Digital behavioural interventions for people with sickle cell disease

Objectives

This is a protocol for a Cochrane Review (intervention). The objectives are as follows:

To identify and assess the effects of digital behavioural interventions focused on behavioural change in people with SCD on:

• medication adherence or disease management (such as managing acute and chronic pain), or both, on health‐ and other‐related outcomes;

• specific subgroups defined by age (i.e. children, adolescents and adults) and type of modality or delivery (e.g. cell phone, the Internet).

Background

Description of the condition

Sickle cell disease (SCD) is an inherited haemoglobin disorder affecting more than five million individuals globally; and annually affecting 250,000 to 300,000 live births worldwide (Piel 2013; Piel 2017). It is important to note that both prevalence and incidence are estimates and given that newborn screening does not exist in many countries, these numbers are likely underestimating the global burden of SCD. In the USA, SCD is seen in 100,000 to 120,000 Americans, primarily those of African‐American or Hispanic descent, who are diagnosed through the newborn screening program. In some parts of the world, there are major limitations with respect to screening programs for SCD and the implementation of treatment guidelines, both of which are likely to contribute to a negative impact on health outcomes. People with SCD face inequalities in both healthcare and health information technology (Brousseau 2010; Hassell 2010), which could limit the individual's access to digital behavioural interventions.

SCD is a chronic debilitating illness caused by a single gene mutation, affecting almost all organs in the body (Piel 2017). People with SCD inherit the abnormal haemoglobin variant (HbS), either from both parents (homozygous HbSS) or from one parent, along with another abnormal variant, including haemoglobin C (HbSC disease), or with β‐thalassaemia (HbSβ⁰ or HbSβ⁺) (Piel 2017). The lack of oxygen or the presence of cellular stress or dehydration within the erythrocytes (or both), results in the polymerisation of HbS, causing erythrocyte damage with associated changes in rheology and expression of adhesion molecules, leading to haemolysis, anaemia and blockage of blood flow in vessels (i.e. vaso‐occlusion) (Rees 2010).

The most common SCD‐related complication is pain, recognised as the hallmark of this disease (Piel 2017; Rees 2010), and it is the main reason for hospitalisations and a significant driver of healthcare costs in this population (Kauf 2009). People with SCD usually experience intermittent, unpredictable, debilitating pain episodes (Piel 2017; Rees 2010), which can worsen as they move through adolescence to early adulthood with higher rates of chronic pain (Dampier 2017). Approximately 30% of individuals with SCD report daily pain symptoms with different peaks of pain at different time points across their lifespan (Albo 2020; Brandow 2020; Smith 2008). Other serious complications include acute chest syndrome, pulmonary hypertension, cerebrovascular disease, and long‐term end‐organ damage (Badawy 2016a; Rees 2010; Yawn 2014). These complications lead to significant changes in health‐related quality of life (HRQOL) over time, particularly as they relate to physical and psychosocial well‐being (Badawy 2017a; Badawy 2017b; Palermo 2002; Panepinto 2012), leading to increased healthcare utilization (Badawy 2018a; Candrilli 2011) and culminating in early mortality (Maitra 2017).

Description of the intervention

Digital behavioural interventions for promoting medication adherence and for symptom and disease management (WHO 2019), such as for managing acute and chronic pain, include the delivery of education, reminders, or behavioural skills through cell (mobile) phones (e.g. text‐messaging and mobile applications), the Internet (e.g. web‐based applications), or other mobile technology tools (e.g. calendar reminders, platforms that allow feedback from the SCD team or trial investigators). We will compare these interventions to no intervention, standard medical care, or non‐digital interventions. Digital behavioural interventions could:

• enhance the communication between people with SCD and healthcare providers;

• offer skills for acute or chronic pain management;

• address comorbid psychological challenges and difficulties;

• provide education about SCD and available medications;

• promote adherence to medications using reminders, either daily (e.g. hydroxyurea, L‐glutamine, or voxelotor) or monthly medications (i.e. crizanlizumab);

• offer a network for social support among people with SCD;

• support decision making for people with SCD and their parents or caregivers; and

• co‐ordinate care among different healthcare providers or systems.

There has been growing evidence to support the feasibility, acceptability, and efficacy of self‐management electronic health (eHealth) behavioural interventions in chronic diseases, but data are limited in SCD.

How the intervention might work

Digital behavioural interventions could:

• enhance an individual's self‐efficacy, organizational skills, or change adherence behaviour (e.g. reminders for daily or monthly medications, clinic appointment reminders, transfusion reminders, feedback on adherence to daily or monthly medications);

• provide a form of communication (e.g. health professionals);

• establish social support networks (e.g. advocacy groups, peer‐to‐peer networks); or

• provide education about SCD, daily medications (e.g. hydroxyurea, or voxelotor) and necessary steps for optimal disease management.

• teach behavioural and cognitive skills to cope with acute or chronic pain or to manage psychological distress.

Digital behavioural interventions may influence individuals’ health behaviours and improve self‐management of chronic illnesses by promoting self‐efficacy skills (Bandura 1977; Modi 2012) and providing support mechanisms (Christakis 2004; Cohen 1985). These interventions may also provide education and training to enhance problem‐solving skills among people with SCD, and in this way increase their confidence in carrying out the activities and behaviours needed to optimise disease management, including non‐pharmacological treatment of acute and chronic pain as well as psychosocial support for associated comorbidities.

Why it is important to do this review

People with SCD and their families are responsible for managing complex and time‐consuming treatment regimens as described in most published guidelines for SCD, including daily medications (e.g. hydroxyurea), laboratory monitoring, imaging studies (e.g. transcranial doppler), and attendance at routine clinic appointments with a variety of health care professionals (Yawn 2014). Therefore, managing SCD represents a challenge, a major logistical burden, and perhaps an associated psychological burden for children and adults as well as their caregivers (Yawn 2014).

Recent publications have found a high rate of low adherence to medications, imaging studies, and routine clinic visits as well as poor self‐management skills among children, adolescents and adults with SCD (Badawy 2018c; Badawy 2018d; Cronin 2018a; Haywood 2011; Loiselle 2016; Raphael 2008; Stettler 2015; Thornburg 2010; Walsh 2014). Furthermore, low adherence to medications (e.g. hydroxyurea) has been associated with more frequent SCD‐related complications (Candrilli 2011), worse HRQOL (Badawy 2017b), and increased healthcare utilization (Badawy 2018a; Candrilli 2011). These findings were supported by similar evidence of adherence challenges in other chronic health conditions (DiMatteo 2002; Pai 2011; Rapoff 2010). Nevertheless, effective engagement in self‐management is one key pathway to optimising both medication adherence and clinical outcomes, so as to reduce or minimise avoidable healthcare utilisation and costs (Cronin 2019; Modi 2012). Moreover, with the increasing prevalence of chronic pain (Dampier 2017), opioid overexposure (Ballas 2018; Han 2018; Sinha 2019; Telfer 2014) and psychological distress, particularly depression, among people with SCD (Moody 2019; Pecker 2019), there has been growing need for digital interventions that deliver non‐pharmacological treatment, such as cognitive behavioural therapy focused on coping skills training and psychosocial support.

Access to personal computer and mobile technology tools is almost ubiquitous in the USA's general population (Perrin 2017; Perrin 2019) as well as among individuals with SCD (Badawy 2016b; Shah 2014), although in some parts of the world unequal access to technology remains. These tools include standard cell phones, smart phones, tablets, the Internet, and social networking (Silver 2019). Therefore, the widespread availability and frequent use of these technologies by individuals with SCD and their caregivers across age groups present an opportunity for delivery of digital behavioural interventions to promote self‐management, optimise medication adherence, link patients with their providers, and improve overall health outcomes (Alberts 2020; Badawy 2016b; Badawy 2017c; Badawy 2018b; Creary 2019; Cronin 2018b; Estepp 2014; Johnson 2019; Jonassaint 2018; Jonassaint 2020; Palermo 2018a; Palermo 2016; Palermo 2018b; Pernell 2017; Shah 2014; Utrankar 2018). There has been growing interest and evidence to support the utility as well as feasibility, acceptability and efficacy of digital behavioural intervention strategies to improve medication adherence and self‐management in healthy individuals and those with chronic medical conditions (Badawy 2017d; Badawy 2017; Badawy 2020; Bonoto 2017; Liu 2014; Payne 2015; Pfaeffli Dale 2016; Radovic 2020; Ramsey 2020; Thakkar 2016; Whitehead 2016), including SCD (Badawy 2018b). Nevertheless, to date, the cost‐effectiveness of these interventions remains unclear (Badawy 2016c; Iribarren 2017) and further economic evaluation is needed; however, a summary of the evidence for cost‐effectiveness is beyond the scope of this review. We recently completed and published a systematic literature review of technology‐based interventions in SCD which found modest evidence that various eHealth behavioural interventions may improve multiple components of self‐management in children and adults with SCD (Badawy 2018b). Given the fast pace of this growing field of digital behavioural interventions, evaluating the most recent evidence for the efficacy of these interventions in SCD is warranted.

Objectives

To identify and assess the effects of digital behavioural interventions focused on behavioural change in people with SCD on:

• medication adherence or disease management (such as managing acute and chronic pain), or both, on health‐ and other‐related outcomes;

• specific subgroups defined by age (i.e. children, adolescents and adults) and type of modality or delivery (e.g. cell phone, the Internet).

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials (RCT) and quasi‐RCTs comparing single‐ or multi‐component interventions versus no intervention, placebo or standard care. We also plan to exclude studies with a cross‐over design since any intervention focused on improving disease knowledge will leave that knowledge with a residual 'carry‐over' effect. We plan to include cluster‐RCTs, if they have at least two intervention sites and two control sites.

Given the growing evidence in the field and the possible paucity of research studies, in particular RCTs, evaluating digital behavioural interventions in people with SCD, we wanted to broaden our eligibility criteria to be able to report the up‐to‐date current status of the field and identify gaps. We will use the Cochrane Effective Practice and Organization of Care (EPOC) Group’s definition of study designs to consider studies for inclusion (EPOC 2017) and will include non‐randomised studies of interventions (NRSI), specifically, controlled before‐after (CBA) studies, interrupted‐time‐series (ITS) studies and repeated‐measures studies which have a clearly defined point in time when the intervention occurred and at least three data points before and at least three data points after the intervention.

We plan to exclude ITS studies that do not have a clearly defined point in time when the intervention occurred, fewer than three data points before and after the intervention, or if the ITS study has ignored secular (trend) changes, performed a simple t‐test of the pre‐ versus post‐intervention periods and re‐analysis of the data is not possible (EPOC 2017).

Types of participants

People with any SCD genotype of all ages (children, adolescents and adults) and parents or caregivers of people with SCD.

Types of interventions

Digital behavioural interventions, delivered via:

• cell phones, including smart phones;

• tablets;

• the Internet; or

• other technology or mobile devices.

versus

• other technology interventions;

• no interventions; or

• standard of care; or

• placebo.

We will include remote and web‐based patient‐ or parent/caregiver‐centred behavioural interventions (or both) delivered via technologies giving people with SCD access to digital information to provide education and promote medication adherence and disease management, including pain management, coping skills training, and psychosocial support. These e‐health behavioural technologies include personal computers (PCs) and applications (apps) for mobile technology such as iOS tablets (iPads), Android tablets and smart phones with different operating systems. These interventions need to be self‐administered or user‐centred (where the intervention design process focuses on user needs). These digital technologies could be the only intervention in the study or combined with other non‐digital intervention components.

We will also include as possible comparison groups (whenever reported): face‐to‐face support; educational material (either as hard copy or digital documents); or self‐management tools (either as hard copy or digital documents).

It is important to emphasise that these digital behavioural interventions have the potential to enhance self‐management and health outcomes in people with SCD, in addition to, not instead of, usual standard of care with in‐person interactions with SCD providers.

We will exclude studies that focus on using monitoring devices without an active intervention that requires individual participation and involvement in using the intervention during the study period. We will also exclude clinician‐administered interventions, in‐person or virtual, such as tele‐monitoring or telemedicine or other provider‐centred technologies that involve the participation of healthcare professionals as end users.

Types of outcome measures

We will include the following outcomes.

Primary outcomes

1. Medication adherence (as measured by one or more of the following)

   1. individuals recording their daily medication use (e.g. hydroxyurea or iron chelators) on their smartphones, either by logging their medication or taking videos

   2. electronic pill bottles (e.g. medication even monitoring system (MEMS) Caps or AdhereTech bottles)

   3. digital pills (e.g. Proteus Digital Health)

   4. laboratory markers of adherence (e.g. fetal haemoglobin % and mean corpuscular volume for hydroxyurea and serum ferritin for iron chelators)

   5. pharmacy records (i.e. medication possession ratio)

   6. self‐reported adherence rate (i.e. surveys or questionnaires)

   7. radiological markers of iron overload for those on chronic transfusions with iron overload (i.e. MRI of liver R2* and MRI of heart T2*)

2. Disease management outcomes (as measured using self‐report questionnaires or surveys in one or more of the following domains)

   1. coping skills and strategies

   2. pain severity (intensity or frequency)

   3. depression, anxiety and other psychosocial evaluation scores

   4. self‐efficacy and self‐management scores

   5. other important relevant patient‐reported outcomes (PROs) such as HRQOL

Secondary outcomes

1. Disease‐specific complications (e.g. the number of vaso‐occlusive crises and the number of acute chest syndrome episodes)

2. Healthcare utilisation (including the number of hospitalisations and emergency room visits)

3. Knowledge about SCD (in general as well as commonly used and approved medications (such as hydroxyurea, voxelotor, crizanlizumab and L‐glutamine)) measured with self‐report questionnaires

4. User evaluation of the mobile technology interventions (such as acceptability, satisfaction and usefulness questionnaires)

5. Adverse events (such as issues of privacy and disclosure and failure or delay in the intervention delivery)

Search methods for identification of studies

We will search for all relevant published and unpublished trials without restrictions on language, year or publication status.

Electronic searches

The Cochrane Cystic Fibrosis and Genetic Disorders Group's Information Specialist will conduct a systematic search of the Group's Haemoglobinopathies Trials Register for relevant trials using the terms: ((sickle cell:kw) OR (haemoglobinopathies AND general):kw)) AND telemedicine:kw.

The Haemoglobinopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and weekly searches of MEDLINE. Unpublished work is identified by searching the abstract books of five major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting; the Caribbean Public Health Agency Annual Scientific Meeting (formerly the Caribbean Health Research Council Meeting); and the National Sickle Cell Disease Program Annual Meeting. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

In addition to the above, we will conduct a search of the following databases:

• CENTRAL (the Cochrane Library, current issue) (www.cochranelibrary.com/);

• PubMed (Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, for recent records not yet added to MEDLINE) (www.ncbi.nlm.nih.gov/sites/entrez);

• MEDLINE (OvidSP, Epub Ahead of Print, In‐Process & Other Non‐Indexed Citations, Ovid MEDLINE Daily and Ovid MEDLINE, 1946 to present);

• Embase (OvidSP, 1974 to present);

• CINAHL (EBSCOHost, 1937 to present);

• PsycInfo (EBSCOHost, 1900 to present);

• ProQuest Dissertations & Theses Global (ProQuest, 1861 to present);

• Web of Science & Social Sciences Conference Proceedings Indexes (CPSI‐S & CPSSI, 1990 to current);

• Institute of Electrical and Electronics Engineers Explore (IEEE Xplore, 1963 to present).

Additionally, we will search the following trial databases for trials:

• ISRCTN registry (www.isrctn.com/);

• ClinicalTrials.gov (www.ClinicalTrials.gov);

• World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) Search Portal (apps.who.int/trialsearch/).

See Appendix 1 for the full search strategies.

Searching other resources

We will further aim to identify unpublished work by searching the abstract books of the International Society for Research on Internet interventions (ISRII) annual meeting; the Society for Behavioral Medicine (SBM) annual meeting; the American Society of Hematology (ASH); the American Society of Pediatric Hematology/Oncology (ASPHO); and the Annual Society of Pediatric Psychology Conference over the past 10 years (2010 to 2020).

Reference lists

The reference lists of all included articles and relevant systematic reviews will be reviewed to identify any additional studies. We will contact the lead authors of the included studies to identify any unpublished material, missing data or information regarding ongoing relevant studies.

Data collection and analysis

Selection of studies

We will select studies according to chapter 4 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2021). Two review authors (SB and RC) will independently screen all electronically‐derived citations and abstracts of papers identified by the search strategy for relevance. We will exclude all articles that are clearly irrelevant at this stage based on the title and the abstract. Two review authors (SB and RC) will independently assess the full texts of all potentially relevant trials or studies for eligibility against criteria outlined above. If we cannot reach a consensus, we aim to resolve any disagreements by discussion and consultation with a third review author (TP). We will seek further information from study authors if studies or abstracts contain insufficient data to make a decision about eligibility. We will design a study eligibility form which will include ascertaining whether the participants have SCD, if the study addresses digital behavioural interventions to improve adherence and disease management, and whether the study design is randomised or a relevant NRSI. We will also record the reasons why potentially relevant studies failed to meet the eligibility criteria.

Data extraction and management

Two review authors (SB and RC) will extract data according to Cochrane guidelines for RCTs and NRSI (Higgins 2021a; Reeves 2021). We will aim to resolve any disagreements by consensus. We will pilot data extraction forms for RCTs and all relevant types of NRSI; thereafter, two authors (SB and RMC) will independently conduct data extraction for all the studies using templates modified to reflect the outcomes in this review. In addition, we will use the available tables in Review Manager 5 (RevMan 2020) to extract data on study characteristics as below.

General information

Review author’s name, date of data extraction, study ID, first author of study, author’s contact address (if available), citation of paper, and objectives of the study.

Study details

Study design, location, setting, sample size, power calculation, treatment allocation, inclusion and exclusion criteria, reasons for exclusion, comparability of groups, length of follow‐up, stratification, stopping rules described, statistical analysis, results, conclusion, and funding.

Characteristics of participants

Age, gender, total number recruited, total number randomized, total number analysed, SCD genotype, loss to follow‐up numbers, dropouts (percentage in each arm) with reasons, protocol violations (if any), and comorbidities.

Interventions

Details of the digital behavioural interventions, including purpose (e.g. adherence promotion, coping skills training or psychosocial support), modality used (cell phone, the Internet or other technology), length of intervention, how the intervention is being delivered (i.e. electronically only, with or without human support, or electronically in addition to group, face‐to‐face, written information) and by whom (i.e. clinicians, researchers, patients or parents) and where the intervention is being delivered (i.e. hospital, clinic, home or other settings). Data from different modes of interventions will be analysed separately (e.g. cell phone versus standard care, the Internet versus standard care, etc.).

Outcomes measured

We will collect data on outcomes related to medication adherence, disease management and other key outcomes to allow us to fully report our primary outcome measures listed above.  Similarly, we will also collect data relating to our secondary outcome measures.

For all types of NRSI we will collect data, if available, on: confounding factors, such as age, gender, genotype, treatment strategy, comorbidities and other socio‐economic factors (Table 1); the comparability of groups on confounding factors; methods used to control for confounding and on multiple effect estimates (both unadjusted and adjusted estimates) as recommended in chapter 13 of the Cochrane Handbook of Systematic Reviews of Interventions (Reeves 2021). We will use both full‐text versions and abstracts as data sources and use one data extraction form for each unique study. Where sources do not provide sufficient information, we will contact authors for additional details. One review author will enter all data, and a second review author will check these for accuracy.

1. List of potential confounders for study outcomes.

Potential confounders

Age

Sex

Sickle cell genotype

Treatment strategy

Comorbidities

Other socio‐economic factors (e.g. annual household income and educational level)

Assessment of risk of bias in included studies

Two review authors (SB and TP) will assess all included studies for possible risks of bias, as described in chapter 8 of the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2021b). In our assessment, we will include information about the design, the conduct and the analysis of the study outcomes.

RCTs

We will assess each criterion using Cochrane's RoB 2 tool for assessing the risk of bias for RCT outcomes (classed as 'low risk', 'high risk' or 'some concerns' for bias) in the following areas.

Bias arising from the randomisation process

1. Was the allocation sequence random?

2. Was the allocation sequence concealed until participants were recruited and assigned to interventions?

3. Were there baseline imbalances that suggest a problem with the randomisation process?

4. What is the predicted direction of bias arising from the randomisation process?

Bias due to deviations from intended interventions

1. Were participants aware of their assigned intervention during the trial?

2. Were carers and trial personnel aware of participants' assigned intervention during the trial?

3. Were there deviations from the intended intervention beyond what would be expected in usual practice?

4. Were these deviations from intended intervention unbalanced between groups and likely to have affected the outcome?

5. Were any participants analysed in a group different from the one to which they were assigned?

6. Was there potential for a substantial impact (on the estimated effect of intervention) of analysing participants in the wrong group?

7. What is the predicted direction of bias due to deviations from intended interventions?

Bias due to missing outcome data

1. Were outcome data available for all, or nearly all, participants randomised?

2. Are the proportions of missing outcome data and reasons for missing outcome data similar across intervention groups?

3. Is there evidence that results were robust to the presence of missing outcome data?

4. What is the predicted direction of bias due to missing outcome data?

Bias in measurement of the outcome

1. Were outcome assessors aware of the intervention received by study participants?

2. Was the assessment of the outcome likely to be influenced by knowledge of intervention received?

3. What is the predicted direction of bias due to measurement of the outcome?

Bias in selection of the reported result(s)

1. Are the reported outcome data likely to have been selected, on the basis of the results, from multiple outcome measurements (e.g. scales, definitions, time points) within the outcome domain? Or from multiple analyses of the data?

2. What is the predicted direction of bias due to selection of the reported result?

Overall bias

The response options for an overall risk‐of‐bias judgement are the same as for individual domains. Low risk of bias is determined when the study has low risk of bias for all domains for this result, while some concerns for bias is considered when the study raises some concerns in at least one domain for this result, but not to be at high risk of bias for any domain. The study is judged to be at high risk of bias in at least one domain for this result or have some concerns for multiple domains in a way that substantially lowers confidence in the result.

NRSI studies

We will use the ROBINS‐I tool to assess the risk of bias of NRSIs (including CBA studies) outcomes (Sterne 2021). The ROBINS‐I tool uses signalling questions and covers seven domains (listed below) where the quality of evidence is rated as 'low', 'moderate', 'serious', 'critical', or 'no information'. A judgement of overall low risk of bias means the NRSI is considered comparable to a well‐performed randomised trial. A critical risk of bias suggests that the study is too problematic to provide useful evidence and would not be included in any synthesis. Further details of the ROBINS‐I process are available in the Cochrane Handbook for Systematic Reviews of Interventions (Sterne 2021).

Bias due to confounding

1. Is there potential for confounding of the effect of intervention in this study?

2. Was the analysis based on splitting participants’ follow‐up time according to intervention received?

3. Were intervention discontinuations or switches likely to be related to factors that are prognostic for the outcome?

4. Did the authors use an appropriate analysis method that controlled for all the important confounding domains?

5. Were confounding domains that were controlled for measured validly and reliably by the variables available in this study?

6. Did the authors control for any post‐intervention variables that could have been affected by the intervention?

7. Did the authors use an appropriate analysis method that adjusted for all the important confounding domains and for time varying confounding?

8. Were confounding domains that were adjusted for measured validly and reliably by the variables available in this study?

Bias in the selection of participants into the study

1. Was selection of participants into the study (or into the analysis) based on participant characteristics observed after the start of intervention?

2. Were the post‐intervention variables that influenced selection likely?

3. Were the post‐intervention variables that influenced selection likely to be influenced by the outcome or a cause of the outcome?

4. Do start of follow‐up and start of intervention coincide for most participants?

Bias in classification of interventions

1. Were intervention groups clearly defined?

2. Was the information used to define intervention groups recorded at the start of the intervention?

3. Could classification of intervention status have been affected by knowledge of the outcome or risk of the outcome?

4. What is the predicted direction of bias due to measurement of outcomes or interventions?

Bias due to deviation from intended interventions

1. Were there deviations from the intended intervention beyond what would be expected in usual practice?

2. Were these deviations from intended intervention unbalanced between groups and likely to have affected the outcome?

3. Were important co‐interventions balanced across intervention groups?

4. Was the intervention implemented successfully for most participants?

5. Did study participants adhere to the assigned intervention regimen?

6. Was an appropriate analysis used to estimate the effect of starting and adhering to the intervention?

7. What is the predicted direction of bias due to deviations from the intended interventions?

Bias due to missing data

1. Were outcome data available for all, or nearly all, participants?

2. Were participants excluded due to missing data on intervention status?

3. Were participants excluded due to missing data on other variables needed for the analysis?

4. Are the proportion of participants and reasons for missing data similar across interventions?

5. Is there evidence that results were robust to the presence of missing data?

6. What is the predicted direction of bias due to missing data?

Bias in measurement of outcomes

1. Could the outcome measure have been influenced by knowledge of the intervention received?

2. Were outcome assessors aware of the intervention received by study participants?

3. Were the methods of outcome assessment comparable across intervention groups?

4. Were any systematic errors in measurement of the outcome related to intervention received?

5. What is the predicted direction of bias due to measurement of outcomes?

Bias in the selection of the reported result

1. Is the reported effect estimate likely to be selected, on the basis of the results, from multiple outcome measurements within the outcome domain? Or from multiple analyses of the intervention outcome relationship? Or from different subgroups?

2. What is the predicted direction of bias due to selection of the reported result?

ITS studies

Specifically for ITS studies, we will use the risk of bias criteria below (as suggested for EPOC reviews) (EPOC 2017) as follows.

• Was the intervention independent of other changes?

• Was the shape of the intervention effect pre‐specified?

• Was the intervention unlikely to affect data collection?

• Was knowledge of the allocated interventions adequately prevented during the study?

• Were incomplete outcome data adequately addressed?

• Was the study free from selective outcome reporting?

• Was the study free from other risks of bias?

We will aim to resolve disagreements on the assessment of quality of an included study by discussion until consensus is reached or by consultation with a third review author (RC or RL).

Measures of treatment effect

RCTs

We plan to report the our outcome measures as binary or continuous data, depending on data availability.

For continuous outcomes, we plan to extract and report the absolute change from baseline, adjusting for baseline differences, in both the treatment and control groups. We will record the mean, standard deviation (SD), or median, interquartile range (IQR), and total number of participants in both the treatment and control groups. For those using the same scale or outcome, we will perform analyses using the mean difference (MD) with 95% confidence intervals (CIs). For those reported using different scales or outcomes, we will use the standardised mean difference (SMD) with 95% CIs. We will extract and report the relative change adjusted for baseline differences in the outcome measures (i.e. the absolute post‐intervention difference between the intervention and control groups, as well as the absolute pre‐intervention difference between the intervention and control groups divided by the post‐intervention level in the control group) (EPOC 2017). For studies reporting continuous outcomes as rates, we will include and synthesize data as rate ratios.

For studies reporting binary outcomes, we will include and synthesise data as risk ratio, odds ratio or risk difference, as applicable.

For cluster RCTs, we will extract and report direct estimates of the effect measure (e.g. relative risk (RR) reduction with a 95% CI) from an analysis that accounts for the clustered design.

NRSI studies

For continuous variables in the included studies, if available, we will extract adjusted outcome values from regression models as reported by the trial authors, noting the adjustments made as part of the regression. An adjusted change of outcomes is required in NRSI, we will consider and evaluate confounding in the included studies. If available, we will extract and report the relative change adjusted for baseline differences in the outcome measures (i.e. the absolute post‐intervention difference between the intervention and control groups, as well as the absolute pre‐intervention difference between the intervention and control groups divided by the post‐intervention level in the control group) (EPOC 2017).

Specifically for ITS studies that fulfil the inclusion criteria of analysis, and from which we can extract relevant information, we will standardise data by dividing the level (or time slope) and standard error (SE) by the SD of the pre‐intervention slope, in order to obtain the effect sizes. Where appropriate, we will report the number‐needed‐to‐treat‐to‐benefit (NNTB) and the number‐needed‐to‐treat‐to‐harm (NNTH) with 95% CIs. If we are not able to report the available data in any of the formats described above, we will produce a narrative report, and if appropriate, we will present the data in tables (Hudson 2019).

Unit of analysis issues

We expect to identify issues related to units of analysis, given the inclusion of cluster RCTs or NRSI, and multiple observations for the same outcome. Therefore, if we include any of these study designs in our review, we will treat these in accordance with the advice given in chapter 23 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019c). For studies with multiple treatment groups, we will include subgroups that are considered relevant to the analysis, when data are available in the included studies or when we contact the study authors for clarification and additional information. When appropriate, we will combine groups to create a single pair‐wise comparison. If this is not possible, we will select the most appropriate pair of interventions and exclude the others (Higgins 2021c). We will deal with any unit of analysis issues arising from the inclusion of ITS studies according to the EPOC recommendations (EPOC 2017).

Dealing with missing data

If we identify occasions where we suspect data are missing or unclear, we will contact the study authors directly. We will record the number of participants lost to follow‐up for each study. Where possible, we will analyse data on an intention‐to‐treat (ITT) basis, but if insufficient data are available, we will present per protocol analyses (Higgins 2021b).

Assessment of heterogeneity

If the clinical and methodological characteristics of individual studies are sufficiently homogeneous, we will combine the data to perform a meta‐analysis. We will analyse the data from RCTs and different types of NRSI separately. We will assess the statistical heterogeneity of treatment effects between studies using a Chi² test with a significance level at P < 0.1. We will use the I² statistic to quantify the degree of potential heterogeneity and classify it as moderate if I² is greater than 50%, or considerable if I² is greater than 75% (Higgins 2003). If statistical heterogeneity is moderate within the studies selected for inclusion; in such cases, we will use the random‐effects model. If statistical heterogeneity is considerable within the studies selected for inclusion, we will not report the overall summary statistic. When possible, we will assess the potential causes of heterogeneity by sensitivity and subgroup analyses (Deeks 2021).

Assessment of reporting biases

Where we identify at least 10 studies for inclusion in a meta‐analysis, we plan to explore potential publication bias with a funnel plot and using a linear regression test. We plan to consider a P value of less than 0.1 as significant for this test (Deeks 2021).

Data synthesis

If studies are sufficiently homogenous in their study design, we will conduct a meta‐analysis according to Cochrane recommendations (Deeks 2021). We will analyse RCTs and NRSI separately using the random‐effects model, as we expect the true effects to be related, but not the same for included RCTs and NRSI. If we cannot perform a meta‐analysis, we will include a narrative describing the results and present the results from all studies in tables.

For RCTs, where meta‐analysis is feasible, we will use the inverse variance method for continuous outcomes, or outcomes that include data from cluster‐RCTs. If we identify heterogeneity above 75%, we will explore further with subgroup analyses. If we cannot identify a cause for this heterogeneity, then we will not perform a meta‐analysis.

If meta‐analysis is feasible for the different types of NRSI, we will analyse these separately. We will only analyse outcomes with adjusted‐effect estimates, if these are adjusted for the same factors using the inverse variance method as recommended in chapter 13 of the Cochrane Handbook of Systematic Reviews of Interventions (Reeves 2021).

If meta‐analysis is feasible for ITS studies, we will use the effect sizes (if reported in the included studies or obtained, as described earlier) and we will pool these using the generic inverse variance method in RevMan (RevMan 2020). We will report data for our listed outcomes at the following time points: pre‐intervention, immediate post‐intervention and at first follow‐up (up to 12 months).

Subgroup analysis and investigation of heterogeneity

If adequate data are available, we will perform subgroup analyses according to Cochrane recommendations (Deeks 2021) for each of the following criteria, and separately for the different study design types included in the review in order to assess the effect on heterogeneity. We will base the subgroup analysis on:

• delivery mode, personal computer‐based versus mobile‐based interventions;

• level of complexity, single component (digital only) versus multi‐components (digital plus others) interventions;

• age groups, children (1 to 11 years old) (parent‐focused) versus adolescents (12 to 17 years old) versus adults (18 years and above).

Sensitivity analysis

We will assess the robustness of the review findings by performing the following sensitivity analyses according to Cochrane recommendations where appropriate (Deeks 2021):

• including only those studies with a 'low' risk of bias for randomisation (e.g. RCTs with methods assessed as low risk for random sequence generation and concealment of treatment allocation);

• including only those studies with less than a 20% dropout rate.

Summary of findings and assessment of the certainty of the evidence

We will use the GRADE approach to generate a 'Summary of Findings' table as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021a; Schünemann 2021b). We will rate the quality of the evidence as 'high', 'moderate', 'low', or 'very low' using the five GRADE considerations.

• Risk of bias (serious or very serious)

• Inconsistency (serious or very serious)

• Indirectness (serious or very serious)

• Imprecision (serious or very serious)

• Publication bias (likely or very likely)

For NRSI, the following additional factors will also be considered:

• dose response (yes or no);

• size of effect (large or very large);

• confounding either reduces the demonstrated effect or increases the effect if no effect was observed (yes or no)

We will present the outcomes for RCTs and NRSI in separate tables.

Using GRADE, we will initially rate all types of NRSI as low quality and these will be upgraded according to GRADE guidelines if appropriate.

We will report the following outcomes in each 'Summary of findings' table:

1. Medication adherence ‐ individuals recording their daily medication use 

2. Medication adherence ‐ self‐reported adherence rates

3. Disease management outcome ‐ coping skills and strategies

4. Disease management outcome ‐ pain severity

5. Disease management ‐ self‐management or self‐efficacy (or both)

6. Healthcare utilisation

7. Adverse events

Summary of findings and assessment of the certainty of the evidence

We will use the GRADE approach to generate a 'Summary of Findings' table as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021a; Schünemann 2021b). We will rate the quality of the evidence as 'high', 'moderate', 'low', or 'very low' using the five GRADE considerations.

• Risk of bias (serious or very serious)

• Inconsistency (serious or very serious)

• Indirectness (serious or very serious)

• Imprecision (serious or very serious)

• Publication bias (likely or very likely)

For NRSI, the following additional factors will also be considered:

• dose response (yes or no);

• size of effect (large or very large);

• confounding either reduces the demonstrated effect or increases the effect if no effect was observed (yes or no)

We will present the outcomes for RCTs and NRSI in separate tables.

Using GRADE, we will initially rate all types of NRSI as low quality and these will be upgraded according to GRADE guidelines if appropriate.

We will report the following outcomes in each 'Summary of findings' table:

1. Medication adherence ‐ individuals recording their daily medication use 

2. Medication adherence ‐ self‐reported adherence rates

3. Disease management outcome ‐ coping skills and strategies

4. Disease management outcome ‐ pain severity

5. Disease management ‐ self‐management or self‐efficacy (or both)

6. Healthcare utilisation

7. Adverse events

Summary of findings and assessment of the certainty of the evidence

We will use the GRADE approach to generate a 'Summary of Findings' table as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2021a; Schünemann 2021b). We will rate the quality of the evidence as 'high', 'moderate', 'low', or 'very low' using the five GRADE considerations.

• Risk of bias (serious or very serious)

• Inconsistency (serious or very serious)

• Indirectness (serious or very serious)

• Imprecision (serious or very serious)

• Publication bias (likely or very likely)

For NRSI, the following additional factors will also be considered:

• dose response (yes or no);

• size of effect (large or very large);

• confounding either reduces the demonstrated effect or increases the effect if no effect was observed (yes or no)

We will present the outcomes for RCTs and NRSI in separate tables.

Using GRADE, we will initially rate all types of NRSI as low quality and these will be upgraded according to GRADE guidelines if appropriate.

We will report the following outcomes in each 'Summary of findings' table:

1. Medication adherence ‐ individuals recording their daily medication use 

2. Medication adherence ‐ self‐reported adherence rates

3. Disease management outcome ‐ coping skills and strategies

4. Disease management outcome ‐ pain severity

5. Disease management ‐ self‐management or self‐efficacy (or both)

6. Healthcare utilisation

7. Adverse events

History

Protocol first published: Issue 4, 2021

Appendices

Appendix 1. Search Methods ‐ Electronic Searching

Database/ Resource	Strategy
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (www.cochranelibrary.com/)	[Advanced Search Form] #1 MeSH descriptor: [Anemia, Sickle Cell] explode all trees #2 MeSH descriptor: [Hemoglobin, Sickle] explode all trees #3 ("hemoglobin S" or "haemoglobin S" or "hemoglobin SC" or "haemoglobin SC" or "hemoglobin SE" or "haemoglobin SE" or "hemoglobin SS" or "haemoglobin SS" or "hemoglobin C disease" or "hemoglobin D disease" or "hemoglobin E disease" or "haemoglobin C disease" or "haemoglobin D disease" or "haemoglobin E disease" or "Hb SC" or HbSC or HbAS or HbSS or HbAC or "Hb SE" or "Hb SS" or "Hb C disease" or "Hb D disease" or "Hb E disease" or "SC disease" or "SC diseases") [title, abstract, keyword] #4 (sickle cell* or sicklemia or sickled or sickling or meniscocyt* or drepanocyt*) [title, abstract, keyword] #5 (sickle and SCD) [title, abstract, keyword] #6 ((Hb S or HbS or sickle) near/3 (disease* or thalassemi* or thalassaemi*)) [title, abstract, keyword] #7 #1 or #2 or #3 or #4 or #5 or #6 #8 MeSH descriptor: [Cell Phones] explode all trees #9 (Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone*) [title, abstract, keyword] #10 MeSH descriptor: [Microcomputers] explode all trees #11 MeSH descriptor: [Mobile Applications] this term only #12 (Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps) [title, abstract, keyword] #13 ((mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*)) [title, abstract, keyword] #14 MeSH descriptor: [Internet] explode all trees #15 MeSH descriptor: [Computer Simulation] this term only #16 MeSH descriptor: [Electronic Mail] this term only #17 MeSH descriptor: [Reminder Systems] this term only #18 MeSH descriptor: [Wireless Technology] this term only #19 MeSH descriptor: [Software] explode all trees #20 (internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based) [title, abstract, keyword] #21 (wireless AND (technolog* OR communicat*)) [title, abstract, keyword] #22 MeSH descriptor: [Video Recording] this term only #23 MeSH descriptor: [Videoconferencing] explode all trees #24 MeSH descriptor: [Telemedicine] explode all trees #25 MeSH descriptor: [Text Messaging] this term only #26 (video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service) [title, abstract, keyword] #27 (mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication*) [title, abstract, keyword] #28 #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24 or #25 or #26 or #27 #29 #7 and #28
PubMed	(("Anemia, Sickle Cell"[Mesh] or "Hemoglobin SC Disease"[Mesh] or haemoglobin S[tw] or hemoglobin S[tw] or haemoglobin SC[tw] or hemoglobin SC[tw] or haemoglobin SE[tw] or hemoglobin SE[tw] or haemoglobin SS[tw] or hemoglobin SS[tw] or haemoglobin C disease[tw] or hemoglobin C disease[tw] or haemoglobin D disease[tw] or hemoglobin D disease[tw] or haemoglobin E disease[tw] or hemoglobin E disease[tw] or Hb SC[tw] or HbSC[tw] or HbAS[tw] or HbSS[tw] or HbAC[tw] or Hb SE[tw] or Hb SS[tw] or Hb C disease[tw] or Hb D disease[tw] or Hb E disease[tw] or SC disease[tw] OR SC diseases[tw] or sickle cell[tw] or sicklemia[tw] or sickled[tw] or sickling[tw] or meniscocyt*[tw] or drepanocyt*[tw]) OR (sickle and SCD) OR ((Hb S or HbS or sickle) and (disease* or thalassaemi* or thalassemi*))) AND (“mobile health”[tw] OR “mhealth”[tw] OR “ehealth”[tw] OR “m‐health”[tw] OR “e‐health”[tw] OR “mcare”[tw] OR “cellphone”[tw] OR “cellphones”[tw] OR “cell phones”[tw] OR “cell phone” OR “cellular phone”[tw] OR “cellular phones”[tw] OR “cellular telephone”[tw] OR “cellular telephones”[tw] OR “mobile phone”[tw] OR “mobile phones”[tw] OR “mobile telephone”[tw] OR “mobile telephones”[tw] OR “iphone”[tw] OR “iphones”[tw] OR “microcomputer”[tw] OR “microcomputers”[tw] OR “handheld computer”[tw] OR “handheld computers”[tw] OR “hand held computer”[tw] OR “hand held computers”[tw] OR “ipad”[tw] OR “ipads”[tw] OR “pda”[tw] OR “pdas”[tw] OR “personal digital assistant”[tw] OR “personal digital assistants”[tw] OR “blackberry”[tw] OR “android”[tw] OR “androids”[tw] OR “smartphone”[tw] OR “smartphones”[tw] OR “smart phone”[tw] OR “smart phones”[tw] OR “tablet”[tw] OR “apps”[tw] OR “app”[tw] OR “mobile application”[tw] OR “mobile applications”[tw] OR “mobile communication”[tw] OR “mobile communications”[tw] OR “mobile technology”[tw] OR “mobile technologies”[tw] OR “mobile game”[tw] OR “mobile games”[tw] OR “internet”[tw] OR “computer simulation”[tw] OR “email”[tw] OR “emails”[tw] OR “emailing”[tw] OR “e‐mail”[tw] OR “e‐mails”[tw] OR “e‐mailing”[tw] OR “electronic mail”[tw] OR “reminder systems”[tw] OR “reminder system”[tw] OR “wireless technology”[tw] OR “wireless technologies”[tw] OR “wireless communication”[tw] OR “wireless communications”[tw] OR “software”[tw] OR “video recording”[tw] OR “video recordings”[tw] OR teleconference*[tw] OR “text message”[tw] OR “text messaging”[tw] OR “texting”[tw] OR “text”[tw] OR “texts”[tw] OR “SMS”[tw] OR “short message service”[tw] OR “text messages”[tw] OR "Handheld device"[tw] OR "handheld devices"[tw] OR "mobile tool"[tw] OR "mobile tools"[tw] OR "electronic device"[tw] OR "electronic devices"[tw] OR "electronic tool"[tw] OR "electronic tools"[tw] OR "electronic health"[tw] OR "electronic monitoring"[tw] OR "e‐monitoring"[tw] OR "electronically monitor"[tw] OR "electronic mentoring"[tw] OR "telehealth"[tw] OR "telehealthcare"[tw] OR "telemonitoring"[tw] OR "telementoring"[tw] OR "telecare"[tw] OR "telemedicine"[tw] OR "telecommunication"[tw] OR "telecommunications"[tw] OR "videoconferencing"[tw] OR "videoconference"[tw] OR "bluetooth"[tw] OR "web‐based"[tw])
MEDLINE (OvidSP, 1946 to present)	1. exp Anemia, Sickle Cell/ 2. Hemoglobin, Sickle/ 3. (h?emoglobin S or h?emoglobin SC or h?emoglobin SE or h?emoglobin SS or h?emoglobin C disease or h?emoglobin D disease or h?emoglobin E disease or Hb SC or HbSC or HbAS or HbSS or HbAC or Hb SE or Hb SS or Hb C disease or Hb D disease or Hb E disease or SC disease*).tw,kf. 4. (sickle cell* or sicklemia or sickled or sickling or meniscocyt* or drepanocyt*).tw,kf. 5. (sickle and SCD).tw,kf. 6. ((Hb S or HbS or sickle) adj3 (disease* or thalass?emi*)).tw,kf. 7. or/1‐6 8. exp Cell Phones/ 9. (Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone*).af. 10. exp Microcomputers/ 11. Mobile Applications/ 12. (Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps).af. 13. ((mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*)).af. 14. exp Internet/ 15. Computer Simulation/ 16. Electronic mail/ 17. Reminder Systems/ 18. Wireless Technology/ 19. exp Software/ 20. (internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based).af. 21. (wireless AND (technolog* OR communicat*)).af. 22. Video Recording/ 23. exp Videoconferencing/ 24. exp Telemedicine/ 25. Text Messaging/ 26. (video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service).af. 27. (mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication*).af. 28. or/8‐27 29. 7 and 28
Embase (OvidSP, 1974 to present)	1. exp Sickle Cell Anemia/ 2. Hemoglobin S/ 3. (h?emoglobin S or h?emoglobin SC or h?emoglobin SE or h?emoglobin SS or h?emoglobin C disease or h?emoglobin D disease or h?emoglobin E disease or Hb SC or HbSC or HbAS or HbSS or HbAC or Hb SE or Hb SS or Hb C disease or Hb D disease or Hb E disease or SC disease*).tw. 4. (sickle cell* or sicklemia or sickled or sickling or meniscocyt* or drepanocyt*).tw. 5. (sickle and SCD).tw. 6. ((Hb S or HbS or sickl*) adj3 (disease* or thalass?emi*)).tw. 7. or/1‐6 8. exp Mobile Phone/ 9. (Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone*).af. 10. Microcomputer/ 11. Mobile Application/ 12. (Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps).af. 13. ((mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*)).af. 14. Internet/ 15. Computer Simulation/ 16. E‐mail/ 17. Reminder System/ 18. Wireless Communication/ 19. Software/ 20. (internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based).af. 21. (wireless AND (technolog* OR communicat*)).af. 22. Videorecording/ 23. Videoconferencing/ 24. exp Telemedicine/ 25. Text Messaging/ 26. (video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service).af. 27. (mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication*).af. 28. or/8‐27 29. 7 and 28
CINAHL (EBSCOHost, 1937 to present)	S1 (MH "Anemia, Sickle Cell+") S2 TX ("hemoglobin S" or "haemoglobin S" or "hemoglobin SC" or "haemoglobin SC" or "hemoglobin SE" or "haemoglobin SE" or "hemoglobin SS" or "haemoglobin SS" or "hemoglobin C disease" or "hemoglobin D disease" or "hemoglobin E disease" or "haemoglobin C disease" or "haemoglobin D disease" or "haemoglobin E disease" or "Hb SC" or HbSC or HbSS or HbAC or "Hb SE" or "Hb SS" or "Hb C disease" or "Hb D disease" or "Hb E disease" or "SC disease" or "SC diseases" OR sickle cell* or sicklemia or sickled or sickling or meniscocyt* or drepanocyt*) S3 TX ((Hb S or HbS or sickle) N3 (disease* or thalass?emi*)) S4 S1 OR S2 OR S3 S5 (MH "Cellular Phone") OR (MH "Smartphone") S6 TX Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone* S7 (MH "Microcomputers") OR (MH "Computers, Portable+") S8 (MH "Mobile Applications") S9 TX Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps S10 TX (mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*) S11 (MH "Internet") S12 (MH "Computer Simulation") S13 (MH "Electronic Mail") S14 (MH "Reminder Systems") S15 (MH "Wireless Communications") S16 (MH "Software") OR (MH "Communications Software") S17 TX internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based S18 TX wireless AND (technolog* OR communicat*) S19 (MH "Videorecording") OR (MH "Videoconferencing+") S20 (MH "Telecommunications+") OR (MH "Telehealth+") S21 TX video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service S22 TX mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication* S23 S5 OR S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 OR S19 OR S20 OR S21 OR S22 S24 S4 AND S23
PsycInfo (EBSCOHost, 1900 to present)	S1 DE "Sickle Cell Disease" S2 TX ("hemoglobin S" or "haemoglobin S" or "hemoglobin SC" or "haemoglobin SC" or "hemoglobin SE" or "haemoglobin SE" or "hemoglobin SS" or "haemoglobin SS" or "hemoglobin C disease" or "hemoglobin D disease" or "hemoglobin E disease" or "haemoglobin C disease" or "haemoglobin D disease" or "haemoglobin E disease" or "Hb SC" or HbSC or HbSS or HbAC or "Hb SE" or "Hb SS" or "Hb C disease" or "Hb D disease" or "Hb E disease" or "SC disease" or "SC diseases" OR sickle cell* or sicklemia or sickled or sickling or meniscocyt* or drepanocyt*) S3 TX ((Hb S or HbS or sickle) N3 (disease* or thalass?emi*)) S4 S1 OR S2 OR S3 S5 S1 OR S2 OR S3 OR S4 S6 DE "Mobile Devices" OR DE "Cellular Phones" OR DE "Electronic Communication" OR DE "Blog" OR DE "Computer Mediated Communication" OR DE "Electronic Learning" OR DE "Social Media" OR DE "Text Messaging" S7 TX Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone* S8 DE "Microcomputers" S9 TX Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps S10 TX (mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*) S11 DE "Internet" S12 DE "Computer Simulation" S13 DE "Computer Software" OR DE "Groupware" S14 TX internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based S15 TX wireless AND (technolog* OR communicat*) S16 DE "Teleconferencing" OR DE "Telemedicine" S17 TX video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service S18 TX mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication* S19 S6 OR S7 OR S8 OR S9 OR S10 OR S11 OR S12 OR S13 OR S14 OR S15 OR S16 OR S17 OR S18 S20 S5 AND S19
Web of Science & Social Sciences Conference Proceedings Indexes (CPSI‐S & CPSSI, 1990 to current)	#1 TOPIC: ("hemoglobin S" or "haemoglobin S" or "hemoglobin SC" or "haemoglobin SC" or "hemoglobin SE" or "haemoglobin SE" or "hemoglobin SS" or "haemoglobin SS" or "hemoglobin C disease" or "hemoglobin D disease" or "hemoglobin E disease" or "haemoglobin C disease" or "haemoglobin D disease" or "haemoglobin E disease") #2 TOPIC: ("Hb SC" or HbSC or HbSS or HbAC or "Hb SE" or "Hb SS" or "Hb C disease" or "Hb D disease" or "Hb E disease") #3 TOPIC: ("SC disease" or "SC diseases" or sicklemia or sickled or sickling) #4 TOPIC: (sickle cell* or meniscocyt* or drepanocyt*) #5 #4 OR #3 OR #2 OR #1 #6 TOPIC: (Cellphone* or ((cell* or mobile) and (Phone* or telephone*)) or iphone*) #7 TOPIC: (Microcomputer* or ipad* or pda* or personal digital assistant* or blackberry* or android* or smartphone* or smart phone* or tablet or app or apps) #8 TOPIC: ((mobile or electronic* or handheld or hand‐held) and (application* or communication* or technolog* or game* or tool* or device* or monitor* or mentor* or computer*)) #9 TOPIC: (internet OR computer simulation OR email* OR e‐mail* OR electronic mail OR remind* system* OR software OR Bluetooth OR web‐based) #10 TOPIC: (wireless AND (technolog* OR communicat*)) #11 TOPIC: (video recording* or videoconference* or teleconference* or texting or texts or text message* or SMS or short messag* service) #12 TOPIC: (mobile health or mhealth or ehealth or m‐health or e‐health or mcare or electronic health or e‐monitoring or telehealth* or telemonitoring or telementoring or telecare or telemedicine or telecommunication*) #13 #12 OR #11 OR #10 OR #9 OR #8 OR #7 OR #6 #14 #13 AND #5
Institute of Electrical and Electronics Engineers Explore (IEEE Xplore, 1963 to present)	sickle cell
ISRCTN registry	sickle cell
ClinicalTrials.gov	[Basic Search Form] Status: All studies Condition or disease: sickle cell Other terms: phone OR smartphone OR computer OR mobile OR electronic OR app OR game OR wireless OR email OR video OR text OR sms OR video OR electronic OR internet OR web OR device OR technology OR Bluetooth OR online OR remote OR monitor OR communication OR telecommunication OR videoconference OR videoconferencing OR teleconference OR teleconferencing
WHO International Clinical Trials Registry Platform (ICTRP)	[Advanced Search Form] Condition: sickle cell Intervention: phone OR smartphone OR computer OR mobile OR electronic OR app OR game OR wireless OR email OR video OR text OR sms OR video OR electronic OR internet OR web OR device OR technology OR Bluetooth OR online OR remote OR monitor OR communication OR telecommunication OR teleconference OR videoconferenc* OR teleconferenc* Recruitment Status: All

Contributions of authors

Contributions have been adapted from the Yank study (Yank 1999):

Sherif M. Badawy: conceiving the review, protocol development, methodological expert and content expert.

Robert M. Cronin: protocol development and content expert.

Robert I. Liem: protocol development and content expert.

Tonya M. Palermo: protocol development and methodological expert.

Sources of support

Internal sources

• No sources of support supplied

External sources

• National Institute for Health Research, UK

  This systematic review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Cystic Fibrosis and Genetic Disorders Group.

Declarations of interest

All authors: none known.

New