Assessing Disease Experience across the Life Span for Individuals with Osteogenesis Imperfecta: Challenges and Opportunities for Patient-Reported Outcomes (PROs) Measurement

Background Patient reported outcome (PRO) information is crucial for establishing better patient-provider communication, improving shared decision making between clinicians and patients, and assessing patient responses to therapeutic interventions and increasing satisfaction with care. We used the Brittle Bones Disease Consortium (BBDC) Contact Registry for People with OI, managed by the Rare Disease Clinical Research Network (RDCRN) to (1) to evaluate the construct validity of the Patient-Reported Outcome Measurement Information System® (PROMIS®) to record important components of the disease experience among individuals with OI; and (2) explore the feasibility of using a registry to recruit individuals with OI to report on health status. Our long-term goal is to enhance communication of health and disease management findings back to the OI community, especially those who do not have access to major OI clinical centers. Results We demonstrated the construct validity of PROMIS instruments in OI. Our results confirm that the scores from most domains differ significantly from the general US population: individuals with OI have worse symptom burden and functioning. We found no excessive floor or ceiling effects. Our study demonstrates that the BBDC Contact Registry can be used to recruit participants for online health status surveys. However, there are numerous challenges that must be addressed: lack of self-knowledge of OI type, under-representation of men, limited ethnic diversity, and imperfect questionnaire completion rates. Conclusion Our pilot study demonstrated the feasibility of using a contact registry to recruit respondents from the OI community and to obtain analyzable PROMIS data regarding disease experience. Because the results differ from the general population and avoid excessive floor and ceiling effects, PROMIS instruments can be used to assess response to therapeutic interventions in individuals with OI. Future directions will include (1) development and validation of an OI-specific patient-based classification system that aggregates persons with similar clinical characteristics and risks for complications to identify treatment needs; and (2) integrating these PRO tools into routine patient care and research studies.

This classification preserves the primary four groups described by Sillence and adds OI type V.
The different genetic causes of the OI types are recognized by listing the causative genes as subtypes of OI types I-V [18,19] Particularly over the past decade, there is increasing demand by the OI community to receive better information on the natural history of this disorder. Little information is available about the natural history and progression of OI in adulthood. Especially adults with OI want better delineation of health risks and evidence-based treatments. We need to know more about the patient-centered outcomes of various treatments that patients themselves report or that proxy respondents for individuals in the pediatric age ranges who cannot self-report.

Patient-Reported Outcomes
Despite the potential for mortality and significant morbidity, no measures of patient-reported outcomes (PROs) have been designed specifically for patients with OIcertainly none with input from the OI community. Available outcome measures have been developed chiefly by medical experts, relying on physician-based assessments. Recognition has grown that individuals' experiences and health-related quality of life (HRQOL) should be part of the assessment of new therapies and interventions. Such information is crucial for enhancing patient-provider communication, improving shared decision making between clinicians and patients (or parents), and increasing patient satisfaction with care [20][21][22][23]. Moreover, PRO data need to be linked to and analyzed with patients' diagnostic and treatment information. This would identify clinical predictors of survivorship difficulties and, thus, facilitate early risk stratification and targeted interventions [24].

Disease Registries and the Osteogenesis Imperfecta Patient Population
Developing data to better inform assessment and care for individuals with rare diseases is difficult; patients can be challenging to access and it can be hard to collect enough data to provide informed conclusions. One frequently recommended tool is a registry [25][26][27][28][29][30][31]. Registries are particularly useful in the care of individuals with a rare disorder as they can help patients gain a broader insight into their health status regardless of whether they have access to a major clinical center. The OI community has been very responsive to participating in research registries and to reporting their disease experiences. For more than a decade the OI community in the United States has embraced registry and natural history efforts sponsored by the Osteogenesis Imperfecta Foundation (OIF), a key national OI advocacy organization dedicated to supporting individuals with OI. The OIF effort began in earnest in 2005 with the establishment of the International Osteogenesis Imperfecta Registry [32]. The  The OI ANHI survey included basic demographic information, PROMIS instruments, and a detailed review of systems.
In the OI ANHI survey, PROMIS scores varied by OI disease severity (whether stratified by the 1979 Sillence classification or by patient-reported mild, moderate, or severe disease status).
Scores for OI patients were often worse from those of any relevant comparison or normative population. Moreover, when OI patients were asked to rank their health concerns, such as ambulation, craniofacial and dental problems, or hearing loss (all common problems in OI), the rankings tended to differ greatly from the priorities of physicians [35]. For example, individuals with OI listed vision concerns of greater concern than cardiopulmonary disease, the opposite of the clinician perspectives.

The Disease Experience of Persons with Osteogenesis Imperfecta
This paper reports on the latest phase of the OIF's efforts to enhance the voice of individuals with OI, this time combining an internet-based registry with PRO measures. The OIF is part of the Brittle Bone Disorder Consortium (BBDC), an NIH funded rare-disease multi-centered project designed to provide a better basis for individuals with OI to assess their disease by tracking the natural history of OI and to support the development of other studies that further explore the disorder. Related goals are to help individuals with OI to better direct their health management and to identify areas in which new intervention strategies are needed.

Evaluating the validity of existing PRO measures for persons with OI: A pilot
As we strive to build a standardized and robust platform to comprehensively capture the experiences of OI patients, this pilot study evaluates (1) the feasibility of using an on-line registry to recruit individuals with OI and to stratify appropriately individuals with this rare and very diverse disorder; and (2) the construct validity of PROMIS measures to record important components of the disease experience among individuals with OI. We report on these issues for an adult population of self-responders, as well as for proxy (parent) respondents for children and adolescents.

METHODS
In order to select PRO tools with domains felt to be important to individuals with OI, we convened a diverse Steering Committee comprising individuals with OI, the parent of a child with OI, members of the Data Management and Coordinating Center, physicians specializing in OI, and representatives of the OIF. The Steering Committee reviewed all PROMIS instruments available at the time of study inception. The Steering Committee gave highest priority to using the PROMIS CAT instruments for this project. CAT is a dynamically administered computerbased test in which responses to previous completed questions, within the same PRO scale, are used to select the most appropriate next question from the PROMIS item bank. The CAT system will continue to administer questions until an ideal standard error threshold is met. Compared to fixed length questionnaires, the advantage of CAT-based assessment is reduced respondent burden which can help to improve completion rates of the questionnaire [36]. The Steering Committee selected nine PROMIS CAT-based instruments for adults covering the following PROMIS instruments were not available for children ages 2-4, therefore we also included the Pediatric Outcomes Data Collection Instrument (PODCI) which is designed to document functional status in children and adolescents with musculoskeletal disorders. We included it because of its documented validity in assessing pediatric patients with restricted mobility or disability and because of its use by the BBDC [37]. PODCI was administered using parents as the proxy respondents.
A questionnaire titled "Information About You" was developed by the study team in an effort to capture demographic and basic clinical history, as recalled by the participants. Barring Center, housed at the University of South Florida, manages the BBDC Contact Registry for People with OI as well as all BBDC data. The BBDC Contact Registry sent an initial registrywide call for participation electronically on June 8, 2016, to all registry members. The registry e-mail invitation contained a link to the informed consent form for the pilot project and related questionnaires. The OIF facilitated additional recruitment, through e-mail announcements to its registered website users, social media posts, and an announcement in an electronic newsletter; all these notices encouraged interested persons to become members of the Contact Registry and enroll in the study. Once participants consented to the pilot study, they gained access to the online questionnaires/instruments. In total, the Data and Management and Coordinating Center sent 1,165 emails to 1,034 registrants, inviting them to participate in the study; 908 registrants were contacted once, 121 registrants twice, and 5 registrants three times. The data collection phase of this study closed on January 20, 2017.
To be eligible for project inclusion, respondents (including the proxies for children and adolescents) were required to be English-speaking and an adult, responding to the project either for him/herself or as a proxy for a child or adolescent age 2 to 17 years.
Because we generated a unique link to the project questionnaires for each participant (as part of the consent form), we could determine who had initiated and completed the questionnaires. We sent reminder e-mails to participants who had only partially completed the survey. Once participants completed their questionnaires, responses were downloaded to the Data Management and Coordinating Center.
Study participants entered their responses directly into online forms. All project data were collected via systems created in collaboration with the DMCC and the BBDC; these systems complied with all applicable guidelines regarding patient confidentiality and data integrity.
We conducted the entire pilot project using REDCap, a secure web-based application designed to support data capture for research studies [38]. Within its library are both the PROMIS and the PODCI. We also adapted the "Information about You" questionnaire to REDCap. The selected PROMIS, the PODCI, and the "Information about You" questionnaires were mounted on the web by the RDCRN. Participants could complete the surveys either all at once or in multiple sessions.
The order for the study survey for adults was as follows: (1)  Higher scores on these instruments are indicative of greater disease burden.
The PODCI was scored according to the Version 2.0 Scoring Algorithm from the AAOS [40].
We input the collected scores for the instrument into the scoring algorithm which produced mean, standardized, and normalized scores for each domain. These were then compared to PROMIS domains using Pearson's correlation test to assess for congruent validity (a form of construct validity).
IRB approval for the pilot project was provided by the University of South Florida, the home institution of the Contact Registry.

RESULTS
Three hundred individuals with self-reported OI or serving as parent proxies, representing a wide range of self-reported disease severity, enrolled in the study. Of the 300 original enrollees, 290 (97%) individuals filled out some portion of the survey questionnaires; 10 individuals consented but did not start any questionnaire. Of the 290 respondents, 27 were parent-proxies for children ages 2-4 years, 65 were parent-proxies for children ages 5-17 years, and 198 were adults with OI of ages 18+ years. In all, 273 of the 290 individuals or their proxy respondents, opened all designated questionnaires (94%); 17 opened some questionnaires.
Higher completion rates were noted for adult-specific instruments than for child-specific instruments; 94-98% of adults completed all nine adult-specific PROMIS instruments, whereas 79-86% of parent-proxies completed all six child-specific PROMIS instruments (p<0.01).
Similarly for the six individual PODCI domains we noted lower parent-proxy completion rates ranging from 76-90%. (Table 1). Only 64/92 (70%) parent proxies completed all PODCI domains. General demographics and self-reported clinical history of both adult and child subjects came from the "Information about You" question set. Responses are summarized in Table 2.  (Table 3). Interference and Mobility in children. All were under the generally accepted 15% cut-off point.
No important ceiling effects were detected in adult or parent-proxy instruments. (Table 4). Of the 65 parent proxy respondents for children ages 5-17, 55 filled out both the PODCI and at least one PROMIS instrument. All six parent proxy PROMIS instruments showed statistically significant correlations with at least one PODCI element, with the strongest correlations seen between those instruments focused on physical function, which provides evidence for convergent validity of PROMIS measures. Several outcomes are essentially opposites (e.g. happiness vs anxiety), thus those correlations are negative. (Table 5) severe III OI may feel extremely mobile and unrestricted because they have acquired a top-ofthe-line wheelchair which allows them to participate in school, family, job, and social activities easily. There is an extensive literature that illustrates that, across numerous chronic diseases, people adapt to their situation or condition, and then, within that context have expectations for quality of life that might seem surprising to people not suffering from that condition [41,42]. It is also possible that since OI type was self-reported in this study, incorrect identification of OI type is contributing to these findings.
In addition, our pilot study demonstrates that the BBDC Contact Registry for People with OI can be used to recruit participants for online surveys regarding health status. This capability will allow researchers to better understand the OI community's perspective on health status and quality of life; it will also permit users to capture quantitative PROs using tools such as PROMIS® or PODCI to explore domains that patients identify as important. However, it also underscores the importance of challenges to using registries that must be addressed to expand our understanding of the health issues faced by individuals with OI and then communicate health and disease management findings back to the OI community, especially those who do not have access to major OI clinical centers.
Self-knowledge of OI Type: A significant proportion of respondents did not know their OI type.
This was particularly prevalent in older individuals, a troubling problem as we seek to expand our knowledge of the natural history of OI in adulthood. We believe this result reflects confusion regarding the current and historical classification of OI. Prior to the publication of the 1979 Sillence classification of OI, patients were typically described as having "congenita" or tarda" (fractures and bowing occurring after birth) disease. This has led many older patients to describe themselves as having type 1 or 2 disease. Although 18 OI types have been described in the research literature, Sillence and others recently pleaded to simplify the classification of OI to mild, moderate, and severe. The rationale is that OI type is artificial and sometimes not helpful.
They contend that this simplified categorization, focusing on broad clinical findings, particularly clinical and historical data, fracture frequency, bone densitometry, level of mobility, and patient report tools [19,[43][44][45][46][47], can be used to enhance communication between patients and professionals.
We believe that a critical next step for the BBDC research team is leveraging the clinical data of The Match (or Mismatch) between Self-and Proxy-Responses for Children: Parent-proxy reported measures of PRO results may well differ from child self-reported results, especially for adolescents and possibly for older children [49]. For this study, we did not ask children to complete self-reported instruments; we relied on parent-proxy instruments. This prevented analysis of congruency between the self-perceived disease experiences of children and the estimations of caretakers. Future studies will need to explore the similarities and differences found in parent-proxy and patient PRO responses, at least for the pediatric age groups for which reliable and valid self-report measures exist. Including tools that can be answered by older children and adolescents is essential.
Respondent Burden: CATs instruments were developed to reduce respondent burden by limiting the number of questions that participants need to answer, and our results underscore the importance of that philosophy [36]. Recognizing the voice of the patient: Finally, but perhaps most important, the issues of concern to patients with OI frequently differ from the typical clinician focus. Indeed, the PROMIS instruments chosen for the study are not typically topics covered in a routine clinic visit. The wide range of existing PROMIS instruments offers an opportunity to explore a variety of health concerns for which there may not be time to discuss during a standard clinic visit.

Conclusion
Our pilot study demonstrated the feasibility of using the RDCRN BBDC Contact Registry for People with OI to recruit respondents from the OI community and to obtain analyzable PROMIS ® and PODCI data regarding their disease experience. The tools selected performed well, demonstrating statistically significant scores relative to the general population and no excessive floor or ceiling effects. We will therefore be incorporating PRO instruments into our BBDC longitudinal study to assess health status, outcomes and responses to interventions in individuals with OI. Significant work remains ahead, however, if we are to meet our broader goal of improving quality of life for individuals with OI by improving their access to OI-specific health information, regardless of whether they have access to a major OI clinical center.
Our next step will be to leverage the intimate knowledge of OI that persons with this rare, extremely heterogeneous disorder hold and the clinical data accumulated by the BBDC Natural History Study. Doing so will allow us to validate an OI-specific patient-based classification system that aggregates persons with similar clinical characteristics and risks for complications as a basis for identifying treatment needs and developing disease management recommendations as well as generating hypotheses for pharmaceutical and clinical management studies. We will also expand our identification of existing PRO measures (e.g., PROMIS) and/or develop new PRO measures in partnership with the OI community to detect discernable differences in health status as a basis for evaluating health status and treatment results. • Consent for publication Not applicable.

Abbreviations
• Availability of data and material The datasets generated and/or analysed are not currently publicly available. They will be available via dbGaP one year after publication of planned analyses.

• Competing interests
The authors declare that they have no competing interests.

• Funding
The