Study overview
This study consisted of two parts as shown in Fig. 1. Part 1 was comprised of in-depth, semi-structured, qualitative telephone interviews involving individuals with SMA and caregivers from the US, between November 2019 and January 2020. Part 2 consisted of an online survey completed by a larger sample of individuals with SMA and caregivers from Canada, France, Germany, Italy, Poland, Spain, the US and the UK, between February 2020 and April 2020. Ethical approval and oversight of the qualitative interview study was provided by Copernicus Group Independent Review Board (IRB), a centralized IRB in the US (approval reference number IRB 20192527). The online survey content included a reduced set of questions from the qualitative interviews. The online survey was conducted following principles consistent with British Healthcare Business Intelligence Association guidelines for Adverse Event reporting and General Data Protection Regulation guidelines, which are applicable to all countries. Participants in both parts of the study were individuals or caregivers of individuals with a self-reported genetic diagnosis of either Type 2, non-ambulant (unable to walk unaided [without braces, assistive devices or person/hand-held assistance] for 10 m or more) or ambulant (can walk at least 10 m unaided) Type 3 SMA.
Overview of interview resources relating to the MFM32
The MFM32 measure is comprised of 32 items that assess a range of different motor functional abilities across three functional domains: standing and transfers (D1: 13 items), axial and proximal motor function (D2: 12 items) and distal motor function (D3: 7 items) [10]. These domains assess a broad spectrum of abilities including gross and distal motor functioning of the upper and lower limbs. Each MFM32 item is scored on a 4-point Likert scale from 0 (cannot initiate the task) to 3 (performs the task fully). Item scores are summed, and the raw score is transformed to an overall total score ranging from 0 (severe functional impairment) to 100 (no functional impairment). As part of both the qualitative interview study and the quantitative online survey, eligible participants completed a patient-friendly version of the MFM32 to obtain insights into the perceived level of physical function of the individual with SMA. This patient-friendly version of the MFM32 was developed based on the ‘task to perform’ terminology in the MFM User Manual [18] input from clinical experts and patient advocacy groups. The items of the validated clinician-reported version of the MFM32 were reworded into patient-friendly language by reducing clinical terminology, while maintaining focus on the specific ability assessed by each item in the clinician-reported version. The purpose of the patient-friendly MFM32 was to facilitate participant understanding of the motor function abilities associated with each item of the clinical scale to allow discussion with participants about their perception of how the abilities assessed by the MFM32 items could be related to ADLs.
Since the MFM32 items were not administered to participants using the exact clinical language used in the validated clinician-reported version but instead were modified to ensure patient understanding, they are referred to throughout this manuscript as ‘patient-friendly MFM32’ items. For example:
Item 14 - validated clinician-reported MFM32 item: Seated on the chair or in the wheelchair, head in flexion: from head in complete flexion, raises the head then maintains it raised for 5 s, the head stays in midline position throughout the movement and holding position.
Item 14 - patient-friendly MFM32 item: When seated and looking at the floor, can you lift your head up and keep it lifted for 5 s?
The patient-friendly version of the MFM32 items were also reordered, based on prior Rasch measurement theory analyses, by increasing level of difficulty to allow exploration of the items most relevant to the individual’s current level of functioning. For the qualitative interviews, the 4-point Likert scale (0–3) of the MFM32 was retained and response options were written in patient-friendly language. Further, the maximal ability was assessed for each item, and intermediate abilities associated with specific scores were not captured as in the validated version of the MFM32. Patient-friendly response options for the qualitative interviews were as follows:
0: Unable to start the ability.
1: Able to start the ability but not able to finish it.
2: Performs the ability but with some help, slowly, without complete control or cannot hold it for long.
3: Performs the ability fully.
For the quantitative online survey, the response options were collapsed to “can do (either partially or fully)” and “cannot do”, given that it would not be possible to provide additional clarification to participants or to confirm understanding of more granular response options, if required. Similarly, based on patient advocacy group feedback, some of the patient-friendly MFM32 items were simplified further for the survey in order to be confident that interpretation of the concept would be consistent in the context of the online administration. The patient-friendly MFM32 item and the equivalent clinical item wording are presented in Supplementary Table 1.
Part 1: qualitative interview study
Overview
Participants were identified in collaboration with Cure SMA (a patient advocacy group in the US) and Rare Patient Voice (a non-profit organization that manages patient/caregiver panels) who advertised the study to their SMA communities. Written informed consent to participate was obtained prior to scheduling a telephone interview. Semi-structured telephone interviews were conducted with participants by trained qualitative interviewers in English (the participants’ first language). Interviews aimed to explore the content validity and relevance of the abilities assessed by the patient-friendly MFM32 items to daily activities important to individuals with SMA. Participants enrolled were caregivers of individuals 2 years and older and patients 18 years and older, given the potential complexity of the questions asked in relation to the MFM32 and given the lack of available visualizations of the MFM32 items, which would have been important to facilitate discussion with participants younger than 18 years old. The interview guides used with caregivers of individuals 2 years and older and patients 18 years and older can be viewed in Supplementary File 1 and 2, respectively.
Interview procedure
Responses on the patient-friendly version of the MFM32, which was completed prior to the interviews, were used to inform the order of questioning during the interviews. Firstly, for all patient-friendly MFM32 items in which the individual with SMA scored a maximum score of 3 (performs the ability fully), participants were asked: 1) “Tell me about things that you do/the individual with SMA does in your/his/her daily life that involve this movement/ability?” and 2) “Is this an important ability for you/him/her to be able to do? Why/why not?”. Time permitting, participants were also asked these questions in relation to the patient-friendly MFM32 items that the individual with SMA scored a 2, 1 and 0 on.
Data analysis
All interviews were audio recorded and transcribed verbatim. The verbatim transcripts were analyzed using thematic analysis methods and ATLAS. Ti software [19]. Thematic analysis is a foundational, theory-free, qualitative analysis method, which offers flexibility to provide a rich, detailed and complex synthesis of data that meets a very specific and applied aim [20, 21]. An induction-abduction approach was taken to identifying themes in the data where themes were identified both by topics emerging directly from the data (inductive inference) and by applying prior knowledge (abductive inference) [22]. This enabled the analysis to remain rooted in the data, allowing participants to identify areas of importance for them, but also to take into consideration prior knowledge. After analyzing each transcript, a list of participant verbatim statements was generated for each coding domain. Concept frequency was determined by counting the number of participants who mentioned a concept (ADL), at least once, during the interview. However, given that not all patient-friendly MFM32 items were discussed with every participant, conceptual saturation analysis could not be performed. Systematic subgroup analysis for SMA type, age and participant respondent (i.e., patient versus caregiver) was not possible due to the small sample size. However, key themes relating to the type of ADLs that were considered relevant were explored and any examples of participants reporting items not being related to ADLs were extracted.
Part 2: quantitative online survey
Overview
Participants eligible to take part in the survey were identified in collaboration with international patient advocacy groups, namely SMA UK, PatientenStimme SMA (Germany), Famiglie SMA (Italy), FundAME (Spain), Fundacja SMA (Poland), AFM Telethon (France) and CureSMA (US and Canada). Patient/caregiver panels were also used to supplement participant identification where necessary. Participants were sent a link to the quantitative online survey which had been translated into their local language and contained an electronic informed consent form where participants completed a tick box indicating consent to participate prior to survey completion. The online survey can be viewed in Supplementary File 3.
Survey procedure
As part of the survey, participants were presented in turn with each of the patient-friendly MFM32 items. For each patient-friendly MFM32 item where the response, “can do” was selected, participants were first asked to select any ADLs they considered to be related to the item from a pre-specified list of options. This list of options was developed based on the most frequently reported specific ADLs in the first 10 qualitative interviews. Participants were also presented with an open text field for each patient-friendly MFM32 item in which they could write in any additional ADLs which they considered relevant to the ability not listed in the pre-defined options. Participants also had the option of not selecting an ADL and moving to the next question. Secondly, for the first three patient-friendly MFM32 items where the participants responded “cannot do”, participants were asked to select reasons why some improvement in the ability assessed by the patient-friendly MFM32 item would be considered important. These reasons were from a list of pre-specified options based on the first 10 qualitative interviews. Participants were also presented with an open text field for each patient-friendly MFM32 item in which they could write in any other reasons for importance. However, once a participant selected “cannot do” for five consecutive items, this section of the survey was terminated to avoid asking questions that were not relevant to the individual’s current functional ability.
Participants were also asked to select from a pre-defined list of other symptoms or impacts of SMA that would be important to maintain or improve which were not measured by motor function assessments such as the MFM32. The pre-defined list of options developed by clinical experts and patient advocacy groups were: level of fatigue/lack of energy (tiredness), level of endurance (ability to carry out tasks for longer), voice (tone, pitch, volume), clarity of speech, difficulty sleeping, pain and tremors. Participants were also given the option to specify additional symptoms/impacts by selecting the “other” response option.
Data analysis
Survey results were analyzed using PowerBI [23] software whereby concept (ADL) frequency was determined by the number of participants who selected each response option or reported an ADL in the open text field. Due to the number of subgroups by age (5), type (3) and country (8) in the quantitative online survey leading to a wide range in the number of respondents per patient-friendly MFM32 item; therefore, a systematic subgroup comparison was not conducted. Instead, general themes by subgroup were evaluated relating to any obvious differences in the specific ADLs associated with the patient-friendly MFM32 item, and individual item response rates were explored in order to assess the average non-response rate.