<div>4.Discussion</div><div>This is the first systematic review of the suitability of HRQOL
questionnaires used to assess primary biliary cholangitis, with the goal
to provide evidence for clinicians and researchers concerning its use
within clinical practice and research. We explored the suitability of
these instruments through their psychometric properties and their
content. There are 15 HRQOL questionnaires currently available.</div><div>First, this review found that a high degree of heterogeneity in HRQOL
used instruments in the primary biliary cholangitis studies: fifteen
different types of instruments were used in forty-four included
articles. Among these forty-four included articles, only three articles
were randomized and among non-randomized controlled trials, only eight
assessed HRQOL as a primary endpoint. This finding shows that the
relevance of HRQOL is not fully recognized in primary biliary
cholangitis studies. If we consider observational studies, few studies
were longitudinal; the others were cross-sectional with no possibility
of exploring a change over time.</div><div>Many studies used translated HRQOL questionnaires. While there were good
examples of translated validity in PBC-40, there were many studies where
this procedure was either not conducted or reported. It is essential
that HRQOL questionnaires are translated and validated using well
recognized and standardized procedures to ensure that they are
appropriately adapted to accommodate cultural differences. Since one’s
functional status, such as language barriers, quality of education,
literacy level will have a direct effect on HRQOL scores. Strenthening
investigators’ ability to interpret results and formulating clinically
relevant conclusions when using HRQOL questionnaire will ameliorate
variability of scores. Inductive method was performed to assess
psychometric properties of instruments in this review, minimal important
difference, responsiveness and floor/ceiling effects, test-rest
reliability, internal consistency (Cronbach’s alpha) and various forms
of construct validity (convergent, content and concurrent ) were
assessed. Except PBC-10, no other questionnaire provides complete
psychometric validation in patients with PBC. Another common problem of
most studies was that no sample size calculation was provided, which
offers stronger implications on validity.</div><div>Our review highlights the questionnaire options available, reminding
researchers should take into account psychometric properties and content
when choose which HRQOL is the most appropriate to use in primary
biliary cholangitis. The PBC-40 was the most widely studied
questionnaire, with most extensive psychometric evaluation, which is the
first disease-specific HRQOL assessment tool for PBC patients.
Cronbach’s α scores in all six domains were above 0.7, three of the
domains (fatigue, cognitive, and itch) met the recommended minimum of
0.7 for individual patient comparisons. Test-retest reliability scores
were above 0.8<sup>[17]</sup>. PBC-40 is a good choice for a
research study if extensive experience of use of an HRQOL questionnaire
is important. Its disadvantage is that it is too lengthy and time
consuming to use in the normal clinical practice. The next most commonly
used tool was the SF-36. Of generic quality of life questionnaires, the
SF-36 performed best in terms of internal consistency and test-retest
reliability. Though SF-36 provides a generic HRQOL assessment tool, it
is less sensitive to impairments in HRQOL caused by pruritus and did not
explore the quality of sleep and quality of wake
domains<sup>[29, 30]</sup>. Briefer tools with simplified
scoring for use in the clinical and research settings are needed
urgently. The PBC-27 is one such example, which was shown to be equally
effective in detecting the impact of PBC on HRQOL. However, the PBC-27
has potential language problems, since its original version was
developed for use in Italian and Japanese patients with primary biliary
cirrhosis<sup>[12]</sup>. Evaluations of PBC-27 in Poland
were performed after translating it into
Polish<sup>[31]</sup>. Thus, the PBC-27 requires testing of
its measurement stability for the different language versions. Another
short HRQL questionnaire, PBC-10, had good internal consistency
(Cronbach’s α 0.905) and test-retest reliability. PBC‐10 demonstrated no
ceiling effects but a floor effect was noted, which requires further
study<sup>[15]</sup>. The CLDQ, a liver disease-specific
HRQOL questionnaire, was developed to measure longitudinal change in
individuals with chronic liver disease, although it didn’t cover
pruritus and fatigue domains in PBC patients well<sup>[32,
33]</sup>. The CLDQ-I(CLDQ Italy vision) and LDSI 2.0 are liver
disease-specific HRQOL questionnaires. However, the LDSI 2.0 lacks
comprehensiveness as a QOL instrument in terms of emotional
well-being/emotional functioning and, if used, should be used in
conjunction with other measures of well-being. The SF-12, 15D, NIDDK
LTD-QOL, NIDDK-QA, HUI-Mark-2, HUI-Mark-3, NHP, NHANES Ⅲ and PROMIS-29
are generic HRQOL tools. The psychometric properties of the above tools
has not been verified in PBC patients（except for NIDDK-QA）,thus it is
not recommended use them in PBC patients.</div><div>There are some limitations in our systematic review. First, PRISMA is
just one methodology that can be used to synthesis or evaluate outcome
measures and other methods might be equally valid or provide different
perspectives. Secondly, we did not search the gray literature (inability
to identify ongoing or unpublished studies), which produces selection
bias. And our review was limited to English-language articles , some
studies may not have been included due to this.</div><div>5.Conclusion</div><div>PBC-specific HRQOL questionnaires used in primary biliary cholangitis
have generally good psychometric properties. But lots of studies
directly applied the HRQOL tools without verifying the HRQOL tools
validity and reliability in PBC patients. Investigators should select
questionnaires for their study based on the ease of administration and
the questionnaire’s correlation with the primary health domain under
investigation. Thus, more robust psychometric design studies to test the
measurement properties of HRQOL questionnaires as the primary outcome of
investigation are highly needed.</div><div>Conflict of interest</div><div>The authors have no conflict of interest to declare.</div><div>Contributions</div><div>X.A. contributed significantly to the conception and design of the
study, data extraction, critical appraisal, interpretation of data and
drafting of the manuscript. X.Y. and J.-M.X. were involved in literature
search, critical appraisal and interpretation of data and drafting.
W.-X.Y. was involved in critical appraisal and drafting. Y.-M.T. was
involved in the drafting and review of the manuscript. All authors have
given their final approval on the manuscript to be published.</div><div>Funding</div><div>This work was supported by grants from the National Natural Science
Foundation of China (NO.81660102), Project of Science and Technology
Innovation team in Colleges and Universities in Yunnan Province, Yunnan
Natural Science Foundation (NO.201701UH00618), Yunnan Health Science and
Technology Program Project (NO.2017NS280) and Yunnan Provincial Science
and Technology Department - Kunming Medical University applied basic
research joint special fund project(2018FE001（-051）).</div><div>Patient consent for publication</div><div>Not required.</div><div>Copyright permissions</div><div>All figures and tables were original.</div><div>References</div><div>[1] E.J. Carey, A.H. Ali, K.D. Lindor. Primary biliary cirrhosis.
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