walking
interviews.
The sub-study of stakeholder perceptions, surveys and project data review will primarily focus
on the processes, mechanisms and context (i.e. process evaluation criteria with focus on fidelity,
dose, reach, context and adaptation) of implementation including adaptations made.
6.4.3 Cost and modelled cost-effectiveness study
x
Full implementation cost of the intervention per focal country (cost to health system as
well as direct costs paid by the household to the health system)
x
Cost per child assessed using pulse oximetry devices and CDSA per country compared
to without these supports.
x
Cost per DALY averted attributed to the introduction of pulse oximetry both without
and with CDSAs across focal countries. This will be modelled comparing proportions
referred to hospital on day zero or by day 7 or requiring secondary hospitalization by
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day 28 in each arm and the predicted outcomes in each case, using published
literature supplemented where necessary by expert opinion. We will also utilize data
on any other severe outcomes, and also use medical indicators on children who are
admitted to hospital to try to assess level of severity of illness.
6.5 Participant timeline
6.5.1 Quasi-experimental pre-post study
The study flowchart is presented in Fig. 5. Research assistants will screen and recruit
participants in the waiting area prior to consultation as outlined in Section 9.3. Following
informed consent and enrolment, research assistants (RAs) will record participant name,
address and contact details (including personal and alternate contacts) for Day 7 follow-up,
basic sociodemographic details, reason for attendance and care-seeking. This will be collected
from the caregiver before consultation, except in critical / emergency cases who will be seen
immediately by the healthcare provider. The clinical consultation will be conducted by
healthcare providers, who in the post-intervention phase will have been advised to use the
devices as described above.
After the consultation, the RA will use extract information from the clinical records from the
caregiver (child health card and / or referral note), and / or from clinic ledgers or medical
records. Information will be extracted and recorded on the final diagnosis, oxygen saturation
and results of laboratory investigations (if performed), prescribed medication with dosage,
referral or follow-up advice and the usage of the pulse oximeter device and/or CDSA (if
applicable). Research assistants will seek clarification from healthcare providers in cases where
the diagnosis is not clear from the records.
Follow-up at Day 7 will be conducted by phone by an RA. If phone follow-up fails, three
attempts will be made on the subsequent three days to reach the caregiver. Community
mechanisms to facilitate follow-up (such as arranging a call with a community health worker)
will be used, with consent, for caregivers without access to a phone. A structured questionnaire
will be administered to assess the primary and secondary outcomes, including details of any
government or private hospital admission. In case of non-recovery, if the child is still at home,
the study team will advise the family to return to the PHC clinic for a follow-up consultation.
Additionally, visit information from government-designated hospital records will be collected
retrospectively for children whose caregiver reported at Day 7 phone follow-up that they
attended hospital, including clinical assessment on arrival (vital signs, admitting diagnosis),
admission details (duration, if oxygen was administered, intensive care admission) and
admission outcome (final diagnosis, discharge against medical advice, death). The same data
will be collected for children who attended a non-hospital higher-level of care (emergency or
admission unit of a primary or secondary care facility).
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It is expected that some participants may present at the same or another health facility enrolled
in the study during the follow-up period. These visits and the findings will be recorded on the
appropriate scheduled / unscheduled visit eCRFs.
Fig. 5. Flowchart of the pre-post study. CDSA = Clinical Decision Support Algorithm. CG = Caregiver. HCP =
Healthcare provider. OPD = Out-patient department.
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Tab. 4. Schedule of the visits and associated CRFs for the pre-post study. The different types of staff collecting data are represented by the following icons:
Research assistant rotating
Facility-based research assistants
between different referral health
facilities
Healthcare providers
as part of
Call centre-based research assistant
intervention clinical
routine
Time point
Data collection method
Health facility baseline
visit
Day 0
Prospective data collection
Higher level of care
visit1,2
Day 0-7
Review of medical records
Follow-up or unscheduled visit at
enrolled health facility
Day 1 -7
Prospective data collection
Phone
follow-up
Day 7
[7 - 10]
Phone
interviews
Events
Informed consent
Screening
Study phase
Pre
Post3
Pre
Post3
Forms
-
TIMCI-01
Identification & contact
information
Socio-demographics
Visit info
Clinical presentation & medical
history
Full identification
Contact information
Identification and contact information
check
Referral facility identification
Follow-up identification check
Care seeking behaviour, transport and
costs for visiting health facility reported
by caregiver
Visit and admission info recorded by
referral facility (medical records,
registries)2
Patient journey reported by caregiver at
follow-up
Clinical presentation and medical
history reported by caregiver at
baseline
Medical history recorded in clinical
notes and / or facility registries
Chief complaints and medical history
recorded in CDSA
TIMCI-02a
TIMCI-02b
TIMCI-02c
TIMCI-02d
TIMCI-02e
TIMCI-03
TIMCI-04a
TIMCI-04b
TIMCI-04c
TIMCI-05a
TIMCI-05b
TIMCI-05c
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Basic measurements & physical
exams
Respiratory rate & pulse
oximetry
Laboratory investigations
Diagnosis & care management
Follow-up at Day 7
Basic measurements and physical
exams recorded in clinical notes and /
or facility registries
Basic measurements and physical
exams recorded in CDSA
Respiratory rate and pulse oximetry
recorded in clinical notes and/or facility
registries2
Respiratory rate and pulse oximetry
recorded in CDSA2
Respiratory rate and oxygen saturation
recorded at arrival by referral facility2
Laboratory investigations recorded in
clinical notes and / or facility registries2
Laboratory investigations recorded in
CDSA2
Diagnosis and care management in
clinical notes and / or facility registries
(medical records, discharge
summaries)
Diagnosis and care management
recorded in CDSA
Diagnosis and care management
recorded by referral facility (medical
records, discharge summaries)
TIMCI-06a
TIMCI-06b
TIMCI-07a
TIMCI-07b
TIMCI-07c
TIMCI-08a
TIMCI-08b
TIMCI-09a
TIMCI-09b
TIMCI-09c
TIMCI-10
1 Data will be collected retrospectively for visits at facilities offering a higher level of care, including district hospitals, any study facility receiving referrals or admitting patients. 2
If appropriate for clinical management.
3 The schedule assumes the intervention includes pulse oximetry plus CDSA.
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6.5.2 Other mixed methods studies
An overview of the timeline for participants recruited to the mixed methods studies and how
they are embedded into the pre-post study is shown in Fig. 6. In the sub-sample of children
(and their caregivers) selected as part of the SPA, two additional time-points of data collection
will occur – during the consultation (observation), and after their clinical consultation (for the
exit interview).
IDIs and FGDs with caregivers will take place after the day 7 follow-up phone call.
Healthcare providers for the SPA will be invited to participate in the interview and consultation
observations at the time of the first SPA assessment at that facility, after information has been
provided to and assent obtained from the facility in-charge. At subsequent assessment rounds,
the SPA team will meet with the in-charge and HCPs briefly, provide information on updates if
required and answer any questions. Prior to participation in the interview or observation,
continued consent will be checked verbally by a member of the SPA team. If the supervisor was
not involved in a previous round, they will be fully informed as per the first round, and similarly if
an HCP was not previously recruited, the full written informed consent process will be
adhered to.
Healthcare providers recruited for qualitative interviews or FGDs will be invited for an interview/
FGD from SPA and/or non-SPA facilities. The final selection of stakeholders (outlined in Section
5.7) will be determined during implementation and based on implementation experience.
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Fig. 6. Overview of the mixed methods studies and how they are embedded within the pre-post study in Kenya
and Senegal. CG = Caregiver. HCP = Healthcare provider. Healthcare provider focus group discussions will group
healthcare providers from different facilities.
6.5.3 Cost and modelled cost-effectiveness study
Facility-based medical and non-medical personnel who provide information for costing will be
approached at a time convenient for them so as not to interfere with clinical or health service
delivery. Information will be provided about the study and consent will be sought for personal
data as outlined in 9.3.3. These providers will be approached pre-intervention and then again
during intervention for data collection, though different providers may be approached in case of
staff rotation.
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6.6 Sample size
The estimated sample sizes for each of the studies are described below, but may be revised
during the course of the study. In the case of the pre-post study, this is due to uncertainty of
some of the assumptions (such as eligibility rate and outcome proportions in routine care, for
which data reliability is a challenge). Final qualitative sample sizes will be determined based on
reaching thematic saturation, i.e. when no new concepts are emerging.
The remaining sample sizes, for SPA, process mapping and time-flow study, have been chosen
pragmatically and will vary according to country depending on the degree of difference in care
processes between facility types and location, whilst allowing for exploratory analysis into more
in-depth aspects of quality of care from baseline to intervention and over time within the
intervention period (both due to changes in implementation uptake and seasonal variation in
burden of disease).
The sample size for the pilot phase will also be pragmatically based on the degree of difference
between facility types and location (and thus the potential need to understand and refine the
intervention strategy according to context), but is likely to include between 2 and 6 facilities
per country.
6.6.1 Quasi-experimental pre-post study
The sample size for the quasi-experimental pre-post study is calculated separately for each
country, based on comparison between pre- and post-intervention periods.. The following
assumptions are used:
x
power 80%
x
alpha 0.05
x
pre-intervention referral to a higher level of care 3% (based on informal estimates from
country research teams and SPA data from various countries), with a minimum
detectable difference of 50%
o We have chosen a large detectable difference for referral from primary care as
not all children referred will complete referral, i.e. a 50% increase in referral rate
may only result in a 20 – 30% total increase in completed referrals (this will be
assessed as a secondary outcome and is therefore not a component of the
sample size calculation)
x
pre-intervention antibiotic prescription of 60% (based on informal estimates from
countries, SPA data and other observational studies)
x
intra-cluster correlation coefficient (ICC) of 0.005 for referral and 0.05 for antimicrobial
prescription
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x
Kenya – estimated average cluster size of 230 children / month (assuming a cluster ratio
of health centres : dispensaries 1:2, with 100 / month in dispensaries and 500 / month in
health centres
x
Senegal – estimated cluster size of 170 children per month (based on DHIS2 data on
outpatient consultations in Thies in 2019)
For the referral primary outcome, we therefore initially estimated requiring the following
sample size:
x
Kenya – 17 facilities, recruiting an average of 690 children per facility in each period,
equating to 11,730 children per period
x
Senegal – 18 facilities, recruiting an average of 510 children per facility in each period,
equating to 9,180 children per period
For the antibiotic prescription primary outcome, this would enable a minimum detectable
reduction of 18% in Kenya and Senegal.
Following lower than anticipated recruitment in the pre-intervention period, sample size
calculation was revised. As a result, two additional facilities were added per country and the
pre-intervention period was extended from an initially anticipated 3 months to a 6 – 8 month
period. A decision was also taken to target a post-intervention sample size of at least the same as
the pre-intervention sample size, as well as a minimum duration of 9 months post-
intervention to allow for stabilisation over time and some seasonal overlap of pre- and post-
intervention periods.
6.6.2 Mixed methods studies
We will conduct the assessment in 8 – 10 study facilities, stratified by rural / urban location and
facility type, at 5 time points – pre-intervention, and early and late intervention over the post-
intervention period. We will also conduct the SPA in the pilot facilities to inform intervention
refinement.
At each facility at each time point, observation and exit interview assessments will be
conducted over 3 – 10 working days, in order to achieve a sample size of 10 – 30 children per
facility. In smaller facilities with only one provider, the target will be a minimum of 10
observations and exit interviews, whereas in larger facilities, the target will be a minimum of 20
observations and exit interviews with at least 5 for any single provider. This would result in an
estimated sample size of 800 – 1000 observations over the study period. Interviews will be
conducted with all consenting healthcare providers responsible for the care of sick children at
the study facility during the first assessment. These will only be repeated if details have changed
(e.g. training updates), or for new staff not present at the first assessment. We estimate around
20 – 40 healthcare provider interviews (depending on facility size). The full facility assessment
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will be done at the first visit, and only variables which change over time will be recollected at
subsequent visits.
We will conduct facility-based process mapping and time-flow assessments in each of the SPA
facilities. One process map (and associated notes on the care process and its rationale or
deviations) will be developed per facility during baseline, which will be revisited and revised
during early and late intervention phases to reflect changes over time, resulting in 3 maps per
facility. Process maps will also be developed in the pilot facilities to inform intervention
refinement. Each map will involve informal discussion with 2 – 4 healthcare providers in the
facility, and non-participant observation over a period of one week, during which time-flow
data will also be collected (for an estimated 10 – 30 children depending on facility size).
IDIs with caregivers: A purposive sample of caregivers will be selected for IDIs including those
who completed referral (and arrived in the hospital within 24 hours) as well as those that did
not adhere to the advice, and those that were not referred. Within these sub-categories,
participants will be purposively selected with varying socio-demographic characteristics such
as rural / urban location, age of caregiver/child, and education. An estimated total of 35-45
IDIs with caregivers in each country throughout the entire project are expected. Approximately
10 – 12 in-depth interviews with caregivers will be conducted across different time points (pilot,
early, mid and late intervention) within one geographical area of each country. However, if
geographical variation in health-seeking behaviour and outcomes is felt to be significant, fewer
time points may be selected in favour of greater geographical diversity. In Kenya and Senegal
only, a further 10-12 IDIs will also take place in the pre-intervention phase. Caregivers for IDIs
will be different from FGD participants.
FGDs with caregivers: One geographical area will be selected per country, in which a total of 6
FGDs (3 in urban and 3 in rural location) will be conducted, each with 8 – 12 participants. These
will be divided between early and late intervention. Caregivers for FGDs will be different from
IDI participants. Where possible participants will be divided by age groups and gender as well as
number of children.
Walking interviews with caregivers: A purposive sample of 6 – 8 caregivers per country, having
received referral advice for their sick child, will be selected towards the end of the intervention
period. Care givers may be followed through (to IDI) if of interest; otherwise caregivers for
walking interviews will be different for IDIs and FGDs.
IDIs with healthcare providers: An estimated total of 35– 45 IDIs during the intervention phase
per country is expected, allowing to document change over time. This will include
approximately 10 – 12 IDIs with healthcare providers at different time points (pilot, early, mid,
late intervention), purposively selected from facilities with divergent implementation. In Kenya
and Senegal only, a further 10-12 IDIs will also take place in the pre-intervention phase. Where
possible, some healthcare providers will be interviewed repeatedly over time.
A total of 6 FGDs with healthcare providers will be conducted per country, with 6 – 8
participants per group. Healthcare providers at both, SPA and non-SPA-facilities may be invited
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for IDIs and/or FGDs, with purposive sampling of early and late adopters at a later stage of
data collection during the intervention.
KIIs with stakeholders: A total of approximately 45 key-informant interviews during the pilot
and intervention phase will be carried out. This will include approximately 3-6 KIIs at global
and 10-12 KIIs at national level at different time points (between pilot, early and late stages) of
the project. In Kenya and Senegal only, a further 10-12 IDIs will also take place in the pre-
intervention phase. The final selection of type and number of different types of stakeholders
(outlined in Section 5.7) for the intervention phase will be determined during implementation
and based on implementation experience.
6.6.3 Cost and modelled cost-effectiveness study
Cost data will be collected from eight facilities per country (4 urban and 4 rural), and in
countries where there are big size differences among health facilities, we aim to include four
larger and four smaller facilities. At each facility, the most senior medical professional and the
most senior administrative professional available will be interviewed to obtain the majority of
the unit cost data, and the senior medical staff member to obtain information on time
allocation of front-line staff (time seeing patients, time in supervision etc).
6.7 Recruitment
To reach the required sample size, and to ensure data collection across different seasons, it is
estimated that recruitment will take place over 15 months. As we intend to validate eligibility
and recruitment rate estimates in the pre-intervention phase, we may either recruit additional
facilities or slightly increase the study duration if necessary. Participants will be recruited during
working hours, Monday to Friday, though evenings and weekends may be included if high
volumes of patients attend at those times (depending on country and facility type).
Child and caregiver participants will be recruited for the SPA and time-flow observations on
the relevant study assessment days consecutively until the sample size requirements detailed
above have been met. Children and their caregivers will be enrolled to these studies at the
same time as they are enrolled to the pre-post study. Longer assessment periods will be
required for low-volume facilities. All healthcare providers providing care for children under 5
years of age and present at facilities during SPA assessments will be invited to participated in
the SPA interview.
Participants in the qualitative studies will be recruited as follows:
Caregivers for IDIs and FGDs will be selected based on pre-defined queries (e.g. based on
information from the database) after Day 7 follow-up has occurred in order to identify
potential participants within a selected geographical area. During the call, caregivers will be
asked for their verbal assent to be contacted by a person responsible for the recruitment of
participants for qualitative studies. Of those caregivers, who agreed to be contacted, a list will
be generated for the recruiter with basic socio-demographic details (divided into referred and
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not referred for IDIs) of double the number of participants required (to allow for unreachable
participants or refusals to participate) for the time point in question. The qualitative researcher
will then contact participants by phone to arrange IDIs or FGDs. If recruitment with this strategy
proves challenging, individuals may be approached directly at facilities to arrange a follow-up in
the community after 7 days or at the community level (i.e. by a community health worker).
Health care providers from study facilities will be invited to participate in the studies by the
qualitative researcher. . First, research assistants in the facilities will provide brief information
on the qualitative studies planned and seek verbal assent from HCPs that a person responsible
for the recruitment for qualitative studies can contact them. Based on few selected variables
(e.g. sex, years of practice, urban/rural, professional background, time at facility) a purposive
sample of HCPs will be contacted. Those interested to participate will be invited and an
appointment scheduled. Some of the same healthcare providers invited to participate in the
FGDs and IDIs will be re-invited over time. After initial implementation, a pre-defined list of
variables (e.g. from the pre-post study) will be used to classify healthcare providers into early
and late adopters of the intervention; and change in uptake over time. This will help to inform
the focus of the qualitative inquiry over the implementation period. However if the recruitment
process proves challenging due to staff rotation, clinical commitments or research fatigue, a
broader range of healthcare providers will be approached from both SPA and non-SPA
facilities.
Recruitment of healthcare providers in the pre-intervention / pilot / early intervention phase:
Where only one healthcare provider is present at the facility s/he will be invited. If more than
one healthcare provider is working at the same facility a purposive selection will be made,
based on a variety of sociodemographic factors to ensure a diverse sample as outlined above.
Recruitment of healthcare providers in the mid/late intervention: Healthcare providers may be
purposively selected from facilities with divergent implementation. Divergent implementation
will be identified as described above.
Stakeholders will be purposively selected with a focus on a diverse sample presenting the
different levels of implementation (global, national, regional and local level) as well as their
level of direct involvement in the project. Stakeholder mapping will be conducted to identify
potential participants internal and external to the project. All pre-selected key stakeholders will
be invited by the research assistant to participate in the study. The same respondents will be
invited over time. If the recruitment process proves challenging (e.g. due to staff rotation) the
same principles as with healthcare providers apply.
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perceptions of
seeking
7 Data collection, management and analysis
The data used within the TIMCI project are described in Tab. 5. Primary research data will be
generated in study and pilot facilities through case report forms, questionnaires, interviews,
focus group discussions and surveys. In addition, relevant routine data will be extracted for all
intervention facilities (i.e. including those in which primary research data will not be collected).
This will include individual consultation data recorded in the CDSA for clinical purposes and
aggregate facility data that are reported to the national HMIS.
Tab. 5. Summary of the data used within the TIMCI project. CDSA = Clinical Decision Support Algorithm.
MedAL-R is the front-end application developed by Unisanté/Wavemind (Lausanne, Switzerland) to
implement ePoct+, the clinical algorithm. EDC = Electronic Data Capture. FGD = Focus Group Discussion.
HMIS = Health Management Information System. IDI = In-Depth Interview. KII = Key Informant Interview.
SARA = Service Availability and Readiness Assessment.
Ref
1.1
1.2
2.1
2.2
Methodology
Routine data
Pre-Post study
Service
provision
assessment
Facility-based
process
mapping and
time-flow study
Data collection
CDSA individual
consultation data
Aggregate facility
data
Quasi-
experimental pre-
post study
Modified
demographic and
health survey
Process map
Time-flow study
Tool
MedAL-R with
ePoct+
National HMIS
Electronic case
report forms
(EDC platform)
Facility
assessment
(modified
SARA
questionnaire)
Healthcare
provider
interview
Sick child
observation
protocol
Structured exit
interview
Process map
tool
Time-flow tool
Data format
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Abstract
Textual,
numerical,
categorical
Data origin
Primary
Secondary
Primary
Primary
Primary
Primary
Primary
Primary
Primary
Data
classification
Sensitive personal
Non-personal
Sensitive personal
Non-personal
Sensitive personal
Sensitive personal
Sensitive personal
Non-personal
Sensitive personal
Data
reuse
1.2
2.5
1.2
2.1
2.5
2.1
2.2
2.3
2.4
2.5
2.5
2.5
2.5
2.5
2.5
2.5
3.1
2.3
2.4
Healthcare
Semi-structured in-
SURYLGHUV·     depth interviews
acceptability
and perceptions
of the
Focus group
intervention                 discussions
&DUHJLYHUV·Semi-structured in-
the
depth interviews
intervention
and health-
Focus group
be
hav
io
ur                   discussions
IDI tool for
healthcare
providers
FGD tool for
healthcare
providers
IDI tool for
caregivers
FGD tool for
caregivers
Audio,
Textual,
numerical,
categorical
Audio
Textual,
numerical,
categorical
Multimedia
(audio, drawings),
Textual
Numerica
Multimedia
(audio, video-
/photo-
documented),
Primary
Primary
Primary
Primary
Sensitive personal
2.5
Sensitive personal
2.5
Sensitive personal
2.5
Sensitive personal
2.5
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Walking interviews
Walking
interview tool
Textual,
numerical,
categorical
Audio
GPS tracking
Textual,
Primary
Sensitive personal
2.5
numerical,
categorical
2.5
6WDNHKROGHU
perceptions
and project
data review
Key informant
interviews
Survey for
stakeholders
KII tool
Online survey
tool
Audio
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Primary
Primary
Sensitive personal
2.5
Sensitive personal
2.5
Cost and
3.1
modelled cost-
effectiveness
Project data review
Cost analysis
Modelled cost-
effectiveness
Document
review matrix
Medical
personnel
questionnaire
Non-medical
personnel
questionnaire
Hospital costs
Textual
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Textual,
numerical,
categorical
Secondary
Primary
Primary
Primary
Secondary
Non-personal
Sensitive personal
Sensitive personal
Non-personal
Non-personal
N/A
2.5
3.1
2.5
3.1
2.5
3.1
2.5
7.1 Data collection methods
Quantitative research data for the quasi-experimental pre-post and mixed-method studies will
be collected using a secure third-party cloud based electronic data capture (EDC) platform that
meets research / ethical standards. CDSA routine individual consultation data will be extracted
from MedAL-R, a software developed by Unisanté/Wavemind (Lausanne, Switzerland) to
implement the clinical algorithm (ePoct+), while HMIS aggregate facility data will be extracted
from the national HMIS, following MoH approval. Qualitative research data will be collected
using both EDC, audio recordings, photo documentation and video recordings (in the case of
method acting) and hand-written paper notes and drawings. GPS data will be collected using a
mobile device.
7.1.1 Quasi-experimental pre-post study
For each participant enrolled in the quasi-experimental pre-post study, data will be captured
during the pre- and post-intervention periods according to the different assessments and Case
Report Forms (CRFs) described in the visit schedule displayed in Tab. 4. A description of the
variables collected in each CRF is available in the appendix.
Health facility visits
Quantitative research assistants will use an EDC mobile application to enter the research data of
enrolled participants. The quantitative research assistant will collect from the caregiver
screening information, information on care seeking behaviour, transport and costs, and clinical
presentation and medical history. A number of in-depth sociodemographic and household
variables will also be collected either as surrogate measures of household wealth, or known to
be associated with health-seeking behaviour and / or child mortality (including maternal
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education). Household wealth indicators were selected from DHS and other surveys in the
study countries as those which best estimate wealth index that can be directly collected from
the mother / caregiver and with a reasonable time vs. reliability trade-off. Data on laboratory
investigations (if performed), final diagnosis, prescribed medication, referral or follow-up
advice will be extracted from clinical notes and / or facility registers. Quantitative research
assistants will seek clarification from healthcare providers only in cases where these variables
are not clear from the records. Personally identifiable information (PII), including participant’s
name and date of birth, as well as caregiver’s phone number and physical address, will be
collected for linking data and detecting possible duplicates and carrying out the study follow-
up.
During the post-intervention period, the research data of participants enrolled in the study will
be linked with their CDSA consultation data. Additional information on oxygen saturation will be
collected as recorded in clinical notes and / or facility registers. Pulse oximeter device
savings will be cross-checked by quantitative research assistants at the end of the consultation
where possible.
Follow-up
Quantitative research assistants will conduct the phone follow-up interviews using an EDC
mobile application. Personally identifiable information (PII) will be used for contacting
caregivers. A window of +3 days (Day 7 to Day 10) applies to Day 7.
Data that will be collected at Day 7 follow-up will include cure status (recovery from illness as
reported by the caregiver), hospitalisation and death between Day 0 and Day 7. If appropriate,
name of the referral facility and duration of hospitalization will be collected to facilitate the
retrospective data collection at referral hospital level.
Higher level of care visit
Data collection at this level of care will be conducted retrospectively. A quantitative research
assistant using the EDC mobile application will collect data from referral facility records,
registries and discharge summaries for children whose caregiver reported at Day 7 phone
follow-up that they attended a government-designated referral facility between Day 0 and Day
7. This includes attendance to hospital or emergency / inpatient area of a larger primary or
secondary care facility (e.g., study facilities that can admit paediatric patients). Personally
identifiable information will be collected to cross-check the identity of the patients. Arrival date
and time, basic clinical information on arrival and, if admitted, admission and discharge
diagnosis and admission duration will be collected. If available, data on oxygen saturation at
admission, oxygen administration and intensive care unit (ICU) admission and duration will also
be recorded.
7.1.2 Routine data
CDSA individual consultation data
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Routine individual consultation data will be recorded in the CDSA in all intervention facilities in
the post-intervention period. As part of the intervention, healthcare providers will be asked to
use MedAL-R during their consultations. When they do so, they will routinely enter all data
necessary for the clinical management of children 0 – 59 months of age into MedAL-R. Data
used within TIMCI will cover clinical presentation (including symptoms and dangers signs),
medical history (including HIV and TB status if known), all physical exams and measurements
relevant for clinical assessment (including pulse oximetry), and laboratory investigations.
Automated recommendations from CDSA on diagnosis and child management will also be
collected, as well as healthcare provider’s agreement or disagreement with these
recommendations and possible additional diagnoses and treatments, which will be manually
entered. A description of the variables extracted from CDSA is available in the appendix.
HMIS aggregate facility data
HMIS data will include the total number of outpatient consultations – for all patients and for
children 0 – 59 months of age (disaggregated by new and follow-up visit if possible) –, disease
burden, and any other relevant indicators if available (such as referral rate or mortality rate),
disaggregated by age and sex if routinely collected with this granularity.
7.1.3 Other mixed methods studies
Some data required for the SPA (observation and caregiver exit interview) are common with
the pre-post study and will not be collected again. To reconstruct the full SPA dataset, SPA
observation and caregiver exit interviews will be linked with the pre-post study as described in
Section 9.4.3. The consultation observation will be conducted by a standardised clinical
observer who will record information asked or provided by the healthcare provider and / or
caregiver during the consultation on key aspects relating to adherence to IMCI (or national
guidelines) and the use of pulse oximetry and CDSA (post intervention). The observer will not
ask any questions directly of the caregiver, but at the end of the consultation will ask a limited
number of questions of the healthcare provider to record diagnosis and management.
In line with the WHO guidance on Ethical Issuesin Patient Safety Research, observers in Senegal
and Kenya (deemed to have sufficient experience and expertise) will be advised to intervene in
the consultation only in the event that they witness an error, or suspect an imminent error,
during the consultation that is “highly likely to result in direct, severe or irreversible harm” and
could be mitigated by their intervention. Should they intervene, the observer will record the
intervention in the sick child observation protocol instrument. No information on individual
performance will be shared with supervisors, or anyone else. However, in order to mitigate the
ethical issues of non-intervention when poor performance has been observed, observers in
Senegal and Kenya will provide a short supportive feedback to the individual providers if they
agree to it at the end of the period of observation. This will be structured in line with supervision
procedures of respective MOHs. Feedback provided will be recorded.
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The exit interview will be performed after the consultation by a non-clinical research assistant
who will record responses to questions on additional sociodemographic and clinical details
and experience of care. The healthcare provider interviews will collect information from
healthcare providers involved in the care of children 0 – 59 months, on qualifications, in-service
training and experience related to child health and pulse oximetry and experience of the
working environment. The facility assessment will focus on the basic infrastructure, staffing,
services, diagnostics and medicines relevant to child health, with additional information
collected on pulse oximetry, records and reporting and management. At the end of the SPA
assessment at the facility, the clinical observer and research assistant will note down additional
(prompted) summary observations about the use of pulse oximetry and / or CDSA in the facility.
For the process mapping and time-flow study, pre-drawn, country-specific process maps will
be reviewed and modified by research assistants with informal input from facility staff and
observation. Time data will be recorded using an individual follow-through (timing one child
from arrival to exit) and/or area-based (waiting area timing, consultation timing, further
diagnostic timing, etc.) approach. Notes based on non-participant observation will be taken by
research assistants on observations within the facility (e.g. if devices are not charged, waiting
rooms are crowded, the type of interactions between patients and providers, change in
provision of care (e.g. new triage system introduced)) and will not include any individual patient
data.
If FGDs are conducted, they will be facilitated by a moderator and have an assigned note taker (in
charge of documentation). Prior to moving to the main topics of discussion, ice-breaker
exercises will be used to establish trust with participants and to provide an overview of the
topic for discussion (pulse oximetry and CDSA). The classical FGDs with healthcare providers
(and possibly caregivers) will use clinical vignettes which will be presented and jointly
discussed.
Qualitative data from IDIsand KIIs will be collected by trained qualitative research assistants
using a voice recorder, in addition to paper-based notes and drawings and a tablet for
quantitative data collection. Interviews will be conducted using a semi-structured guideline
interview tool, with emphasis placed on building trust and using open-ended questions with
probes.
Key-informant interviews with stakeholders will either be conducted in-person or via
telephone/Skype/Zoom. Interviews will be scheduled and interview questions shared in
advance if wished. Surveys (using an online survey tool such as Survey Monkey) for selected
stakeholders will be sent out on a regular basis via email. Participants will be asked to answer
the questions and upload additional documents. A single reminder will be sent in case no
response was received. Documents will be requested from partners on regular basis; a desk-
review will be conducted and data entered into a document matrix.
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7.1.4 Cost and modelled cost-effectiveness study
Cost data collection will occur pre- and during intervention as shown in Fig. 3.
Definition of costs using an activity-based approach
An activity-based approach will be explored using available cost data. Specific activities in the
intervention will be allocated to different cost centres. In order to provide cost estimates that
will be as managerially-, policy- and programmatically-relevant as possible, the cost analysis
will adopt this approach as this separate research costs from the main programme
implementation costs. The focus will be on those costs that are expected to change with the
introduction of pulse oximetry and CDSAs. Costs including utilities and large equipment costs
will remain the same with or without the introduction of pulse oximetry and CDSAs.
To apply the activity-based approach, we will identify specific activities that are to be costed.
These will be referred to as “cost centres” (See Tab. 6). Cost centres are a way in which the
resources used to produce the intervention activities—and the costs of those resources—are
grouped. Cost centres are defined in such a way that:
x     The sum of the cost centres is comprehensive—including all the resources used to
produce each and every activity of the program—and together, the entire program, and
x
They are mutually exclusive—thus avoiding double counting any of the resources used
to provide the program.
It is important to note that this cost methodology is not comprehensive. As described in 5.8, it
does not include the indirect costs incurred by the consumer (patient) e.g. the caregiver’s time or
transport costs. Rather, it focuses exclusively on the provider’s direct costs, whether borne by
the health system or paid out of pocket by the patient’s household. The cost resources for each
cost centre may differ between each country according to availability of services.
Tab. 6. Activity-Based Cost Centres of the TIMCI programme
1
Training cost for staff involved in delivering the programme:
-
Consumable costs (including where applicable stationary, and other consumables)
-
Personnel costs
-
Overhead costs (including where applicable, rent for training venue, administrative costs, per
diems and transport costs, and other overheads)
2
Delivery of intervention
-
Annualized1 fixed/equipment costs (including pulse oximetry device and CDSA tablet costs)
-
Consumable costs (including medicines, diagnostic tests, and other consumables)
-
Personnel costs
3
Out of pocket costs
-
Any out of pocket costs paid by patients’ households to the health system to access care and
prescribed treatment will be collected, including resources purchased outside the facility due to
unavailability in the facility. However, care not prescribed by facility healthcare professionals will
not be included.
1. Since costing needs to account for both capital and recurrent costs, annualizing capital costs (i.e. calculating the annual
value of a capital item) is the easiest way of combining capital and recurrent costs meaningfully. Annualizing capital cost is
based on three pieces of important information: the initial purchase price of the item, its expected useful life, and a discount
rate
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Recurrent (costs incurred every year
e.g. staff, maintenance, fuel)
Sources of cost data
Personnel and procurement units of the organisations involved in the TIMCI intervention,
especially through different local PATH offices and sampled facilities will be sourced for the
cost data. Centrally available databases will be used to estimate personnel and consumable
(including medicines and diagnostics) costs where available.
Start-up costs, which will include training and community sensitisation costs, will be collected
pre facility enrolment and intervention from PATH offices. After facility enrolment, cost data
will be collected from non-medical administrative personnel. All personnel costs for those
involved in the pre-intervention and intervention phase will also be collected since time in
supervision, time of administrative support staff is as important as that of front line staff seeing
patients. Personnel time, and volumes of diagnostic tests and treatments prescribed, will be
obtained from the time-flow and service provision assessment studies. Data on time required
for supervision and administrative tasks such as taking patient notes will be obtained from the
senior medical professional at the facility, along with grades of personnel. Salaries of personnel
according to grade will be sourced from centrally available databases which would include
government salary publications for health facility workers (medical and non-medical) and
complemented with salary costs sourced from health facility administrative databases where
needed. Costs of consumables will also be sourced centrally where available and would for
instance include cost of items on the National Essential Medicine List. Referral and
hospitalization costs will be sourced from interviewing senior administrative personnel at
referral health facilities.
Total programme cost and cost per child will be estimated. We will collect administrative data
from appropriate levels in each country depending on organization of the specific health
system, and will use time-flow data, and data collected elsewhere in the project before and
after the intervention.
The table below lists the broad areas of cost data collection for each cost centre and the
respective data sources.
Tab. 7. Sources of cost data
Type of Cost
Identification
Measurement
Valuation
Personnel (staff)
Consumables
Categories
All staff involved
(field workers
and managers,
administrators,
support staff
(drivers), etc)
Disposable
items used per
child per
intervention
Costing
method
Percentage of
time spent on
different
activities
within TIMCI;
grade of
personnel
Quantity of
consumables
used per child
Sources of
data
Time data
collected by
operational
research
Medical
personnel at
health facility
Valuation
methods
Gross
remuneration
package costs
Market prices
Sources of
data
Centrally from
government
databases and
complemented
with provider’s
payroll
department
Centrally from
government
databases and
complemented
with provider’s
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procurement
department
Equipment/
Capital
(incurred every
few years)
Out of pocket
costs
Pulse oximetry
devices, tablets
etc
All out of pocket
costs paid by
patients’
households to
the health
system for fever
management
Annualised
cost of items
Direct fees
and charges
paid by
households to
health
systems
Interview,
observations,
and timing
Cost borne by
households
Replacement
prices
Financial cost
Provider’s
financial
syndicate
office
Cost data
collected form
health system
administrative
records;
information
from interview
of senior non-
medical
personnel
Definitions of types of costs and data to be collected
Staff time: For each activity within the TIMCI project, the responsible staff member involved
with the activity will be identified. Secondly the time involved will be ascertained from the time-
flow study and quantified. Supervision costs will similarly be estimated.
Consumables: The type and quantity of medicines, diagnostic tests and consumables used for
each activity will be identified. In addition, unit costs of each consumable item will be obtained
(for example the cost of an oxygen cylinder) and the size of unit (the time average spent on
oxygen per patient).
Equipment: All equipment used for each activity will be identified and the price for which it
was purchased. For the equipment costing, the lifespan for the equipment (usually between 3 –
5 years for smaller items including electronic tablets and pulse oximetry devices) will be
obtained and annualized. Annualization will follow the cost recovery methodology where item
cost, life span, and a defined interest rate is used to estimate the annual cost of an item. For
equipment that is shared with other activities, the time spent per consultation will be obtained as
a percentage of total time spent using each equipment and used to calculate the cost
associated with the intervention after annualization. For donated equipment, market price
information will be sought.
Equipment inventories and training records will be used to collect retrospective costs. Time
spent by staff on consultations with children 0 – 59 months of age will be collected from data
obtained in the time-flow study. Time costs will then be determined by combining staff annual
salaries obtained from government sources and/or payroll offices with time spent in
consultations with children. Where applicable, this personnel cost will be disclosed only to the
principal researcher without the identity of staff involved. Consumables used will be examined
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to determine the unit cost of each consumable, while equipment will be annualized to
determine their unit costs.
All capital and start-up costs will be annualised using an appropriate length of life and discount
rate. Out of pocket payments to health systems borne by households will be estimated to
capture all health system costs. These costs might vary across different settings since there
might be flat rates in one setting and a varied fee schedule in another. Hence, the cost data
collection for out of pocket payments will be country specific. The cost of hospital referrals
where applicable, will also be estimated from interviews with senior healthcare professionals at
the hospital level. Data will be captured and analysed in an excel workbook.
7.2 Data management
All data management procedures will be further described in the Data Management Plan
(DMP).
7.2.1 Data flow, storage and transfer
The data management system will process and combine two main data flows: the research data
flow, which will be managed by a secure third-party cloud based EDC platform, and the routine
consultation data flow, which will be managed by a customized PostGreSQL Server
(Unisanté/Wavemind, Lausanne, Switzerland). As illustrated in Fig. 7, there will be separate
secured databases with restricted access rights for storing and processing CDSA consultation
data, research data for each study, PII that are necessary for all research operations, and
(possible) linking between the different databases.
x
Study databases – These databases will contain de-identified quantitative research
data collected in study facilities. Unless specified otherwise per country requirements
in the DMP, these databases will be hosted on a device owned and maintained by the
country research partner.
x
CDSA consultation database – This database will contain routine consultation data
extracted from CDSA in all intervention facilities. CDSA consultation data from study
facilities will be de-identified, i.e. a link will exist between these data, the pre-post study
database and the identification database. There will be no such link for CDSA
consultation data from non-study facilities, which will then be fully anonymised. Unless
specified otherwise per country requirements in the DMP, this database will be hosted
on a device owned and maintained by the country research partner.
x
Identification database – This database will contain PII collected in study facilities. It
will be kept under strict operating procedures, in particular it will not be shared or
accessible outside of the country. The database will be used for generating follow-up
call logs and random selection of a purposive sample of caregivers for qualitative
studies. It will also be used for flagging possible duplicates in children enrolled in the
pre-post study.
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x
Mapping database – This database will be used for linking data from the study
databases and the identification database. Each table will be maintained confidential
under strict operating procedures for the duration of the study. The mapping between
databases will not be shared or accessible outside of the research institution. When all
data validation and regulatory requirements have been met, the mapping database will
be destroyed, so that all the study databases and CDSA consultation database are
ultimately fully anonymized and independent from each other.
In addition, qualitative study repositories with restricted access rights will store raw (audio-
recordings, notes, drawings, photos, videos, GPS coordinates and document review grids) and
processed (transcribed, translated and coded) labelled qualitative material. Unless specified
otherwise per country requirements in the DMP, these repositories will be hosted on a device
owned and maintained by the country research partner.
A data transfer agreement will be requested from the national competent authorities for
providing access to and sharing a full copy of the de-identified study databases, de-identified
consultation database and de-identified qualitative material with the core team at Swiss TPH. A
subset of these database will be additionally shared with UoW as needed for the cost and cost-
effectiveness study. Following approval from the national competent authorities, the copies
will be stored on servers hosted in Switzerland / Canada. Data ownership will remain with the
country research partner. After study termination or premature termination of the study, the
de-identified databases and de-identified qualitative material will be archived by the country
research partner in accordance with national laws. The shared copies will be archived for 10
years by Swiss TPH and UoW, unless otherwise stipulated by the applicable legislation.
Research partners will archive study data according to the applicable national regulations. After
the mandatory retention period has ended, a periodic review will check if data storage is still
needed for research purposes. If not, the study data will then be deleted. All repositories,
databases and related software files will be backed up by the administrator in conjunction with
any updates or changes.
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Fig. 7. Overview of the research data and consultation data flows and supporting IT architecture used
within the TIMCI project. MedAL-R can receive updates directly from MedAL-C to be able to deploy
patches as needed. The MedAL-C server is hosted in Switzerland and managed by the IT Unisanté team in
Lausanne. This server will receive connection logs from the tablets when a network access is available.
7.2.2 Data entry, handling and validation
Quantitative research data
The EDC mobile application will perform offline validation (e.g., range and consistency) checks
that immediately detect and request the correction of erroneous data entry, and prevent
missing values upon compulsory data entry, guaranteeing completeness of the mandatory
datasets. Standardized dictionaries such as SNOMED CT and ICD-10 will be implemented
within the data collection tools (and hence available offline) in order to code clinical findings
and symptoms in a consistent way. To ensure the integrity of the study-related duties and any
data generated, each quantitative research assistant will log into the EDC mobile application
using their secure user name and password. All passwords will be strictly personal and
confidential. Electronically signed data from the mobile application will be regularly
synchronized with the central server.
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Procedures for cleaning and coding quantitative data will be developed by the core data
manager at Swiss TPH to ensure consistency across countries. These procedures will be further
described in the Data Management Plan. Data cleaning and coding activities will be supervised
by the data manager in charge in each country, with possible country-specific additions. These
activities will include, but will not be limited to, data de-identification, duplicate management
and free text management. Data quality checks will be run on a daily basis. A follow-up log
based on baseline visits and referral facility log based on Day 7 phone follow-up outputs will be
generated daily. The server will certify the integrity of data by using in-built range and
consistency checks to prevent errors during data manipulation.
An audit trail will be maintained for the life of the study for all quantitative research data. If a
correction is required for an entry, the time and date stamps will track the person entering or
updating entry and creates an electronic audit trail. There will be access control on the audit
trails so that a user cannot view information about another user or site that they are not allowed
to see. A synthetic visualization of the audit trail will be readily accessible by the data manager in
charge in each country, so that they can check all modification to data and meta-data and who
made them, as well as all successful and attempted system logins. At critical junctures of the
pre-post study, the research database will be reviewed and cleaned per established
procedures, before being locked. Consistency between the data cleaning procedures in each
country will be regularly reviewed. In addition, a dashboard will be developed for facilitating
the review of key indicators to trigger in-depth data review.
CDSA individual consultation data
Each patient attending an intervention facility will be given a unique identifier in the CDSA used
by this facility. Each new visit at the same facility will create a new case for the patient. Similar to
EDC mobile application, MedAL-R will perform offline validation checks and relies on
standardized dictionaries code clinical findings and symptoms in a consistent way. MedAL-R
will allow the modification of consultation data by different healthcare providers within the
health facility until the case has been closed to ensure the flexibility required by the clinical
workflow. Routine consultation data from MedAL-R will be regularly synchronized with the
CDSA server. Consultation data records will be electronically signed before being transferred to
the central research database. A timestamp (date, time, device identifier number) will
guarantee the integrity of the data associated with the electronic signature.
In non-study facilities, CDSA consultation data will be anonymised before transfer, so that no PII
will leave the facility and these data can never be re-associated with the underlying
individual.
Qualitative research data
Qualitative data will be voice recorded and complemented by written notes, drawings, photos
and videos and GPS coordinates by a dedicated qualitative researcher. Audio-recordings,
notes, drawings, photos, videos, GPS coordinates and document review grids will be either
written up in electronic files and/or directly transferred to the qualitative researcher’s computer
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and uploaded to the central server. Electronic files will be stored on two separate password-
protected devices according to country specific mechanisms (e.g. audio recording stored on a
password protected computer and on an external drive in a password protected folder in
locations where internet cannot be accessed; back-up on server as soon as internet is available
and deleting from external drive).
Qualitative research data will be backed up at the first possible opportunity. Where connectivity
to the central server is not possible, field teams will make a second back up on an encrypted
external hard drive. Transcription and translations from voice recordings and hand-written
notes will be entered into Word documents and translated into English and/or French. Hand-
drawn process maps and health care seeking pathways will be digitalized.
7.2.3 Data privacy protection
Personally identifiable information will be maintained confidentially under strict SOPs,
complying with all applicable international regulations. Study team members with access to PII
will sign a confidentiality agreement prior to collecting or accessing any of the data. Each
participant will be given a different unique alphanumeric identifier for each study in which
he/she is associated. Voice recording files and written notes that refer to the same participant
interview will be labelled using the same identifier. The IT infrastructure will provide password
protected devices, laptops with encrypted hard drives, fileserver with customizable access
rights, and documented and audited access right management. All transfer of data via the
internet will be done via secure, encrypted connections.
All quantitative data collection instruments will be stored in closed, locked file cabinets with
restricted access. The EDC platform will be encrypted and password protected. All study
databases will be safeguarded against unauthorized access by established security procedures. A
double coding procedure will ensure that participant re-identification is not feasible. The
name of the facility of enrolment, geographic information and some elements of dates related to
facility visits will also be de-identified. To further prevent re-identification of individuals
(patients, caregivers and healthcare providers), where appropriate, data will be de-identified so
that their level of granularity that does not allow indirect identification of an individual. In
addition, the data imported from another study datasets will be processed (e.g., aggregated
data, categorization of numeric values) so that a unique combination of facility and individual
characteristics does not allow indirect identification of an individual.
Voice recordings, photos and videos, as well as GPS mapping, will be deleted from the devices
after transcription, translation and digitalization. Transcriptions and translations of audio data
and typed-up field notes will be stored on the central database in password protected folders
accessible only to authorized qualitative researchers. Hand-written notes and drawings will be
stored in locked filing cabinets in an area with restricted access. During the coding process
qualitative data uploaded into the coding software will be manually de-identified (i.e. replacing
names, locations, other personal identifiers) ensuring that only de-identified interview material is
stored in the programme.
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7.2.4 Data quality assurance and control
Quality assurance activities across all studies will be more intense during study start-up to
ensure quality data practices are instituted from the start of the trial. Further details will be
given in the DMP and SOPs.
All research assistants will be trained to provide information and seek written consent using
the information and consent form. Separate trainings will cover all aspects of quantitative data
collection and all aspects of qualitative data collection. A competency assessment using
scenarios will be done before commencing field work.
Data reconciliation between the different visits of the same child will be one of the most crucial
data quality activities in the pre-post study. Specific procedures will be developed for this
purpose. To identify repeat visits of children that may re-attend the study facility where they
enrolled, or any other study facility during the follow-up period, participants will be given a
study card (or sticker) with a unique ID number. Retrospective search for data at referral level
will be restricted to facilities within the geographical area where the study is running and will be
targeted to include only children reported to have attended hospital by the caregiver at
follow-up and those lost to follow-up. The name of the referral facility will be requested during
the follow-up call. If available, it should further restrict the scope of the search and the
probability of negative matches when cross-checking the participant identity. Children who re-
attend any study facility more than 28 days after their previous enrolment will be enrolled for
the new disease episode and given a new ID number. If available, the old ID number will be
recorded to facilitate linking of the different disease episodes. Data to be potentially reconciled
will be flagged by automated cross-check of a set of personal identifiers. Given that personal
identifiers may not be identically recorded at each visit, fuzzy matching methods will be used to
calculate a score of similarity between records and likelihood that they relate to the same child.
Reconciliation of records with high similarity scores will be manually validated.
The validity of quantitative data will be ensured through data definitions and field restrictions in
the electronic systems. Acceptable error rates in critical quantitative data will be established
during the pilot phase and documented in the DMP. Pre-defined automated high-frequency
checks will be performed including checks of completeness and indicators of other
irregularities such as completion time. Reports will be shared with individual quantitative
research assistants and their supervisors. In addition to reviewing automatically generated
reports for their supervisees, supervisors will perform random accuracy checks of research data
compared to available source data. In the pre-post study, quantitative research assistants
responsible for the Day 7 call will be audited through random checks of phone logs and repeat
phone calls. After confirmation that the study databases contain all expected data, an internal
review will check their accuracy and quality. Once all the required data quality assurance and
control have been completed and passed, the study databases will be “locked”.
During the pilot phase, qualitative tools will be translated and back translated, and tested using
cognitive interviewing to ensure questions asked are understood as intended and felt to be
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appropriate. Regular quality checks of transcriptions and translations will be conducted by the
qualitative researcher in each country.
7.3 Statistical methods
Statistical methods will be described in detail in the Statistical Analysis Plan (SAP). We will
conduct all analyses described below per country, in addition to a pooled cross-country
analysis. Quantitative analyses will be conducted using Stata (or alternative statistical analysis
software, depending on investigator for certain country-specific or sub-studyspecific analyses).
7.3.1 Quasi-experimental pre-post study
Analysis will include all eligible, consenting and enrolled children. Baseline characteristics will
be described by country and across all study time points with summary statistics such as
median and interquartile range or number and percentage. Outcomes will be described for
each time period using summary statistics and results from the pre-intervention period and
the post-intervention period will be compared. The two primary outcomes will be assessed
using a random effects logistic regression models with the cluster (facility) included as a
random effect. All models will be adjusted for individual-level baseline characteristics such as
gender and age whose distribution at the facility may have changed between the time periods.
Results will be reported with odds ratios and 95% confidence intervals (CI). Binary secondary
outcomes will be evaluated in the same way. Continuous secondary outcomes will be assessed
using random effects linear regression models, reporting adjusted mean differences between
time periods with 95% CIs.
We will conduct planned subgroup analysis of the primary outcomes to assess for potential
effect modification in variables such as clinical presentation (particularly cough / difficulty
breathing) and diagnosis (particularly severity classification). If these variables are found to be
balanced between the two time periods, effect modification will be assessed by incorporating
an interaction between the time period and the variable in the model, acknowledging that
power will be low. Additional individual or facility level characteristics to be considered in the
model will be further detailed in the statistical analysis plan (SAP).
We will conduct the primary analysis on all visits (for visits by the same child, this implies visits
greater than 28 days apart as per the exclusion criteria). However, we will conduct a sensitivity
analysis excluding repeat visits of an individual child within the same quarter, to address the
possibility that outcomes of children attending for more than one disease episode are
correlated and impact the interpretation of the study. Due to the challenge in correctly
identifying all repeated visits, the fairly low likelihood of repeat visits (based on available
literature) and the acuity of the majority of sick child visits, we do not expect these analyses to
produce very different results. We will conduct sensitivity analyses for measured and
unmeasured confounders over time to assess robustness of the findings, which will be detailed in
the SAP.
An exploratory interrupted time series analysis will be conducted to assess change over time.
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7.3.2 Routine data
Relevant aggregated data from routine HMIS will be used to monitor trends over time in all
facilities and administrative regions where the project is running (i.e. both study facilities and
non-study facilities) pre- and post-intervention.
Routine CDSA clinical data will be used to conduct descriptive analysis on the use of pulse
oximetry and prevalence of hypoxaemia in non-pre-post study facilities post-intervention.
Univariate and multivariate analyses will assess factors associated with hypoxaemia such as
age, sex and clinical presentation. This data will also be used to estimate health outcomes in
facilities not involved in the pre-post study, building a model from the data collected in facilities
that are involved in the study. This estimate will then be gauged against HMIS data to identify
indicators for longer term monitoring of the intervention.
7.3.3 Other mixed methods studies
Quantitative
Descriptive analysis will be conducted of the data obtained from the SPA studies by country,
facility type andlocation and child and healthcare provider characteristics. Indices of adherence
to key practices will be described and compared between and time points (pre-intervention
and the 4 post intervention time points). Time-flow data will also be compared between pre-
intervention and each of the post-intervention periods. Effect modifiers will be explored.
Monitoring and evaluation data from non-pre-post study intervention facilities will be analysed
along with aggregated HMIS data, with comparison to pre-post study facilities to draw
inferences on the impact and uptake of the wider programme of implementation.
Qualitative analyses
Quality assurance steps for transcription and translation will be built into the process.
Qualitative data will be transcribed verbatim using modified transcription rules by Kallmeyer
and Schütze51 and translated into English and/or French. A random sample of transcripts and
translations will be quality checked by listening to audio-recordings and back translations and
measures taken accordingly. After familiarization with all interviews/FGDs, an experienced
qualitative researcher will code the transcripts using a qualitative coding software. A random
sample of a total of 10-15% of the qualitative interviews will be coded using the framework
analysis by Gale et al.52 following an inductive and deductive approach; in-vivo codes will be
created where applicable. The final draft code tree will be exported, codings deleted and the
same interviews coded by a second and independent qualitative researcher for inter-rater
reliability check. The Kappa-Cohen value will be calculated. Differences in coding will be
discussed and a joint solution developed. A Kappa-Cohen value above 80% will allow using the
code tree after minor adaptations based on joint agreements by the two coders and for final
coding. The finalized code tree will be used to code the entire material. Finally, each code and
each sub-code with its coded material will be exported into excel tables. A team of qualitative
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researchers will review the tables and jointly analyse the data identifying patterns, similarities,
and differences as well as change over time. Secondary analysis of data (i.e. including
comparison of final code trees) from all study countries may be conducted jointly and findings
compared across countries.
Document review
The document review data will be entered into a grid with predefined categories in line with
process evaluation criteria. Data will be triangulated against qualitative and quantitative data
collected.
Process evaluation
The process evaluation will draw on data from the various sub-studies to describe the context,
implementation process and mechanisms of impact as outlined in Fig 8.
Fig 8. Overview of MRC process evaluation of complex interventions (Image credit Moore et al)35
7.3.4 Cost and modelled cost-effectiveness study
When all the cost components have been collected, the data will be aggregated or collated in
Excel. Once the summary is completed, a cost profile of the programme activities will be derived
and after the total costs of the programme have been calculated, the unit costs will then be
derived (i.e. total costs divided by the sample size). These profiles are useful in highlighting
major cost components (and thus identifying potential areas where improvements in efficiency
may have significant impact on costs). For this evaluation, analysis will focus on full costing and
incremental costing approach. Total, average and incremental costs per year will be estimated.
Costs associated with increasing the oxygen saturation referral threshold will be estimated
based on the additional proportion of children meeting referral criteria.
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When available, effectiveness data will be combined with the cost data and cost per DALY
averted will be estimated. Effectiveness will be modelled using the information on severe
outcomes such as mortality, and secondary hospitalization, adjusting as far as possible the level
of severity of illness of the child at presentation.
At primary care facilities, these will include measurements (when taken by healthcare providers)
such as anthropometry, respiratory rate, temperature and routine investigations where
available (e.g. haemoglobin, CRP), and oxygen saturation (post-intervention/in intervention
arms). We will also use diagnosis and severity classification recorded by primary care providers.
At hospital level, we will also utilize the same measurement data, and other vital sign data (such
as a paediatric early warning score if recorded), decision to admit, intensive care and / or
ventilation, provisional and final diagnosis, admission outcome (discharge, death, left against
medical advice) and length of hospital stay. We will then use these indicators, along with
mortality from phone call follow-up data by Day 28, to predict probability of mortality based on
available literature. The DALY calculation will be based primarily on probability of mortality over
a relatively short horizon (to be determined based on a review of literature, likely between three
and six months to reflect the time windows used in post hospital discharge mortality studies).
The types of illnesses considered do not typically lead to long-term disability, and the duration
of illness is too short to have a big impact on DALY calculations. We will not use age weights: we
will use GBD (2017) DALYs, 53 and we will not use country-specific disutility data, both since we
are unsure these exist for all the countries, and they render cross-country comparisons more
difficult.
Sensitivity analysis
As not all data will be available precisely, we will explore possible assumptions using sensitivity
analysis which will assess how the estimates would react to percentages changes in the value of
the assumptions. It can help the reviewer to determine which parameters are the key drivers of a
model’s results. Guidelines and standard textbook recommend that economic evaluations
should include sensitivity analysis.54 We will undertake one-way sensitivity analysis of key
parameters using the major outcome and cost parameters. Typically. Such analyses are more
sensitive to the assumptions about outcomes, and for this we have to rely on the best
judgement of the epidemiologists.
8 Monitoring
All studies will be conducted in accordance with the protocol and international and applicable
national regulatory requirements. The Clinical Operations Unit within the Department of
Medicine at Swiss TPH will provide training of trainers on ethics and monitoring for research
partners if required. Country research partners will be responsible for setting up and carrying
out the monitoring plan, in consultation with Swiss TPH. This will include regular monitoring of
screening data, consent, recruitment rates and missing data on primary and important
secondary endpoints. Outliers on key indicators will trigger site visits.
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9 Ethics and dissemination
9.1 Research ethics approval
Following two independent scientific merit reviews, the protocol will be submitted to all
relevant research ethics committees / institutional review boards in each country. Receipts of
submission to each local ethical review board will be submitted with the master protocols to
the WHO Research Ethics Review Committee (ERC).
For Kenya, this is the University of Nairobi-Kenyatta National Hospital ERC (KNH-UoN ERC)
For Senegal, this is the Comité National d’Ethique por la Recherche en Santé (CNERS)
9.1.1 Regulatory status of the intervention
Pulse oximetry
The pulse oximetry device selected for the TIMCI project is the Acare AH-MX device. This was
selected as it is available through the UNICEF catalogue, which infers a level of quality and
device appropriateness. The competitive procurement process established by UNICEF
incorporates pulse oximetry specifications developed through a collaborativeprocess involving
global and national level experts. Devices in the catalogue have regulatory approval from a
stringent regulatory authority (SRA) such as the United States Food and Drug Administration
(US FDA) or Conformité Européenne (CE) mark.
Country level regulatory approval will vary. It is possible that the devices will have approval in
some of the countries. If the device does not have pre-existing regulatory approval in a project
country, the project team will work with the MOH to receive a waiver to use the device for the
study purposes. If appropriate, the study team will continue to work with the manufacturer and
MOH in each country to receive a permanent regulatory approval to facilitate scale of that
device.
Clinical Decision Support Algorithm
The regulatory classification of clinical decision support software is currently subject to debate at
the US FDA, depending on how and in what context the software is used. In this study, the CDSA
is intended to provide decision support for the diagnosis and treatment of childhood illness.
It will collate and analyse patient-specific information to suggest possible diagnoses and
recommend treatment plans or diagnostic tests to healthcare providers (HCPs). These
suggestions and recommendations will be evidence-based and will support the decision-
making of the HCP when considering treatment options or diagnostic tests for a patient. The
HCP may then use this information to make a decision about the care of the patient, along with
other information and factors of which he/she is aware. In addition, the CDSA presents a low
risk profile since it will support the implementation of and strengthen the adherence to
standard clinical guidelines. These functions do not meet the definition of a medical device per
country regulatory authorities and the CDSA is therefore regarded as a non-regulated device.
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9.2 Protocol amendments
Any important protocol modifications will be submitted to relevant research ethics committees,
trial registries and study sites including participants where appropriate.
9.3 Consent or assent
9.3.1 Quasi-experimental pre-post study
Information and consent procedures will be conducted in concordance with national regulatory
and ethical requirements (for example on the criteria applied to determine capacity of a
caregiver to provide consent). Prior to study start, information and consent mechanisms and
content will be reviewed and refined with community advisory boards and piloted with
participants and modifying if necessary to ensure appropriate.
As the intervention is at the facility level, approvals from relevant authorities will be sought
before engaging with facility management and staff prior to study start.
Informed consent from caregivers will be sought for the collection of data and follow-up of
individual children in the pre-post study. Information will be provided in the waiting area of
facilities in accordance with country-specific mechanisms, which may include written, pictorial,
video or spoken information. Potentially eligible children will be identified at registration
(based on age) during working hours and will be screened by a research assistant in the waiting
area for eligibility. Consecutive caregivers of eligible children will be provided with more
detailed information on the study and provided with an opportunity to ask questions. Written
informed consent will be obtained for those that agree to participate. In the case of an illiterate
caregiver, an impartial witness will be asked to sign on their behalf, along with a thumbprint of
the caregiver. Caregivers will be informed that they can withdraw at any point up to study
completion (and anonymization) and that non-participation or withdrawal will not affect their
care in any way. If the clinical condition of the child requires immediate treatment, this will
supersede the written consent process, which will be conducted once the child is stabilized,
and if this is still not possible, they will not be included in the study.
9.3.2 Other mixed methods studies
Additional consent from caregivers, healthcare providers and stakeholders will be sought for
the embedded mixed methods studies. For the SPA, this will be conducted at the health facility
as per the pre-post study.
The person responsible for the recruitment for qualitative studies (possibly with the help of an
assistant such as a community health worker) will invite caregivers for participation providing
verbal information and asking for verbal consent. Prior to the start of the IDI or FGD participants
will receive written information and asked to provide written consent. For method acting FGDs,
explicit consent will be sought for photo- and video-recording. Participants will have the option
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to take part in the FGD but withhold consent for video-/photo-recording. In this instance, the
respective participants will be kept out of shot.
For healthcare providers written information will be provided and written consent sought. No
information on individual decisions to accept or decline participation will be shared, neither
with supervisors nor with health authorities. For key stakeholders, written information will be
provided and verbal consent sought prior to an interview via telephone; or written consent if an
interview is conducted person-by-person.
9.3.3 Cost and modelled cost-effectiveness study
We will obtain consent from healthcare providers (including medical and non-medical
personnel) participating in the costing study. An information sheet on the study will be
provided prior to data collection, discussed with target providers from sampled health facility
before written consent is obtained. Data relevant to the costing study collected as part of other
studies will be extracted and provided as anonymised, summary data for the purposes of the
costing study.
9.4 Confidentiality
Participant identifiable data will only be collected for the purpose of study conduct (participant
follow-up, duplicate checking, as well as qualitative analysis) and will be destroyed in
accordance with standard operating procedures.
9.4.1 Quasi-experimental pre-post study
Study and participant data will be handled confidentially and will only be accessible to
authorised personnel who require the data to fulfil their duties within the scope of the study. All
personnel who have access to data forms will be asked to sign confidentiality agreements. We
will make sure consent forms make provision for future sharing of data.
A unique identifier number will be assigned to each participant (including healthcare providers)
and facilities.
9.4.2 Other mixed methods studies
Qualitative data will be audio recorded using an encrypted device after which it will be
transcribed and translated verbatim (personal identifiers not removed) in each country with
staff signing a confidentiality clause. During walking interviews audio-recordings will only be
done during the bilateral interview between the caregiver and data collector (but e.g. switched
off when the caregiver has a conversation with a third person). Hand-written notes of relevant
conversations and observations will be taken in addition. Audio data will be fully de-identified
when uploaded to and read through in the qualitative coding programme and according to
SOPs including use of pseudonyms. GPS tracking data of the walking interviews, as well as
photos and videos of the method acting FGDs will be additionally analysed. Audio tracks from
videos will be removed after transcription has been conducted and replaced by transcripts
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and/or sub-titles. Only the qualitative data collectors facilitating the FGD and the authorised
qualitative researchers (including qualitative researchers in country, in other TIMCI countries,
and the Swiss TPH lead social scientist) will view the non-de-identified acting method
videos/photos for the purpose of primary analysis, after signing a confidentiality agreement
and agreeing with the Code of Conduct. All raw qualitative material will be destroyed after
validation of the final database of consolidated qualitative material. Further information on
data management can be found in Section 7.2.
9.4.3 Linking between quasi-experimental pre-post study and mixed methods
studies
Data collected during the mixed-method studies will be linked with a subset of data collected
during the pre-post study. The privacy protection of enrolled participants will be ensured
following a multiple coding procedure: each participant will be given a different unique
alphanumeric identifier for each study in which he/she is associated. These identifiers will be
linked with the pre-post study identifier by the clinical management system. This means that
the knowledge of both codes and their mutual link is needed to access the full dataset about
a participant. The link between two study identifiers will be maintained confidential information
under strict operating procedures (in a central, secured database with restricted access rights)
for the duration of the study. In particular, this information will not be shared or accessible
outside of the research institution. When all data validation and regulatory requirements have
been met, the link between study identifiers will be destroyed, so that all study databases are
ultimately fully independent.
9.4.4 Cost and modelled cost-effectiveness study
Confidentiality of personnel cost of staff participatingin the study will be ensured by protecting
the identity of staff whose grade level will be collected as part of the study. Information on
staff salaries collected will be stored in a restricted cabinet with only access to the principal
investigator. All data collected will be stored with other intervention data in the research server
with limited access. We will assign unique identifiers to health facilities and maintain a link
between facility name and identifier stored in the research server. However, for the analyses
which will be performed in Waterloo, Canada, only de-identified data will be used.
9.5 Risks and benefits to participants
No major risks are foreseen given the low risk nature of the intervention. The only potential
risk envisaged is the time involved in participation in the study, which will be clearly outlined
during the informed consent process. The potential risk of delaying care of sick children as a
result of recruitment to the study will be mitigated by training of research assistants and
sensitization of healthcare providers to ensure that they are aware that no research activity
should take priority over clinical care. Scenarios in which they should not attempt to recruit
participants will be provided during training to ensure this is clearly understood.
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No participants will receive incentives, but participants, particularly in studies requiring greater
time commitment, may receive a small reimbursement (monetary/non-monetary) for their time
(e.g. to compensate for travel costs or lost time) and according to country specific standards.
In order to avoid the risk of diverting healthcare providers from clinical duties, all data
collection from healthcare providers will be scheduled at appropriate times. . For the SPA
interviews, this will be at a less busy time of the day (e.g. towards the end of the day) or just
after the end of their shift. IDIs and FGDs will take place after hours or at weekends unless
express (generic, not participant-specific) permission is provided to conduct during working
times without clinical duties.
Whilst there are no direct benefits to participants, this study could benefit them and their
community in future as a result of the understanding generated by this study.
9.6 Access to data
Access to study data will be governed by a data sharing agreement between each country
research partner, Swiss TPH, UoW and PATH, in accordance with country-specific regulations.
The final, anonymised datasets will be made available on an open access data sharing platform
after the end of the study, in order to promote transparency and facilitate global cooperation in
child health research.
9.7 Dissemination policy
The protocol will be published after all ethical approvals have been received.
Findings from the study will be shared through community engagement mechanisms
described in section 6.3. Findings will also be shared with the healthcare providers at facilities
involved in the study, and supervisors / other stakeholders within district health management
teams. Advocacy work through various mechanisms at national and international level based
on the findings of the study will be conducted as part of Output 4 of the TIMCI project.
Globally, the project is collaborating closely with technical partners, UN agencies, and the WHO
to refine research plans and ensure evidence generation is directly applicable to national and
global scale-up. A key output of the TIMCI project is focused on advocacy and policy adoption.
Policy and guideline landscapes have been conducted in each country and these are informing
advocacy strategies that are under development. The goal of these advocacy strategies is to
work with the governments to incorporate learnings from these studies into routine practice.
Pulse oximeters are currently available at a wide range of prices and PATH is planning to
provide technical assistance to the governments to support procurement of appropriate
devices for scale-up. Other activities to support scale-up focus on clinical guidelines, HCW
training curricula, procurement guidance, financing plans, and annual budgets.
Results will be shared with the wider scientific community through presentations at national
and international conferences, and through open-access peer-reviewed journal publications.
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Impact of intervention on QoC
(health outcomes, key practices)
Evaluation of implementation (incorporating process
evaluation, acceptability framework, realist approach)
Tab. 8. Multi-method intervention evaluation overview
Sub-study title
Pragmatic cluster
randomised
controlled trial
(India & Tanzania)
Quasi-experimental
pre-post study
(Kenya, Senegal)
Service provision
assessments
Facility-based
process mapping and
time-flow study
Healthcare provider
perceptions of the
intervention
Caregiver
perceptions of the
intervention and
health-seeking
behaviour
Stakeholder
perceptions
Project data review
Objectives
Large-scale evaluation of impact of pulse oximetry and
CDSAs on health outcomes (death, hospitalisations, cure
rate) and healthcare provider practice (antimicrobial
prescriptions, referral decisions)
To evaluate impact of pulse oximetry / CDSAs on quality
of care (referral, antimicrobial prescriptions with
exploratory assessment of outcomes
To evaluate the effect of the intervention on adherence
to IMCI guidelines, including the correct classification
and management of children under five years & to
evaluate health system factors associated with impact
To understand change in care processes including time
taken for consultation and use of devices
To understand acceptability, usability of devices by HCPs
and gain insight on perceived facilitators and barriers to
successful implementation
To understand knowledge, attitudes and behaviour (i.e.
experience of care, care seeking pathways, perception of
devices, adherence to advice (in last consultation), child
health literacy) related to the health care received
To explore knowledge, attitudes, values, beliefs related
to the devices, experiences with clinical care with a
focus on aspects of quality of care (i.e. people-centred
outcomes, provision of care and experience of care).
To understand health care provision pre-intervention;
the intervention mechanisms / decision-making,
identification of facilitators and barriers to
implementation, best practices, inform package for scale
Design
3-arm parallel cluster RCT comparing:
x
Pulse ox + CDSA
x
Pulse ox + paper job aid
x
Routine care (refresher training)
Quasi-experimental pre-post:
x
6-8 mo baseline
x
9 – 12 mo intervention (early/late)
x
comparison pre- , early and late
Periodic assessment (in each phase) using
Service Provision Assessment methodology –
i.e. collecting data at facilities for (1-5) days
per facility per quarter
Baseline and intervention process mapping
with group discussion at sample of facilities,
with observation and timing of key steps
Qualitative work with HCPs from a sample of
facilities in pilot, early and late intervention
Community follow-up of individual
caregivers, purposively selected (e.g. referred
/ unreferred, adverse / non-adverse
outcomes) during intervention period
FGD of purposively selected caregivers
(urban / rural, type of facility, location)
grouped by age/sex; During pilot, early and
late intervention phases
Baseline & late intervention
Late intervention
Tools
D0 – clinical/sociodemographic
data at facility
D7 – primary outcome
D28 – secondary outcome
D0 – clinical/sociodemographic
data at facility
D7 - outcome / health-seeking
Facility assessment
HCP interview
Sick child observation
Exit interview
Process map
Time-flow study
IDIs
FGDs
IDIs, Case Studies
FGDs
KIIs with govt & project
stakeholders
Desk review incl. project data
e.g. on devices, training
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10 References
1.
United Nations Inter-agency Group for Child Mortality Estimation (UN IGME). Levels & Trends in
Child Mortality: Report 2019, Estimates developed by the United Nations Inter-agency Group for
Child Mortality Estimation. (2019).
2.
UN General Assembly Resolution. Transforming our world: the 2030 Agenda for Sustainable
Development. A/RES/70/1.
3.
Costello, A., Dalglish, S. & on behalf of the Strategic Review Study Team. Towards a Grand
Convergence for child survival and health: A strategic review of options for the future building on
lessons learnt from IMNCI. (2016).
4.
World Health Organization (WHO). Integrated Management of Childhood Illness Chartbook. (2014).
5.
Nguyen, D. T. K., Leung, K. K., McIntyre, L., Ghali, W. A. & Sauve, R. Does Integrated Management
of Childhood Illness (IMCI) Training Improve the Skills of Health Workers? A Systematic Review
and Meta-Analysis. PLoS ONE 8, e66030 (2013).
6.
Krüger, C., Heinzel-Gutenbrunner, M. & Ali, M. Adherence to the integrated management of
childhood illness guidelines in Namibia, Kenya, Tanzania and Uganda: evidence from the national
service provision assessment surveys. BMC Health Serv Res 17, 822 (2017).
7.
Horwood, C. et al. An Evaluation of the Quality of IMCI Assessments among IMCI Trained Health
Workers in South Africa. PLoS ONE 4, e5937 (2009).
8.
Walter, N. D. et al. Why first-level health workers fail to follow guidelines for managing severe
disease in children in the Coast Region, the United Republic of Tanzania. Bull World Health Organ
87, 99–107 (2009).
9.
Bjornstad, E. et al. Determining the quality of IMCI pneumonia care in Malawian children.
Paediatrics and International Child Health 34, 29–36 (2014).
10. Keitel, K., Kilowoko, M., Kyungu, E., Genton, B. & D’Acremont, V. Performance of prediction rules
and guidelines in detecting serious bacterial infections among Tanzanian febrile children. BMC
Infectious Diseases 19, 769 (2019).
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
Page 75 of 82

11. Agweyu, A. et al. Appropriateness of clinical severity classification of new WHO childhood
pneumonia guidance: a multi-hospital, retrospective, cohort study. The Lancet Global Health 6,
e74–e83 (2018).
12. Chisti, M. J. et al. Clinical predictors and outcome of hypoxaemia among under-five diarrhoeal
children with or without pneumonia in an urban hospital, Dhaka, Bangladesh: Clinical predictors
and outcome of hypoxemia. Tropical Medicine & International Health 17, 106–111 (2012).
13. McCollum, E. D. et al. Pulse oximetry for children with pneumonia treated as outpatients in rural
Malawi. Bull. World Health Organ. 94, 893–902 (2016).
14. McCollum, E. D., Bjornstad, E., Preidis, G. A., Hosseinipour, M. C. & Lufesi, N. Multicenter study of
hypoxemia prevalence and quality of oxygen treatment for hospitalized Malawian children.
Transactions of the Royal Society of Tropical Medicine and Hygiene 107, 285–292 (2013).
15. Lazzerini, M., Sonego, M. & Pellegrin, M. C. Hypoxaemia as a Mortality Risk Factor in Acute Lower
Respiratory Infections in Children in Low and Middle-Income Countries: Systematic Review and
Meta-Analysis. PLoS ONE 10, e0136166 (2015).
16. Graham, H. et al. Hypoxaemia in hospitalised children and neonates: A prospective cohort study in
Nigerian secondary-level hospitals. EClinicalMedicine 0, (2019).
17. Subhi, R. et al. The prevalence of hypoxaemia among ill children in developing countries: a
systematic review. The Lancet Infectious Diseases 9, 219–227 (2009).
18. Orimadegun, A. E., Ogunbosi, B. O. & Carson, S. S. Prevalence and predictors of hypoxaemia in
respiratory and non-respiratory primary diagnoses among emergently ill children at a tertiary
hospital in south western Nigeria. Transactions of The Royal Society of Tropical Medicine and
Hygiene 107, 699–705 (2013).
19. Chinawa, J., Ubesie, A., Chukwu, B., Ikefuna, A. & Emodi, I. Prevalence of hypoxemia among
children with sickle cell anemia during steady state and crises: A cross-sectional study. Niger J Clin
Pract 16, 91 (2013).
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
Page 76 of 82

20. Morgan, M. C. et al. Pulse oximetry values of neonates admitted for care and receiving routine
oxygen therapy at a resource-limited hospital in Kenya. Journal of Paediatrics and Child Health 54,
260–266 (2018).
21. Adebola, O., Babatunde, O. & Bose, O. Hypoxemia predicts death from severe falciparum malaria
among children under 5 years of age in Nigeria: The need for pulse oximetry in case management.
Afr H. Sci. 14, 397 (2014).
22. Nantanda, R., Tumwine, J. K., Ndeezi, G. & Ostergaard, M. S. Asthma and Pneumonia among
Children Less Than Five Years with Acute Respiratory Symptoms in Mulago Hospital, Uganda:
Evidence of Under-Diagnosis of Asthma. PLOS ONE 8, e81562 (2013).
23. Institute for Health Metrics and Evaluation (IHME). GBD Compare.
http://vizhub.healthdata.org/gbd- compare (2015).
24. Rojas-Reyes, M. X., Granados Rugeles, C. & Charry-Anzola, L. P. Oxygen therapy for lower
respiratory tract infections in children between 3 months and 15 years of age. Cochrane Database
of Systematic Reviews (2014) doi:10.1002/14651858.CD005975.pub3.
25. Enoch, A. J., English, M. & Shepperd, S. Does pulse oximeter use impact health outcomes? A
systematic review. Arch Dis Child 101, 694–700 (2016).
26. Duke, T. et al. Improved oxygen systems for childhood pneumonia: a multihospital effectiveness
study in Papua New Guinea. The Lancet 372, 1328–1333 (2008).
27. Floyd, J. et al. Evaluating the impact of pulse oximetry on childhood pneumonia mortality in
resource-poor settings. Nature 528, S53–S59 (2015).
28. Blanc, J. et al. Retrospective study on the usefulness of pulse oximetry for the identification of
young children with severe illnesses and severe pneumonia in a rural outpatient clinic of Papua
New Guinea. PLoS ONE 14, e0213937 (2019).
29. Shao, A. F. et al. New Algorithm for Managing Childhood Illness Using Mobile Technology
(ALMANACH): A Controlled Non-Inferiority Study on Clinical Outcome and Antibiotic Use in
Tanzania. PLOS ONE 10, e0132316 (2015).
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
Page 77 of 82

30. Keitel, K. et al. A novel electronic algorithm using host biomarker point-of-care tests for the
management of febrile illnesses in Tanzanian children (e-POCT): A randomized, controlled non-
inferiority trial. PLoS Med 14, (2017).
31. Keitel, K. et al. A novel electronic algorithm using host biomarker point-of-care tests for the
management of febrile illnesses in Tanzanian children (e-POCT): A randomized, controlled non-
inferiority trial. PLoS Med 14, (2017).
32. Lange, S., Mwisongo, A. & Mæstad, O. Why don’t clinicians adhere more consistently to guidelines
for the Integrated Management of Childhood Illness (IMCI)? Social Science & Medicine 104, 56–63
(2014).
33. WHO. Standards for improving the quality of care for children and young adolescents in health
facilities. (2018).
34. Pawson, R. & Tilley, N. Realist Evaluation. (2004).
35. Moore, G. F. et al. Process evaluation of complex interventions: Medical Research Council
guidance. BMJ 350, (2015).
36. Sekhon, M., Cartwright, M. & Francis, J. J. Acceptability of healthcare interventions: an overview of
reviews and development of a theoretical framework. BMC Health Services Research 17, 88 (2017).
37. Michie, S., van Stralen, M. M. & West, R. The behaviour change wheel: A new method for
characterising and designing behaviour change interventions. Implementation Sci 6, 42 (2011).
38. De Silva, M. J. et al. Theory of Change: a theory-driven approach to enhance the Medical Research
Council’s framework for complex interventions. Trials 15, 267 (2014).
39. Taplin, Dana, Clark, H., Collins, E. & Colby, D. C. Theory of Change Technical Papers: A Series of
Papers to Support Development of Theories of Change Based on Practice in the Field. (2013).
40. DHS Service Provision Assessment Tools.
https://dhsprogram.com/pubs/pdf/SPAQ2/SICK_CHILD_OBSERVATION_PROTOCOL_06012012.pdf.
41. Sheffel, A., Karp, C. & Creanga, A. A. Use of Service Provision Assessments and Service Availability
and Readiness Assessments for monitoring quality of maternal and newborn health services in
low-income and middle-income countries. BMJ Glob Health 3, e001011 (2018).
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
Page 78 of 82

42. World Health Organization. Service Availability and Readiness Assessment (SARA) -an annual
monitoring system for service delivery: Reference Manual, Version 2.2.
https://apps.who.int/iris/bitstream/handle/10665/149025/WHO_HIS_HSI_2014.5_eng.pdf?sequenc
e=1 (2015).
43. Acare Technology Co., Ltd. -AH-MX. Acare Technology Co., Ltd.
http://www.acaretech.com/product_872390.html.
44. Uwemedimo, O. T. et al. Distribution and determinants of pneumonia diagnosis using Integrated
Management of Childhood Illness guidelines: a nationally representative study in Malawi. BMJ
Global Health 3, e000506 (2018).
45. Ministry of Health and Social Welfare (MoHSW) [Tanzania Mainland], Ministry of Health (MoH)
[Zanzibar], National Bureau of Statistics (NBS), Office of the Chief Government Statistician (OCGS)
& ICF International. Tanzania Service Provision Assessment Survey 2014-2015.
https://dhsprogram.com/pubs/pdf/spa22/spa22.pdf (2016).
46. Krüger, C., Heinzel-Gutenbrunner, M. & Ali, M. Adherence to the integrated management of
childhood illness guidelines in Namibia, Kenya, Tanzania and Uganda: evidence from the national
service provision assessment surveys. BMC Health Serv Res 17, 822 (2017).
47. Oxygen therapy for children. (World Health Organization, 2016).
48. Rojas-Camayo, J. et al. Reference values for oxygen saturation from sea level to the highest human
habitation in the Andes in acclimatised persons. Thorax 73, 776–778 (2018).
49. Emdin, C. A. et al. Utility and feasibility of integrating pulse oximetry into the routine assessment
of young infants at primary care clinics in Karachi, Pakistan: a cross-sectional study. BMC Pediatr
15, 141 (2015).
50. Boyd, N. et al. Usability Testing of a Reusable Pulse Oximeter Probe Developed for Health-Care
Workers Caring for Children < 5 Years Old in Low-Resource Settings. The American Journal of
Tropical Medicine and Hygiene 99, 1096–1104 (2018).
51. Kallmeyer, W. & Schütze, F. Konversationsanalyse. in Studium
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
Linguistik (Scriptor Verlag, 1976).
Page 79 of 82

52. Gale, N. K., Heath, G., Cameron, E., Rashid, S. & Redwood, S. Using the framework method for the
analysis of qualitative data in multi-disciplinary health research. BMC Med Res Methodol 13, 117
(2013).
53. James, S. L. et al. Global, regional, and national incidence, prevalence, and years lived with
disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic
analysis for the Global Burden of Disease Study 2017. The Lancet 392, 1789–1858 (2018).
54. Drummond, M. F., Sculpher, M. J., Claxton, K., Stoddart, G. L. & Torrance, G. W. Methods for the
economic evaluation of health care programmes. (Oxford university press, 2015).
TIMCI Longitudinal Study Protocol v0.2.5, 5th April 2023
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11 Appendices
11.1 Informed consent forms appended to the protocol
x
01 TIMCI_ICF_LS_V0.3.2_19Nov2020
x
02 TIMCI ICF LS CG SPA V0.2.2, 19Nov2020
x
03 TIMCI ICF LS CG TF V0.2.2, 19Nov2020
x
04 TIMCI ICF LS CG Walking Interview V0.2.3, 19Nov2020
x
05.1 TIMCI ICF LS CG IDI intervention V0.2.3, 19Nov2020
x
05.2 TIMCI ICF LS CG IDI non-intervention V0.2.3, 19Nov2020
x
06 TIMCI ICF LS CG FGD V0.2.3, 19Nov2020
x
07 TIMCI ICF LS CG method actingV0.2.3, 19Nov2020
x
08 TIMCI ICF LS HCP SPA V0.2.2 19Nov2020
x
09.1 TIMCI ICF LS HCP IDI V0.2.3, 19Nov2020
x
09.2 TIMCI ICF LS HCP IDI pre-intervention V0.2.3, 19Nov2020
x
10 TIMCI ICF LS HCP FGD V0.2.3, 19Nov2020
x
11 TIMCI ICF SH KII V0.2.3, 19Nov2020
x
12 TIMCI ICF SH survey V0.2.3, 19Nov2020
x
13 TIMCI ICF LS costing V0.3, 19Nov2020
11.2 Study instruments appended to the protocol
x
1.1 TIMCI LS CRF description v0.1.5, 29May20
x
2.1TIMCI LS SPA Exit Interview instrument v.0.1.4, 24Nov20
x
2.2 TIMCI LS SPA SCO instrument v.0.1.5, 24 Nov20
x
2.3 TIMCI LS SPA HealthCare Provider Interview v0.1.4, 29May20
x
2.4 TIMCI LS SPA FA instrument v0.1.4, 29May20
x
3.1 TIMCI LS process map timeflow tool v0.3.0, 29May20
x
4.1.1 TIMCI healthcare provider IDI v0.5.0
x
4.1.2 TIMCI healthcare provider IDI v0.3.0_KE SE
x
4.2 TIMCI healthcare provider FGD v0.5.0
x
5.1.1 TIMCI caregiver IDI v0.5.0
x
5.1.2 TIMCIcaregiver IDI v0.3.0_KE SE
x
5.2 TIMCI caregiver walking interview v0.5.0
x
5.3 TIMCI caregiver FGD v0.5.0
x
6.1.1 TIMCI stakeholder KII v0.5.0
x
6.1.2 TIMCI stakeholder KII_KE SE
x
6.2 TIMCI stakeholder survey v0.4.0
x
6.3 TIMCI document review matrix v0.3.0
x
7.1 TIMCI non-medical personnel questionnaire 08.06.20
x
7.2 TIMCI medical personnel questionnaire 08.10.20
x
7.3 TIMCI LS hospital costs 09.06.20
x
7.4 TIMCI Training comm sensitization costs 09.06.20
11.3 Budget and collaboration appended to the protocol
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11.4 TIMCI Preliminary Theory of Change
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