Understanding the measurement relationship between EQ-5D-5L, PROMIS-29 and PROPr.

PURPOSE: Many generic patient-reported instruments are available for the measurement of health outcomes, including EQ-5D-5L, and the Patient-Reported Outcome Measurement Information System (PROMIS). Assessing their measurement characteristics informs users about the consistency between, and limits of, evidence produced. The aim was to assess the measurement relationship between the EQ-5D-5L descriptive system and value sets, the PROMIS-29 and PROPr (PROMIS value set). METHODS: Data were extracted from a cross-sectional survey administering measures of quality of life online in Australia. Descriptive analysis, agreement and construct validity assessment methods were used to compare instruments at the item, domain and value set level. RESULTS: In total, 794 Australians completed the survey. Convergent validity analysis found that similar dimensions across instruments were highly correlated (> 0.50), but the PROMIS-29 assesses additional health concepts not explicitly covered by EQ-5D (sleep and fatigue). Known-group assessment found that EQ-5D-5L and PROPr were able to detect those with and without a condition (ES range 0.78-0.83) but PROPr could more precisely detect differing levels of self-reported health. Both instruments were sensitive to differences in levels of pain. DISCUSSION: There is some consistency in what the EQ-5D-5L, PROMIS-29 and PROPr measure. Differences between value set characteristics can be linked to differences what is measured and the valuation approaches used. This has implications for the use of each in assessing health outcomes, and the results can inform decisions about which instrument should be used in which context.

Estimation of a Canadian preference-based scoring algorithm for the Veterans RAND 12-Item Health Survey: a population survey using a discrete-choice experiment.

BACKGROUND: The Veterans RAND 12-Item Health Survey (VR-12) is a generic patient-reported outcome measure derived from the widely used 36- and 12-item Short Form Health Surveys. We aimed to estimate a Canadian preference-based scoring algorithm for the VR-12, enabling the derivation of health utility values for generating quality-adjusted life years (QALYs). METHODS: We conducted a discrete-choice experiment in a sample of the Canadian population in January and February 2019. Participants - recruited from a consumer research panel - completed an online survey, in English or French, that included 11 discrete-choice questions, each comprising 2 health profiles. We defined the health profiles using 8 VR-12 items and a duration attribute. Using conditional logit regressions, where each level of the respective VR-12 items was interacted with duration, we applied the coefficients to estimate health utility values interpretable on a scale of 0 (dead) to 1 (full health). Negative values reflect states considered worse than dead. RESULTS: A total of 3380 individuals completed the survey. Of these, 1688 (49.9%) were females, and 3101 (91.7%) completed the English version of the survey. Across all models, "feel downhearted and blue all of the time" and "pain interferes with your normal work extremely" were associated with the largest decrements in health utility. Excluding the 685 respondents (20.3%) who provided inconsistent responses had a negligible effect on the results. The recommended model, weighted to match population demographics, had health utility values ranging from -0.589 to 1.000. INTERPRETATION: Health utility values that reflect the preferences of the Canadian population can now be derived from responses to the VR-12. These values can be used to generate QALYs in future analyses.

Preference Elicitation Techniques Used in Valuing Children's Health-Related Quality-of-Life: A Systematic Review.

BACKGROUND AND OBJECTIVES: Valuing children's health states for use in economic evaluations is globally relevant and is of particular relevance in jurisdictions where a cost-utility analysis is the preferred form of analysis for decision making. Despite this, the challenges with valuing child health mean that there are many remaining questions for debate about the approach to elicitation of values. The aim of this paper was to identify and describe the methods used to value children's health states and the specific issues that arise in the use of these methods. METHODS: We conducted a systematic search of electronic databases to identify studies published in English since 1990 that used preference elicitation methods to value child and adolescent (under 18 years of age) health states. Eligibility criteria comprised valuation studies concerning both child-specific patient-reported outcome measures and child health states defined in other ways, and methodological studies of valuation approaches that may or may not have yielded a value set algorithm. RESULTS: A total of 77 eligible studies were identified from which data on country setting, aims, condition (general population or clinically specific), sample size, age of respondents, the perspective that participants were asked to adopt, source of values (respondents who completed the preference elicitation tasks) and methods questions asked were extracted. Extracted data were classified and evaluated using narrative synthesis methods. The studies were classified into three groups: (1) studies comparing elicitation methods (n = 30); (2) studies comparing perspectives (n = 23); and (3) studies where no comparisons were presented (n = 26); selected studies could fall into more than one group. Overall, the studies varied considerably both in methods used and in reporting. The preference elicitation tasks included time trade-off, standard gamble, visual analogue scaling, rating/ranking, discrete choice experiments, best-worst scaling and willingness to pay elicited through a contingent valuation. Perspectives included adults' considering the health states from their own perspective, adults taking the perspective of a child (own, other, hypothetical) and a child/adolescent taking their own or the perspective of another child. There was some evidence that children gave lower values for comparable health states than did adults that adopted their own perspective or adult/parents that adopted the perspective of children. CONCLUSIONS: Differences in reporting limited the conclusions that can be formed about which methods are most suitable for eliciting preferences for children's health and the influence of differing perspectives and values. Difficulties encountered in drawing conclusions from the data (such as lack of consensus and poor reporting making it difficult for users to choose and interpret available values) suggest that reporting guidelines are required to improve the consistency and quality of reporting of studies that value children's health using preference-based techniques.

Criteria for developing, assessing and selecting candidate EQ-5D bolt-ons.

PURPOSE: 'Bolt-on' dimensions are additional items added to multi-attribute utility instruments (MAUIs) such as EQ-5D that measure constructs not included in the core descriptive system. The use of bolt-ons has been proposed to improve the content validity and responsiveness of the descriptive system in certain settings and health conditions. EQ-5D bolt-ons serve a particular purpose and thus satisfy a certain set of criteria. The aim of this paper is to propose a set of criteria to guide the development, assessment and selection of candidate bolt-on descriptors. METHODS: Criteria were developed using an iterative approach. First, existing criteria were identified from the literature including those used to guide the development of MAUIs, the COSMIN checklist and reviews of existing bolt-ons. Second, processes used to develop bolt-ons based on qualitative and quantitative approaches were considered. The information from these two stages was formalised into draft development and selection criteria. These were reviewed by the project team and iteratively refined. RESULTS: Overall, 23 criteria for the development, assessment and selection of candidate bolt-ons were formulated. Development criteria focused on issues relating to i) structure, ii) language, and iii) consistency with the existing EQ-5D dimension structure. Assessment and selection criteria focused on face and content validity and classical psychometric indicators. CONCLUSION: The criteria generated can be used to guide the development of bolt-ons across different health areas. They can also be used to assess existing bolt-ons, and inform their inclusion in studies and patient groups where the EQ-5D may lack content validity.

Developing a New Version of the SF-6D Health State Classification System From the SF-36v2: SF-6Dv2.

OBJECTIVE: The objective of this study was to develop the classification system for version of the SF-6D (SF-6Dv2) from the SF-36v2. SF-6Dv2 is an improved version of SF-6D, one of the most widely used generic measures of health for the calculation of quality-adjusted life years. STUDY DESIGN AND SETTING: A 3-step process was undertaken to generate a new classification system: (1) factor analysis to establish dimensionality; (2) Rasch analysis to understand item performance; and (3) tests of differential item function. To evaluate robustness, Rasch analyses were performed in multiple subsets of 2 large cross-sectional datasets from recently discharged hospital patients and online patient samples. RESULTS: On the basis of factor analysis, other psychometric evidence, cross-cultural considerations, and amenability to valuation, the 6-dimension classification used in SF-6D was maintained. SF-6Dv2 resulted in the following modifications to SF-6D: a simpler classification of physical function with clearer separation between levels; a more detailed 5-level description of role limitations; using negative wording to describe vitality; and using pain severity rather than pain interference. CONCLUSIONS: The SF-6Dv2 classification system describes more distinct levels of health than SF-6D, changes the descriptions used for a number of dimensions and provides clearer wording for health state valuation. The second stage of the study has developed a utility value set using discrete choice methods so that the measure can be used in health technology assessment. Further work should investigate the psychometric characteristics of the new instrument.

How Are Debriefing Questions Used in Health Discrete Choice Experiments? An Online Survey.

OBJECTIVES: Debriefing questions can assess if respondents understand discrete choice experiments (DCEs) and are answering in a way consistent with theories of decision making and utility maximization. Nevertheless, there is limited literature about how often debriefing questions are included or how the results are used in health economics. The aim of this study was to conduct a survey of the frequency, type, and analysis of debriefing questions in health DCEs. METHODS: We conducted an online survey of authors of published health DCEs, asking about their use of debriefing questions, including frequency, type, and analysis. We descriptively analyzed the sample characteristics and responses. Free-text questions were analyzed with qualitative thematic analysis. RESULTS: We received 70 responses (43% response rate), of which 50% reported using debriefing questions. They were most commonly designed to assess difficulty (91%), understanding (49%), and attribute nonattendance (31%) rather than learning effects (3%) or monotonicity (11%). On average, 37% of debriefing questions were analyzed (range, 0% to 69%), and the results were used <50% of the time, usually to exclude respondents or interpret overall results. Researcher experience or confidence with DCEs did not affect their use of debriefing questions. CONCLUSIONS: These results suggest that although half of researchers conducting health DCEs use debriefing questions, many do not analyze, use, or report the responses. Given the additional respondent burden, there is a need for reliable and valid debriefing questions. In the meantime, the inclusion, analysis, and reporting of debriefing questions should be carefully considered before DCE implementation.

Valuing the SF-6Dv2 Classification System in the United Kingdom Using a Discrete-choice Experiment With Duration.

OBJECTIVE: An updated version of the SF-6D Classification System (SF-6Dv2) has been developed, and utility value sets are required. The aim of this study was to test the development of a United Kingdom SF-6Dv2 value set, and address limitations of the existing SF-6D value set (which results in a narrow range of utilities). This was done using 2 discrete-choice experiment (DCE) tasks. Interactions and preference heterogeneity were also investigated. RESEARCH DESIGN AND SUBJECTS: An online sample of respondents (n=3014) completed 10 DCE with duration choice sets from an efficient design of 300 (Design 1) and 2 DCE with duration choice sets including immediate death from a set of 60 (Design 2). Conditional logit regression was used to estimate value set models with and without interactions. We investigated preference heterogeneity using latent class models. RESULTS: Models including ordered coefficients within each dimension were developed, with the favored model including an additional interaction term when one dimension was at the most severe level. Value sets differed across Designs 1 and 2. Design 1 models had a wider utility range and a higher proportion of negative values. The most important dimensions were pain, mental health, and physical functioning. Preference heterogeneity was apparent, with a 2-class model describing the data. CONCLUSIONS: We developed and applied a protocol to value the SF-6Dv2 using DCE. The results provide a provisional value set for use in resource allocation. The protocol can be applied internationally. Further work should investigate how to account for preference heterogeneity in value set production.

A new method for valuing health: directly eliciting personal utility functions.

BACKGROUND: Standard methods for eliciting the preference data upon which 'value sets' are based generally have in common an aim to 'uncover' people's preferences by asking them to evaluate a subset of health states, then using their responses to infer their preferences over all dimensions and levels. An alternative approach is to ask people directly about the relative importance to them of the dimensions, levels and interactions between them. This paper describes a new stated preference approach for directly eliciting personal utility functions (PUFs), and reports a pilot study to test its feasibility for valuing the EQ-5D. METHODS: A questionnaire was developed, designed to directly elicit PUFs from general public respondents via computer-assisted personal interviews, with a focus on helping respondents to reflect and deliberate on their preferences. The questionnaire was piloted in England. RESULTS: Seventy-six interviews were conducted in December 2015. Overall, pain/discomfort and mobility were found to be the most important of the EQ-5D dimensions. The ratings for intermediate improvements in each dimension show heterogeneity, both within and between respondents. Almost a quarter of respondents indicated that no EQ-5D health states are worse than dead. DISCUSSION: The PUF approach appears to be feasible, and has the potential to yield meaningful, well-informed preference data from respondents that can be aggregated to yield a value set for the EQ-5D. A deliberative approach to health state valuation also has the potential to complement and develop existing valuation methods. Further refinement of some elements of the approach is required.

Multiple Legionella pneumophila Type II secretion substrates, including a novel protein, contribute to differential infection of the amoebae Acanthamoeba castellanii, Hartmannella vermiformis, and Naegleria lovaniensis.

Type II protein secretion (T2S) by Legionella pneumophila is required for intracellular infection of host cells, including macrophages and the amoebae Acanthamoeba castellanii and Hartmannella vermiformis. Previous proteomic analysis revealed that T2S by L. pneumophila 130b mediates the export of >25 proteins, including several that appeared to be novel. Following confirmation that they are unlike known proteins, T2S substrates NttA, NttB, and LegP were targeted for mutation. nttA mutants were impaired for intracellular multiplication in A. castellanii but not H. vermiformis or macrophages, suggesting that novel exoproteins which are specific to Legionella are especially important for infection. Because the importance of NttA was host cell dependent, we examined a panel of T2S substrate mutants that had not been tested before in more than one amoeba. As a result, RNase SrnA, acyltransferase PlaC, and metalloprotease ProA all proved to be required for optimal intracellular multiplication in H. vermiformis but not A. castellanii. Further examination of an lspF mutant lacking the T2S apparatus documented that T2S is also critical for infection of the amoeba Naegleria lovaniensis. Mutants lacking SrnA, PlaC, or ProA, but not those deficient for NttA, were defective in N. lovaniensis. Based upon analysis of a double mutant lacking PlaC and ProA, the role of ProA in H. vermiformis was connected to its ability to activate PlaC, whereas in N. lovaniensis, ProA appeared to have multiple functions. Together, these data document that the T2S system exports multiple effectors, including a novel one, which contribute in different ways to the broad host range of L. pneumophila.

The Bacillus subtilis chemoreceptor McpC senses multiple ligands using two discrete mechanisms.

Bacillus subtilis can perform chemotaxis toward all 20 L-amino acids normally found in proteins. Loss of a single chemoreceptor, McpC, was previously found to reduce chemotaxis to 19 of these amino acids. In this study, we investigated the amino acid-sensing mechanism of McpC. We show that McpC alone can support chemotaxis to 17 of these amino acids to varying degrees. Eleven amino acids were found to directly bind the amino-terminal sensing domain of McpC in vitro. Sequence analysis indicates that the McpC sensing domain exhibits a dual Per-Arnt-Sim (PAS) domain structure. Using this structure as a guide, we were able to isolate mutants that suggest that four amino acids (arginine, glutamine, lysine, and methionine) are sensed by an indirect mechanism. We identified four candidate binding lipoproteins associated with amino acid transporters that may function in indirect sensing: ArtP, GlnH, MetQ, and YckB. ArtP was found to bind arginine and lysine; GlnH, glutamine; MetQ, methionine; and YckB, tryptophan. In addition, we found that ArtP, MetQ, and YckB bind the sensing domain of McpC, suggesting that the three participate in the indirect sensing of arginine, lysine, methionine, and possibly tryptophan as well. Taken together, these results further our understanding of amino acid chemotaxis in B. subtilis and gain insight into how a single chemoreceptor is able to sense many amino acids.

The major facilitator superfamily-type protein LbtC promotes the utilization of the legiobactin siderophore by Legionella pneumophila.

The Gram-negative bacterium Legionella pneumophila elaborates the siderophore legiobactin. We previously showed that cytoplasmic LbtA helps mediate legiobactin synthesis, inner-membrane LbtB promotes export of legiobactin, and outer-membrane LbtU acts as the ferrisiderophore receptor. RT-PCR analyses now identified lbtC as an iron-repressed gene that is the final gene in an operon containing lbtA and lbtB. In silico analysis predicted that LbtC is an inner-membrane protein that belongs to the major facilitator superfamily (MFS). Although capable of normal growth in standard media, lbtC mutants were defective for growth on iron-depleted agar media. While producing normal levels of legiobactin, lbtC mutants were unable to utilize supplied legiobactin to stimulate growth on iron-depleted media and displayed an impaired ability to take up radiolabelled iron. All lbtC mutant phenotypes were complemented by reintroduction of an intact copy of lbtC. When a cloned copy of both lbtC and lbtU was introduced into a heterologous bacterium (Legionella longbeachae), the organism acquired the ability to utilize legiobactin to grow better on low-iron media. Together, these data indicate that LbtC is involved in the uptake of legiobactin, and based upon its predicted location is most likely the mediator of ferrilegiobactin transport across the inner membrane. The data are also a unique documentation of how an MFS protein can promote bacterial iron-siderophore import, standing in contrast to the vast majority of studies which have defined ABC-type permeases as the mediators of siderophore import across the Gram-negative inner membrane or the Gram-positive cytoplasmic membrane.

Legionella pneumophila LbtU acts as a novel, TonB-independent receptor for the legiobactin siderophore.

Gram-negative Legionella pneumophila produces a siderophore (legiobactin) that promotes lung infection. We previously determined that lbtA and lbtB are required for the synthesis and secretion of legiobactin. DNA sequence and reverse transcription-PCR (RT-PCR) analyses now reveal the presence of an iron-repressed gene (lbtU) directly upstream of the lbtAB-containing operon. In silico analysis predicted that LbtU is an outer membrane protein consisting of a 16-stranded transmembrane ß-barrel, multiple extracellular domains, and short periplasmic tails. Immunoblot analysis of cell fractions confirmed an outer membrane location for LbtU. Although replicating normally in standard media, lbtU mutants, like lbtA mutants, were impaired for growth on iron-depleted agar media. While producing typical levels of legiobactin, lbtU mutants were unable to use supplied legiobactin to stimulate growth on iron-depleted media and displayed an inability to take up iron. Complemented lbtU mutants behaved as the wild type did. The lbtU mutants were also impaired for infection in a legiobactin-dependent manner. Together, these data indicate that LbtU is involved in the uptake of legiobactin and, based upon its location, is most likely the Legionella siderophore receptor. The sequence and predicted two-dimensional (2D) and 3D structures of LbtU were distinct from those of all known siderophore receptors, which generally contain a 22-stranded ß-barrel and an extended N terminus that binds TonB in order to transduce energy from the inner membrane. This observation coupled with the fact that L. pneumophila does not encode TonB suggests that LbtU is a new type of receptor that participates in a form of iron uptake that is mechanistically distinct from the existing paradigm.