Protocol for a comparative cross-sectional study on characterisation of auditory impairment in sickle cell disease and sickle cell trait and its impact on health-related quality of life in Nigeria

Background and rationale

Sickle cell disease (SCD) and sickle cell traits (SCT) are a group of genetically inherited red blood cell disorders common among the black race of African ancestry. Nigeria has one of the highest disease burdens with an SCT prevalence of 25%–30% and SCD prevalence of 2.28%–3%.1–3 Comparatively, the global prevalence estimates of SCD in Africa, Europe and the world were 1.12%, 0.04% and 0.11%.4

SCD is associated with chronic haemolytic anaemia, increased risk of infections, vaso-occlusive crisis and end-organ damage if poorly managed. One of the possible end-organs that can be damaged in this group of patients is the cochlea. A vaso-occlusive event affecting the end arterial supply of the cochlea can result in wide variations of hearing impairment, especially high-frequency sensorineural hearing loss (HL).5 Individuals with SCT are usually clinically stable given their heterozygous genetic formation but can develop vaso-occlusive crisis, under extreme conditions such as infections, dehydration and exercise. Occasional cases of HL resulting in SCT have been reported6 without detailed description, thereby leaving void in the association between SCT and HL.

SCD has also been reported to have a negative impact on the overall health-related quality of life (HRQoL).7–10 Given some adverse conditions that occur due to the patients’ trait status, SCT could also be inferred to impact negatively on HRQoL. There is a lack of research reporting on whether HL associated with SCD or SCT leads to additional negative impact on HRQoL of the individuals. This study will, therefore, investigate the impact of HL associated with SCD or SCT on HRQoL by comparing WHO Disability Assessment Schedule 2.0 (WHODAS) scores of patients with SCD or SCT associated HL versus those without HL. The result of this study may justify the call for routine hearing/auditory assessment of all patients with SCD and SCT, if the outcome confirms HL associated with the disease and trait resulting over time in these individuals.

Aim and objectives of the study

The primary aim of this study is to assess individuals with SCD and SCT for auditory impairments. Specific objectives of this aim include:

1. Determine the prevalence of hearing impairment in individuals with SCD and SCT and compare with age-matched and sex-matched normal (HbAA).

2. Characterise the hearing impairment associated with the various haemoglobin variants with respect to type, degree and symmetry.

3. Compare characteristics of hearing impairment among children and adults living with SCD/SCT.

4. Assess the predisposing factors associated with HL in SCD/SCT.

The secondary aim of this study is to evaluate the HRQoL of SCD and SCT individuals.

The specific objectives of the secondary aim include:

1. Assess HRQoL in individuals with SCD and SCT and compare with age-matched and sex-matched HbAA (control).

2. Assess HRQoL of SCD and SCT participants with auditory impairment and compare with SCD and SCT participants without auditory impairment.

Note: Specific objective #4 was added during peer review as a consequence of the discussion with the reviewers.

Study design

The Strengthening the Reporting of Observational Studies in Epidemiology statement: guidelines for reporting observational studies were followed in writing the manuscript11 (see online supplemental file 1).

This is a comparative cross-sectional study to investigate the association between SCD/SCT and hearing impairment. Cross-sectional study designs are best suited to provide estimates of prevalence of disease, assess traits of a disease; obtaining information in validation and reliability studies.12 The strength of this study design is the ability to collect all variables at once. However, it is limited in its ability to validly determine the sequence of outcome and exposure (ie, which precedes the other).12 Participants in this study will be divided into two broad groups cohort and control group. The cohort will consist of individuals diagnosed with SCD/SCT and the control group will be those with normal haemoglobin gene (HbAA).

Setting

Participants shall be recruited from the otorhinolaryngology, paediatrics, medical, haematology and sickle cell outpatient clinics of the University of Abuja Teaching Hospital (UATH), Nigeria. Ethical principles and Helsinski guidelines (see online supplemental file 2) shall be observed through the recruitment.13

The UATH is situated in Abuja, the federal capital of Nigeria, created in 1976 within the central region of Nigeria. Nigeria is a low-middle-income nation with maternal mortality ratio of about 814 per 100 000, infants and children under 5 years mortalities of 56.2 and 104 per 1000 live births respectively and overall life expectancy of 55.7 years.14 According to the patient headcount statistics at the UATH, about 20 patients with SCD/SCT are seen across the clinics weekly (1040 patients per year) which means that it is possible to recruit all the participants within the study period.

Abuja is a fair representation of the Nigerian population since it attracts migration of the citizens from every part of the country including cities and hinterlands. The inhabitants of Abuja are, therefore, from different ethnic groups in Nigeria who have migrated from their aboriginal homes. The population of Abuja has grown rapidly from about 170 000 in 1991 to a current estimate of 3.65 million thus making Abuja one of the fastest growing cities in world.15 This rapid growth was a result of the official movement of the capital city and seat of central government from Lagos to Abuja in 1995. The metro population of Gwagwalada, the district of Abuja housing the UATH (study site); has an area of 1043 km² and a population growth from 157.770 in 2006 to a current 475 000 in 2022.15 It is inhabited mainly by the middle and lower economic class. The hospital has a well-equipped audiology centre that is capable of providing a comprehensive audiological assessment (ie, pure tone audiometry, immittance and other electrophysiological tests) required for this study.

Participants

The participants will be volunteers attending the paediatrics, haematology, medicine and ear, nose and throat clinics of the UATH Abuja who met the inclusion criteria. The inclusion criteria for both the study and control groups are age 6 months old to 55 years, no previous episode of trauma to the head and neck area or exposure to loud noise, no present or history of use of ototoxic drugs and no history of neurological impairment. SCD and SCT participants who are on admission for vaso-occlusive crisis or those with active middle ear disease and/or known cases of diabetes mellitus or HIV/AIDS will be excluded from the study since they are possible confounders for HL. Patients’ medical records will be reviewed to compliment the information that will be obtained via the questionnaire.

Patient and public involvement in research

The patients (participants) shall be involved at the creation of awareness on the research (departmental presentations); assessment of level of comprehension of the questionnaires and also translation of the questionnaires to the local languages (Gbagi and Pidgin). The findings of this study will also be made available to the participants and the public.

Participants recruitment

Participants will be recruited by the research assistants employed specifically for this study. Recruitment strategy includes notices to be placed around the hospital clinics, direct communication with Heads of managers of relevant departments selected for the study, health talks before the commencement of clinics and one-to-one approach during the patients’ visits. Participants will be provided with the information relevant to the study to enable them to make informed decisions about participating in this study. Participants who agree to participate in this study will be requested to sign the study consent form to indicate their willingness to take part therein. Parents or legal guardians will be asked to sign the informed consent forms for their children and guide minors to sign assent where applicable. Oral assent will be sought from children aged 7–11 years and written assent from older children. Participants will be informed that their participation in the research is entirely voluntary and non-participation in this study will not affect their management in the clinics.

Sample size

The sample size for this study will be 212 participants comprising 106 individuals with SCD/SCT, and 106 HbAA individuals matched for age and sex. The sample size was determined using the minimum number per group of participants required for the study using the standard formula for sample size in a comparative study and setting the study power at 80%.16 To derive our sample size, we used prevalence data from a previously published local study on prevalence of sensorineural HL in SCD17 and control.18

N=sample size.

r=ratio of control to test, which is 1 for equal number of test and control.

p*=proportion of exposed cases plus proportion of control cases/2=0.57.

P₁=proportion in exposed cases=0.66.

P₂=proportion in control=0.47.

Z_β=standard normal variant for 80% power=0.84.

Z_α/2=standard normal variant, which corresponds to 95% confidence level=1.96.

Previous studies have had sample sizes ranging between 68 and 267 and were deemed to have sufficient power.20 Therefore, the proposed sample size of 212 for this study will be adequate. Furthermore, according to the patient headcount statistics at the UATH, about 20 patients with SCD/SCT are seen across the clinics weekly (1040 patients per year) which mean that it is possible to recruit all the participants within the study period.

Procedure (methods of measurements)

All of the participants (cohort and control groups) will undergo a comprehensive ear and hearing assessment comprising: otoscopy, tympanometry, speech audiometry (speech recognition threshold) and pure tone audiometry for participants who are 5 years old or older, while otoscopy, tympanometry and otoacoustic emissions (OAEs) and auditory brainstem response (ABR) (where indicated) for participants younger than 5 years old (figure 1). Furthermore, all participants/parents/legal guardians will be given the demographic and biodata questionnaire (online supplemental file 3) to personally complete in order to obtain information on the biodata. The haemoglobin status of patient and the clinical course of SCD/SCT shall be obtained through their medical records. The WHODAS will be used to assess the individuals’ self-reported HRQoL (S3). Children will be assessed by proxy (parents/legal guardians).

Figure 1

Flow chart of study recruitment pool. This flow chart illustrates the steps to be taken in the recruitment of participants(paediatrics and adults), and also the various audiological tests to be used for each group. SCD, sickle cell disease; SCT, sickle cell trait.

Outcomes measures

These are the essential tools that shall be used in measuring the variables, required for the analyses of results. These include:

• Audiological outcomes: PTA, tympanometry, OAES and ABR.

• Demographical biodata and information on haemoglobin status and exposure variables (risk factors) for auditory complication in SCD (S3-Questionnaire).

• HRQoL–WHODAS.

Data sources/management

Data management shall be in line with the University of Cape Town’s relevant policy.21 All the completed forms and results from diagnostic testing shall follow the administrative processes, will be validated, stored and locked in a secure cabinet in the researcher’s work office. The data shall be protected and processed throughout its life cycle ensuring that its accessibility and timeliness satisfy the needs of data users in accordance with the UCT’s Research data management guidelines. The data abstracted from the learner’s health and academic records will be managed using the REDCap database following guidelines provided in the Research Data Management Policy (2018).21 Data on the REDCap database will be online, password-protected and only accessible to the researchers, research supervisors and statisticians during the research’s life cycle. The data shall be kept for exclusive use of the researcher for maximum of 2 years postpublication before granting open access in line with the UCT policy.

The data will be entered manually into the excel spread sheet, cleaned of duplications structural errors and unwanted outliers. The entries with missing data shall be deleted and the cleaned data sets exported from the excel spread sheet and analysed using the Statistical Analysis System (SAS V.9.4). There will be no identifying information and the data shall be stored in password-protected and encrypted files, to protect the confidentiality and privacy of the data collected from the participants. The data analyses shall be performed.

Bias

Overview

To best of our knowledge, this will be the first study to explore SNHL and the HRQoL in both SCDs and SCTs across children and adults. Previous studies have investigated and documented the prevalence of HL in patients with SCD in Nigeria.5 17 18 20 24 However, there is lack of studies that reported on detailed characterisation of HL and HRQoL associated with SCD and SCT. The HRQoL is an important study component that will give insight on the impact of the HL associated with SCD and SCT on the individuals. Hence, this study will address the current gap in literature with respect to characterisation of hearing impairment in individuals with SCD and SCT as well as assessing the impact of hearing impairment on HRQoL of these individuals.

Uniqueness of the study design

Siting of the study: The strength of the study lies in the choice of Nigeria, which has one of the highest prevalence of SCD (2.28%–3%) and SCTs (20%–30%) in the world; as a study centre.17 18 24 25 This makes the research relevant to the environment and the participants. The recommendation following the outcome of the research shall most probably impact on Nigeria and countries with high prevalence of the SCD. Since this is fundamentally an African and Nigerian disease,1–3 the extrapolation of results of database from endowed societies like the African-American community may not be as representative as the Nigerian study due to the differences following natural selection in previous generation, ethnic and genetic admixtures, living environment and lifestyles.

Diverse sample (with respect to age range): Unique to our study will be the inclusion of young children, a population in which hearing impairment of any degree is known to have significant negative impact.4 7 The age limit of inclusion into the study can affect the overall outcome of the prevalence; hence, there is need for a combined study of children (including those under 6 years old) and adults within the study group in order to obtain a representative prevalence for HL among the SCDs and SCTs. The inclusion of children aged 6 months and above up to adults aged 55 years (to rule out influence of presbycusis) is desirable to ensure that no population group is missed. However, most previous studies focused on adults 18 years and above3 16 24–27 or children alone.17 28–30 The outcome of our study is also expected to contribute towards filling this void and therefore produce a more representative prevalence of HL across the general population. This outcome would also offer an opportunity to compare the prevalence in children and adults from a data obtained within the same population, study site and sample.

The investigations and external measurements

The investigations and external measurements emanating from this study will assist and contribute to the bases of pathophysiological course and the sequelae of SCD/SCT in children and adults.

Inclusion of SCD and SCT

The studies in Nigeria1–5 17–19 24 29 30 and elsewhere in Africa24–28 31 focused on the HL in SCD leaving out the SCT variants. Only one study outside Africa reported HL associated with SCT.6 Hence, our study design took an advantage of this vacuum to study SCDs and SCTs side by side. The outcome of our research shall assist in verifying whether individuals with SCT are vulnerable or predisposed to the development of sensorineural HL or not. This verification is important since the few studies that reported on SCT and HL outside Africa were also not conclusive. For instance, Burch-Sims and Matlock20 did not observe any impairment, although the number of participants was not stated, which is a methodological error. They observed that most severe form of hearing impairment (SNHL) was among the HbSS patients; thus, their study could not correlate hearing status with severity of SCT. Caroca and de Lima31 in São Tomé and Príncipe population observed no increase (control=34 vs test=20 cases) in the proportion of SCT participants with hearing impairment using PTA when compared with HbAA participants, and so they would not conclude that SCT predisposes to the development of hearing impairment. However, their study design was retrospective with multiple confounders.

HRQoL in SCD and SCT with hearing impairment

There is evidence that shows that SCD has a negative impact on HRQoL of the individuals.7 10 32 Research showed severe impairment in quality of life in patients with SCD across age groups including children, adolescents and adults.7–10 30 However, no research to the best of our knowledge has assessed the HRQoL in patients with SCD/SCT with associated HL. We anticipate that the combination of these two factors shall yield a high negative impact on overall HRQoL of the patients. Furthermore, if this is the case; it shall justify every public health measure to be instituted in order to prevent the coexistence of these two distressing conditions. Therefore, we expect that the result shall help the health policy makers in planning for early detection and management of SCD/SCT and its sequelae.

Choice of questionnaire

The type of questionnaire to be used in the assessment of the HRQoL for this study should be suitable to the mixed population (children, adults, educated and non-educated) and satisfactorily generate the information we are seeking to obtain. The search for an easily comprehensible questionnaire, non-voluminous to encourage compliance of participants and also containing the relevant questions led to the choice of WHODAS 2.0 questionnaire.32 WHODAS 2.0 is a generic assessment instrument developed by WHO to provide a standardised method for measuring health and disability across cultures. WHODAS 2.0 was developed from a comprehensive set of International Classification of Functioning, Disability and Health items that are sufficiently reliable and sensitive to measure the difference made by a given intervention. The WHODAS 2.0 passed the readability (table 1), validity and reliability tests (table 2). The questionnaires are self-administered and for participants who may not understand English language a translated version into Gbagi and pidgin languages shall be administered. The assessment of the HRQoL of children shall be done by proxy(through the parents or legal guardians). Series of systematic field studies were used to determine the cross-cultural applicability, reliability, validity and the utility in health services research.33 The outcome for the pretest on this questionnaire was good (positive response rate 98%), and therefore, it was confirmed to be a suitable tool for this assessment.

Audiometric assessment (PTA, tympanometry, OAE and ABR)

PTA, OAE and ABR are standard tests used in HL assessment.34 Their specificity and sensitivity differ in comparison with a comprehensive audiogram conducted by an audiologist as the ‘gold standard’. Sabo et al34 observed a sensitivity and specificity of 87% and 80% for PTA, as compared with 65% and 91%, respectively, for OAE. A systematic review of eight diagnostic studies comparing OAE with ABR as hearing screening tools in newborn revealed sensitivity and specificity of 50% and 49.1% for OAE and 100% and 97.2% for ABR, respectively.35 Tympanometry helps to detect middle ear disorders.

Hence, these tools are appropriate for the measurements they are set for in this research.

Supports

Voluntarism from the staff of University of Abuja and UATH will be very encouraging and shall create a sense of ownership to the departments selected for the study. The Institutional Based Tertiary Education Trust Fund (TETFUND) Research Grant awarded to us in support of this project shall assist partly in the execution of the project. The otorhinolaryngology departmental staff will also be available to help with the logistics especially secretarial and printing of documents.

Limitation of study

Longitudinal over cross-sectional study would have given a more contact period for comprehensive study of the hearing impairment in this study but for the time limitation of my programme. However, a follow-up longitudinal study could be done afterwards.

Anticipated outcome/generalisability

The result of the pilot phase of the study has shown that the protocol is implementable and the objective achievable. The readability and reliability tests conducted on both the test and control groups were satisfactory as shown in tables 1 and 2. This SCD and SCT study is a response to a genetic disorder that predominantly affects people of African descent in part of Africa with the highest incidence. The challenges associated with the current research shall be surmounted to advance human knowledge in this area.