Japanese and French translation and linguistic validation of a patient-reported outcome tool to assess quality of life in patients with Immune Thrombocytopenia (ITP): the ITP Life Quality Index (ILQI)

Objectives The Immune Thrombocytopenia (ITP) Life Quality Index (ILQI) is a 10-item patient-reported outcome (PRO) measure developed in US-English to assess health-related quality of life (HRQoL) of adults with ITP. Analysis of ILQI responses indicated differences between Western and non-Western countries. The objective of this study was to translate and linguistically validate the ILQI for Japan and France. Methods The ILQI underwent dual forwards/backwards translation with reconciliation and resolution. The translations were reviewed prior to conducting cognitive interviews with ITP patients (n = 5 Japan, n = 5 France). Analysis of interview transcripts highlighted required modifications to the ILQI translations. Japanese and French ITP experts reviewed the final translations for cultural relevance and appropriateness. Results Most of the Japanese and French forward/backwards translations were reconciled with no revision. The ILQI instructions and items were well understood by Japanese and French participants. Wording in one item of the Japanese version of the ILQI was revised to better align with the source instrument. Three terms/phrases in the French translation were revised due to misunderstanding, being deemed inaccurate or culturally inappropriate. Following review by ITP experts from Japan and France, minor modifications were made. Conclusion Findings confirm the linguistic validity of the ILQI in Japanese and French.


Introduction
The Immune Thrombocytopenia (ITP) Life Quality Index (ILQI) is a 10-item patient-reported outcome (PRO) measure developed to assess health-related quality of life (HRQoL) of adult patients with ITP. The ILQI was developed to aid discussions between patients and clinicians and to inform treatment decisions. It is intended to be used as a tool in clinical practice to assess changes in HRQoL over time.
Clinical assessments of ITP severity often focus on platelet counts and risk of bleeding and do not always consider the patient's quality of life [1]. Patients with ITP who do not bleed with low platelet counts, or who have sufficient counts to prevent frequent bleeding, may still experience significant impaired quality of life and have unmet needs [2]. The ILQI was developed to specifically target these patients and assess their quality of life.
The ILQI has relatively short instructions, which ask the patient to think about the ways ITP has affected their quality of life over the past month. All items employ a 4-point verbal rating scale (VRS) of 'never, sometimes, more than half of the time and all of the time'. Items 1 and 2, which evaluate impacts on work/studying, include two additional response options to capture patients who are either 'not working/ studying due to ITP' or 'not working/studying due to other reasons'; item 5, which evaluates impacts on 'sex life' also includes a 'not applicable/prefer not to say' response option. The ILQI is a unidimensional scale, and a total score is calculated by adding each of the ten individual item scores. A minimum score of 7 is derived by patients answering at the lower end of the scale for every question in addition to also selecting 'I am not working/studying due to other reasons' for items 1 and 2 and answering 'not applicable/ prefer not to say' to item 5 ('sex life'). A maximum score of 40 is derived by patients answering at the higher end of the scale for every question. A higher score represents a greater impact on HRQoL. Cut points have been established whereby a total score of 17 suggests "impaired HRQoL" and a total score of 23-25 suggests "significantly impaired HRQoL". A total score can be calculated with a maximum of three missing items.
The ILQI was originally developed in English by clinical experts in the field of ITP and content validity was confirmed by conducting individual qualitative interviews with 15 adult patients in the UK [3]. The ILQI was cognitively debriefed with ITP patients and items refined following qualitative analysis and additional clinical input. This qualitative work supported the content validity of the ILQI and confirmed that the concepts assessed are relevant and consistently understood and interpreted by adult patients with ITP [4]. The ILQI was then included in the ITP World Impact Survey (I-WISh), a global observational survey which collected data on the impact of ITP on 1507 patients' HRQoL and collected data on physicians' perceptions on using the ILQI in clinical practice [5,6]. These findings confirmed the psychometric properties of the ILQI, specifically the validity and reliability of the ILQI to assess HRQoL, and confirmed the ILQI had good measurement properties [7]. The cut-off scores derived from the psychometric analysis helped to optimally discriminate between severity groups and aid patient-centered treatment decision making between patients and physicians. The English version of the ILQI is presented in Fig. 1.
The I-WISh included ITP patients from 13 different countries globally (USA, China, UK, France, Germany, Italy, India, Canada, Turkey, Japan, Colombia, Spain and Egypt), however, the aim of the survey was to primarily assess the psychometric properties of the ILQI and only one analysis was conducted to assess any differences between countries. Differential item functioning (DIF) was conducted to assess whether patients in one country answered each item in a similar way to the overall cohort of patients, stratified by disease severity [8,9]. This analysis indicated large differences in the way patients from the USA and patients from non-Western countries (including Japan) answered most items in the ILQI.
From 2009 to 2011, ITP incidence rate in France was 2.9/100,000/year, with peaks among children and those over 60 years of age [10]. From 2004 to 2007, an overall incidence rate of ITP in Japan was 2.16/100,000/year, suggesting it is not markedly different from that of European countries [11]. The incidence rates highlight the need for a reliable and culturally appropriate assessment of HRQoL in ITP, for use in clinical practice in both Japan and France.
The primary aim of this study is to translate and linguistically validate the ILQI, using established methods, to maintain the validity when used in Japan. A secondary aim is to maintain the validity of the ILQI when used in France.

Materials and methods
The ILQI was translated into Japanese for Japan and French for France following guidance from the World Health Organisation (WHO) and the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) [12,13]. Translation certificates are available to confirm the validity of each translation. The Japanese and French versions of the ILQI were also subject to linguistic validation analyses. The process workflow involved in the translation and linguistic validation is presented in Table 1.

Forward and backward translations and reconciliations
The detailed results from the forward and backwards translations and reconciliations for the translation of the ILQI into Japanese for Japan, and French for France, are presented in Tables 2 and 3, respectively. The ILQI was separated into the individual instructions, items, response options and scoring instructions. For each sentence/item, the key concepts were defined by providing a list of alternative words/terms with the same meaning, to aid interpretation and help to ensure an accurate translation. For example, the alternative words/terms for the concept of 'aim', which is included in the ILQI instruction, included 'goal', 'intent' and 'purpose'. Each sentence/item then underwent forwards and backwards translation and reconciliation. Any revisions suggested by the developer or the linguists were noted and reconciled.

3
For most of the sentences/items in the ILQI, the forward and backwards translations into Japanese and French were reconciled with no revision needed. Full details of each step of the translation process for the Japanese version of the ILQI are presented in Table 2. Resolution reasoning was needed for the following Japanese translations: • For the ILQI instructions, 'how much' was back translated as 'the degree' as this more accurately reflected the source instrument. Resolution reasoning confirmed that no revision was needed as the translation accurately conveyed the same meaning. In the second sentence of the ILQI instructions, the forward translation of 'the aim' had to be revised by removing any reference to 'another' and no further revisions were needed. • For ILQI item 1, the back translation was revised to clarify the meaning of 'studies' as being different to 'schoolwork' and no further revisions were needed. • The developer review raised concern that the response options 'majority of the time' was not a direct translation of 'more than half of the time'. Linguistic feedback confirmed that the language was revised to use a more literal translation. • For IQLI item 2, the back translation of 'skip work or school' was revised to 'take time off work or school' and no further revisions were needed. • For ILQI item 3, resolution reasoning identified a difference in the tense between the source instrument and forward translation, which was revised. The concept of 'work' was included in the back translation of 'everyday tasks' which was removed following the developer review to ensure the item was relevant to those patients who were not working. • For ILQI item 7, the back translation identified a difference between the use of singular or plural version of 'task/s' between the source instrument and the translation, however, resolution reasoning confirmed no revision was needed. • For ILQI item 8, the forward translation was revised to ensure the term 'close' conveyed emotional closeness rather than physical closeness. • For ILQI item 9, resolution reasoning confirmed that the difference between the use of the singular or plural version of 'hobby/hobbies' did not require any revisions.
• For ILQI item 10, the back translation suggested that 'exercise' had been translated as 'motor ability', which although still represents a similar concept, the wording was revised to more closely reflect the term 'exercise', used in the source instrument. • The translation of the scoring thresholds were revised to reflect the source instrument more closely. For example, following developer review and linguistic feedback, 'impediments' was changed to 'diminishment' and 'considerable' changed to 'significant.' Full details relating to each step of the translation process for the French version of the ILQI are presented in Table 3. Resolution reasoning was needed with the following French translations: • For the ILQI instructions, the back translation of 'aim' differed between sentences, with one using the term 'goal' and the other using the term 'objective'. Resolution reasoning confirmed that the translations were both correct based on the context and meaning of the source instrument and no revisions were needed.  Two separate native-speaking linguists from Japan and two native-speaking linguists from France  were provided with the US-English version of the ILQI and independently performed forward  translations, aiming for conceptual equivalence to the source instrument and cultural appropriateness for the target countries  Reconciliation A third independent, native-speaking linguist from Japan and another from France compared the two forward translations, identifying any discrepancies or cultural differences to create a unified Japanese translation and a unified French translation Back translation and resolution A native-English speaking linguist with fluency in Japanese and another with fluency in French, translated the reconciled ILQI back into US-English using only the forward translation as source material Resolution of Back and Forward Translation A team consisting of native-speaking linguists fluent in Japanese or French and English resolved any discrepancies between the forward translation, back translation and original US-English version of the ILQI Developer review The reconciled forward and back translations of the Japanese and French ILQI were provided to the ILQI developers for review and comments were assessed by the linguistic teams from each country Cognitive interviewing with patients Qualitative interviews were conducted with five pre-screened respondents from Japan and five pre-screened respondents from France, who were representative of the ITP patient population, to test the translated versions of the ILQI. Of note, due to the rarity of ITP, the participants included in the cognitive interviewing were not diagnosed with ITP, but were diagnosed with a representative condition, for which the items on the ILQI were relevant. The aim of the interviews was to evaluate understanding of the translated ILQI. Updates were made to improve clarity and readability in the target language and to confirm consistency of understanding with the intended meaning Review by ITP experts The translated and linguistically validated Japanese and French versions of the ILQI were reviewed by one ITP expert from France and Japan respectively, to further assess cultural relevance. Experts were selected based on their ITP expertise and clinical experience and interest in PRO development Concept states that "more than half the time" = the majority of the time", however, the FT and BT are revised to use a more literal translation "how often" = how frequently "ITP" = immune thrombocytopenia "impacted" = affected "to concentrate" = to focus your attention "everyday tasks" = common tasks; tasks that are typically part of everyday life "task" = piece of work to be done or undertaken; duty; chore によって、どのくらいの頻 度で日常作業を行う際 の集中力に影響があり

ましたか
How often did ITP impact your concentration when you do your daily work/task?
The FT has been revised to reflect the source, perfect tense "has." The BT has been revised to reflect the updated FT and for consistent tense of "to do." Could we remove the mention of work from this item to ensure it is still relevant for those patients not working "Work" is removed from BT. No revision needed in FT "how often" = how frequently "ITP" = immune thrombocytopenia "impacted" = affected "undertaking of" = taking part in; engagement in; management of "daily" = every day; on a daily basis "task" = piece of work to be done or undertaken; duty; chore によって、どのくらいの頻 度で日常作業の遂行 に影響がありましたか? How often did ITP impact the performance of your daily work/task?
Although the source uses the plural form "tasks," it has been confirmed that no revision is needed to the FT. The BT has been updated from singular "task" to plural "tasks." Again, can we remove the mention of work to make sure it is relevant to all patients "Work" is removed from BT. No revision needed in FT ILQI ITEM 8 How often has your ITP impacted your ability to support people close to you?
"how often" = how frequently "ITP" = immune thrombocytopenia "impacted" = affected "to support people close to you" = to provide emotional support to people that are close to you (close friends, family, etc.)

によって、どのくらいの頻 度で周りの人を手助け する能力に影響があり ましたか?
How often did ITP impact your ability to help people around you?
The FT has been revised to better reflect the source "close" in order to convey emotional connection rather than physical location. The BT has been revised to reflect the updated FT and to use "support" rather than "help" to clarify the meaning conveyed in the source and FT Although the source uses the plural form "hobbies," it has been confirmed that no revision is needed to the FT. The BT has been updated from singular "hobby" to plural "hobbies."

No revision needed
No revision needed The key below provides explanation of each score 解答: Answer: The FT has been revised to reflect the meaning of the source. The BT has been revised to reflect the updated FT

No revision needed
No revision needed Never = 1, Sometimes = 2, More than half of the time = 3, All the time = 4, "never" = not ever; at no point "sometimes" = from time to time; on occasion "more than half the time" = the majority of the time "all the time" = constantly; at all times "due to" = because of; as a result of "ITP" = immune thrombocytopenia Never = 1, Sometimes = 2, Majority of time = 3, Always = 4 No revision is needed Can you confirm that considerable and significant are a direct translation and are comparable?
"Impediments" is revised to "diminishment" in the FT and BT. "Considerable" is revised to "significant" in BT.

No additional revision needed in FT
Score of 30 or above suggests severely impaired quality of life "or above" = or higher "severely" = seriously "impaired" = negatively impacted; diminished "quality of life" = the standard of health, comfort, and happi- "Impediments" is revised to "diminishment" in the FT and BT "how often" = how frequently "ITP" = immune thrombocytopenia "impacted" = affected "undertaking of" = taking part in; engagement in; management of "daily" = every day; on a daily basis "task" = piece of work to be done or undertaken; duty; chore À quelle fréquence votre TPI a-t-elle eu un impact sur la réalisation de vos tâches quotidiennes ?
How frequently has your ITP had an impact upon the performance of your daily tasks?

No revision needed
No revision needed

Cognitive interviews with Japanese and French patients
Following the forward and backwards translations, developer review, linguistic feedback and resolution reasoning, the Japanese and French versions of the ILQI were updated. The revised versions were tested in cognitive interviews with five Japanese participants and five French participants, to assess level of understanding and readability of the translated instrument. The demographic characteristics of the participants are presented in Table 4. All interviews were conducted in October and November 2020. The Japanese participants were 40-65 years old, with a mean age of 51 years. Three of the five participants were female and the majority (4/5 participants) had between 14 and 16 years of education. All Japanese participants had been diagnosed with blood clots, with length of diagnosis ranging from 3 to 21 years and a mean diagnosis of 10 years. The French participants were 33-74 years old, with a mean age of 57 years (similar to the Japanese participants). Three of the five participants were female, and all had at least 9 years of education. Four of the five French participants were diagnosed with phlebitis and all participants had been diagnosed with their respective condition for 1 year.
The results of the cognitive debriefing interviews for the Japanese ILQI are presented in Table 5 and results of the cognitive debriefing of the French ILQI are presented in Table 6. Most of the instructions and items of the ILQI were well understood by both the Japanese and French participants and no issues were reported.
Linguistic feedback and input was required for the following Japanese translations: • While all Japanese participants appeared to understand ILQI item 10, review of their paraphrasing suggested that all participants thought this item was referring to general movement ability rather than exercise. The item wording was revised to better align with the source instrument and relevance confirmed with forward and backwards translations.
Linguistic feedback and input was required for the following French translations: • Despite two participants reporting some problems with the term 'indice' in the title of the ILQI, linguistic feedback confirmed that this term accurately reflects the source instrument and the participants were able to understand the overall meaning of the title. • 4/5 French participants misunderstood the translation of 'standardise', therefore, the forward and backwards translations were revised to clarify this misunderstanding. • 3/5 French participants reported that the term 'jours de repos', in ILQI item 2, was not a true reflection of 'take time off work'. Item wording was revised, and final forward and backwards translations reflect the source instrument. • 3/5 French participants reported that the term 'normal', used in ILQI item 10 can sound judgemental in French and suggested replacing this with a translation of 'usual'. The item wording was revised, and translation confirmed with final forward and backwards translation.

Review by ITP experts
The final step in the linguistic validation process was the review of the translated and cognitively debriefed ILQI by experts in the field of ITP, from Japan and France. While the French ITP expert did not suggest any fundamental changes to the ILQI, some modifications were made to simplify the questions for the patients. Similarly, the Japanese ITP expert did not make any changes to the content of the ILQI but rather modified and softened some of the language to make the Japanese version more culturally appropriate for Japanese patients. The final versions were proof-read by the linguistic experts and proof-reading certificates were issued to confirm that the changes made by the French and Japanese  experts did not change the translations and linguistic validation work conducted to date.

Discussion
As the clinical assessments of ITP often focus on platelet counts and risk of bleeding, there was an unmet need for a valid and reliable PRO assessment to focus on the underreported HRQoL impacts associated with ITP. The ILQI was developed to address this unmet need and the US-English version has been rigorously developed according to regulatory guidance and has demonstrated good content validity and psychometric properties. To ensure the ILQI could be administered as a tool for clinical practice in Japan and France, it was necessary for the ILQI to be translated and undergo the linguistic validation process. Findings from the DIF, conducted as part of the psychometric analyses, identified differences in the way patients from the USA and patients from non-Western countries (including Japan) answered most items on the ILQI. This highlighted that further translational work and linguistic validation work was needed to ensure the ILQI was appropriate and culturally relevant to be used as a tool for clinical practice in Japan. Additionally, while the DIF confirmed that patients with ITP in France answered most items in a similar way to the patients with ITP in the USA, to have confidence that the ILQI is suitable for use in clinical practice in France, it was also necessary to conduct full linguistic validation analysis on the French version of the ILQI. The ILQI was translated and linguistically validated in accordance with the best practice guidelines, according to the ISPOR Task Force.
As expected, the linguistic validation process identified words or phrases that were not interpreted as intended and subtle changes were made to both the French and Japanese versions of the ILQI to improve understanding and cultural relevance. The final versions of the translated and linguistically validated Japanese ILQI is presented in Fig. 2 and final version of the French ILQI is presented in Fig. 3.
While the validation was conducted in accordance with best practice guidelines, there are some limitations of this study which need to be considered. The cognitive interviews were conducted with only five patients from each county; while, a larger sample size may have provided more evidence to support the understanding of the items and instructions, it is noted that according to the COSMIN group, a sample size of 4-6 is considered to be adequate, a sample size of ≥ 7 is considered to be very good [14]. Also, while all patients were diagnosed with a hematological condition, none of the patients were diagnosed specifically with ITP and, therefore, conducting more cognitive interviews with patients diagnosed with ITP would provide further support for the cultural validity of the ILQI. Future work should rewording ("they want to have an overall idea of how ITP affects life") clearly shows the intended meaning was not understood properly The misunderstanding by the majority of respondents is most likely due to the fact that "standardiser" in French means "make sure something comes in conformity with a set standard" (i.e. in this context, make all persons experience the disease in the same way). It cannot mean "regulate" as in "avoid ups and downs" for one given person. The FT and BT have been revised to clarify the source meaning of "standardise" in the FT Le but est d'essayer de réguler l'impact de la TPI sur votre vie, en dehors des saignements   said it sounded "judgmental". In French, "normal" has a "normative" connotation. They all suggested "usual" instead The suggested change by the respondents to use "usual" would be a better option as it would refer to the usual capacity of a person to exercise, and would avoid the idea of a judgement as to what is normal and what is not. The FT and BT are revised Although not mentioned by any respondents during the interviews, it should be noted that "faire du sport" in French does not include low intensity exercise like walking, for example. Since many people, depending on the severity of the disease, may be able to go out for a walk but may be totally unable to "play sports" (i.e. a certain degree of intensity) the FT is also revised to use a more literal translation for "exercise" which could include any intensity level. No revision to the BT for this latter change À quelle fréquence votre TPI a-t-elle eu un impact négatif sur votre capacité habituelle à faire de l'exercice ? How frequently has your ITP had a negative impact upon your usual ability to exercise? focus on conducting linguistic validation analysis in other countries, to ensure the ILQI is appropriate for use in clinical practice in other countries, in addition to the UK/USA, Japan and France.
In conclusion, the ILQI is ready and available for use in clinical practice in the UK/USA, Japan and France and content validity, psychometric validity and linguistic validity have been confirmed. Implementing the ILQI into clinical practice across different countries should help to aid discussions between patients and clinicians, inform treatment decisions and improve the overall HRQoL, comprehensively reflecting experiences of demographically diverse patients with ITP. included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.