Pediatric patient self-reported and parent proxy-reported outcomes are critical components of evaluating the impact of current and planned treatments for pediatric EoE. We report a patient self-report and parent-proxy Pediatric EoE Symptom Score (PEESS™ v2.0) metric with content-validation. The key distinction between the PEESS v1.0 compared to the PEESS™ v2.0 is that the former are physician developed metrics, while the latter was developed from the words and descriptions of patients and families following FDA guidelines published in 2009.
The variety of symptoms reported by pediatric EoE patients and their families in the development of the PEESS™ v2.0 was surprising. The existing literature reports that adult EoE patients often describe varying degrees of dysphagia, whereas children often describe pain without dysphagia as their only symptom [1, 3]. Characterization of dysphagia from multiple perspectives was critical to capturing this important symptom. Patients and parent proxies were often aware that they (or their child) were experiencing dysphagia as assessed by items such as "trouble swallowing" or "food getting stuck while eating." However, the addition of items including "taking a long time to eat food" and "needing to drink a lot of water while eating food" captured the more subtle descriptions of dysphagia. Utilizing two distinct cohorts for the focus interviews and cognitive interviews also yielded invaluable information and allowed further refinement of patient self-reported and parent proxy-reported perspectives, achieving content saturation. In particular, clarification and increased reading ease of directions, addition of a combined pictorial scale and Likert scale, language modification, and changes in instrument layout were all developed from the cognitive interviews.
One particular concern regarding parent-proxy reported outcomes is that they may not be acceptable to the current FDA guidelines regarding product labeling specifications. For FDA-endorsed clinical trials that would use the PEESS™ v2.0, it may be that presently we are only able to obtain specific PRO based labeling for pediatric self-report ages 8-18 years of age. Current opinion at the FDA is that parent observer tools for children 2-7 years of age are recommended to include only symptoms clearly observable by the parent, such as: vomiting, increased time needed to eat, and drinking a large amount of liquids to swallow food. Therefore, only a subscale of questions may able to be used for clinical trials in children 2-7 years of age. However, it is also vital to recognize that FDA opinion for labeling purposes regarding PROs has changed significantly in the past several decades. It is highly possible that the current thinking on parent-proxy metrics (widely supported by many psychometricians and clinicians alike) may also change. In future studies, we will be conducting responsiveness testing of the PEESS™ v2.0 metric, further assessing the parent proxy-report metric and specific subscales. Finally, the PEESS™ v2.0 is intended for use both in and outside of the clinical trial setting. We felt that all of the symptoms important to patients and their parents as proxy are important to capture in order to reflect the true clinical picture of symptomatology.
In developing a metric for pediatric EoE, it is important to ensure that all patient areas of concern are fully elicited - a concept often termed item saturation, and a key reason why we performed our 75 patient and parent proxy interviews in two stages and two separate cohorts. Item saturation was achieved for each question and questionnaire as a whole during the cognitive interviews for each age range. Specific questions are provided in Table 2, including: "how would you change the questions words to make it easier to understand" and the overall assessment question "are there things that we forgot to ask about that you feel are important?" These questions were asked to the patients in the 8-18 year old age ranges and to the parents in the 2-18 year old age ranges. In response, the landscape questionnaire format and front page directions were changed early on, and the final draft was reviewed by patients in this format. This is an important distinction from the Flood et al. metric and the PEESS v1.0 in that items were generated by the patients in one cohort and then reviewed by a second cohort. However, the item content if the PEESS™ v2.0 is supported by the symptom overlap reported by Flood et al. and other investigators [3, 15, 18].
Another controversial area in PRO development is recall period. Some may argue that a one month recall period for the PEESS™ v2.0 is too long to accurately assess change. The use of a one month recall period has been well described by Varni and colleagues [19–26]. In addition, the Mayo Dysphagia Questionnaire developed by Romero and colleagues was shown not to be responsive over a 14 day recall period, but responsive over a 30 day (1 month) recall period . In future studies we will be conducting responsiveness testing of the PEESS™ v2.0 metric and will be assessing different recall periods - 1 week, 2 week and 1 month. One alternative to improve patient accuracy in symptom reporting by a shorter recall period and also allow for a total responsive period of 30 days would be to collect symptom scores on a weekly basis for 4 weeks, and then report a 30 day summation score. Some have also advocated for the use of daily assessments through electronic diaries. We considered using daily electronic diaries, but we have found the patient response-burden too high, and that these diaries are impractical for any but the most highly funded and closely regulated clinical trials. The PEESS™ v2.0 is intended for use both in and outside the clinical trial setting as a simple, yet effective patient-derived metric that does not cause undue burden on patients, families, clinicians, or researchers.
There are several important limitations to this study. Although the PEESS™ v2.0 metric represents an important step forward for the field of pediatric EoE, further testing and modifications will be needed. Despite item saturation, there may be additional EoE symptoms that have not been included. In addition, generalizability to non-Caucasians and to patients with co-morbidities may be a potential concern. For the PEESS™ v2.0 metric development and cognitive interviews, we felt it critical to assess patients' and families' concerns specific to EoE, not those related to other co-morbidities. In the next phase of the PEESS™ v2.0 metric development, we will test the metric construct and reliability in over 200 patients and 250 parents across a variety of demographics and co-morbidities. The fourth phase of psychometric testing will test the responsiveness of the PEESS™ v2.0 metric, key to assessing the potential performance of the PEESS™ v2.0 in clinical trials. The PEESS™ v2.0 metrics are available at http://www.mapi-trust.org.