External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease.

BACKGROUND: Priapism impairs quality of life and has a predilection for males with sickle cell disease (SCD). The Priapism Impact Profile (PIP) is a novel 12-item instrument designed to measure general health-related impact of priapism. The aim of the study was to evaluate the validity and reliability of the PIP in a Jamaican cohort of SCD patients experiencing priapism.
METHODS: One hundred SCD patients with a history of priapism were recruited from a sickle cell clinic in Kingston, Jamaica and administered the PIP questionnaire. Patients rated each item of the PIP for clarity and importance. Statistical testing was employed to evaluate the psychometric performance of the PIP. Content validation was assessed based on patient descriptive rating of the items based on clarity, and importance and criterion-oriented validity were assessed by evaluating the PIP's ability to distinguish between patient subgroups. Test-retest repeatability was assessed in 20 of the 100 patients.
RESULTS: Patients were stratified into active (54) and remission (46) priapism groups based on their experience of priapism within the past year. Patients in the active priapism group were younger (p = 0.011), had a shorter duration of disease (p = 0.023), and had more frequent priapism episodes (p = 0.036) than the remission group. PIP questionnaire scores differed significantly with respect to priapism activity (p < 0.001) and prevalence of erectile dysfunction (p < 0.05) but not by priapism severity (p = 0.62). The PIP questionnaire had good content validity, with questions rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively.
CONCLUSION: The PIP questionnaire was successfully validated in a Jamaican cohort of SCD patients and adequately discriminated patients with active priapism from those in remission. The instrument may be utilized in routine clinical management of patients with SCD-associated priapism. Further clinical investigations are warranted in other populations.

Introduction

Priapism, defined as a persistent penile erection continuing beyond or unrelated to sexual stimulation, is an uncommon disorder [1]. Whereas the incidence of priapism in the general population is quite low, the disease disproportionately affects the population of males with sickle cell disease (SCD) [2,3]. Ischemic priapism is predominantly seen in SCD and is typified by reduced or absent corporal flow. The cumulative incidence of priapism in SCD by age 40 years is as high as 60% [3]. The condition has a predilection for young males, with the peak age of onset in the late teens [4,5]. The probability of a male with SCD experiencing priapism by age 20 years is 89% [6]. Nationwide studies in the United States report that among males with priapism who present to the emergency department, those with SCD are more likely to be hospitalized and at a younger age than those with non-SCD related priapism [7-9]. The burden of priapism in SCD is even greater in Jamaica where 10% of the population carries the defective sickle hemoglobin gene [10].

Priapism is a potentially debilitating complication in SCD and is often associated with frequent episodes of bothersome painful nocturnal erections, frequently referred to as stuttering priapism [1]. The condition often leads to erectile dysfunction (ED) in as many as 47.5% of patients because of recurrent episodes in association with progressive corporal fibrosis [11-13]. Due to its repeated and prolonged episodes of high-pressure vascular distension of the corporal bodies, priapism may also result in conspicuous disfigurement of the penis called megalophallus. All these factors may lead to impairment in overall quality of life in these patients. The psychological impact of priapism in SCD includes despair, embarrassment and isolation [14]. Despite the obvious psychological effects of priapism in these patients, very little is presently done to assess and comprehensively monitor their health-related outcomes.

The priapism impact profile (PIP) questionnaire was pioneered as the first instrument to assess the general health-related impact of priapism [15]. It was originally designed and tested in 54 adult patients with a history of priapism (36 males with SCD and 18 males without SCD) attending the urology and hematology clinics at the Johns Hopkins Hospital between 2011 and 2014. The preliminary study performed well with respect to reliability and validity, distinguishing between patients with active and remitted disease, and those with severe erectile dysfunction. We wished to test the hypothesis that the PIP is a scientifically valid and clinically useful patient reported outcome instrument to ascertain the patient perspective of having priapism by performing an external validation study. We therefore proposed to externally validate the PIP questionnaire in a cohort of patients with SCD having both active and remitted priapism attending a clinic in Kingston, Jamaica.

Materials and methods

Questionnaire composition

The PIP questionnaire consists of 12 items in 3 domains: Quality of life (QoL), sexual function (SF) and physical wellness (PW). Each item has a 7-point scale ranging from 1 (absent) to 7 (very extreme) leading to a total possible score ranging from 12–84. Higher scores indicate greater severity within each domain. Each question was answered based on their experiences over the prior 2 week period to ensure good patient recall.

Population description and enrollment

All patients were recruited from the Sickle Cell Unit, a large outpatient clinic serving only patients with sickle cell diseases and located at the University of the West Indies, Mona, Kingston, Jamaica, from May 1, 2015- June 30, 2017. The clinic is the only one of its kind in the English-speaking Caribbean. Patients were recruited and consented after presenting for routine health maintenance visits. Inclusion criteria were adult males (≥18 years) with self-reports of priapism and hemoglobin electrophoretic-proven diagnosis of SCD [16]. Patients were excluded if they were unable to comprehend and self-complete questionnaires or if they presented with acute illnesses at the time of clinic visits including priapism requiring urgent surgical or medical ablative therapies such as penile shunt surgery, penile prosthesis implantation, penile vascular surgery, or androgen deprivation.

Study procedures

Patients self-completed questionnaires within 15 minutes in a private room in the clinic. The patients were next instructed to evaluate the instrument by descriptively rating each of the items for clarity (i.e. understanding) and importance as low, medium or high. All patients completed the 5-item International Index of Erectile Function (IIEF) questionnaire which objectively assessed erectile function [17]. The recruiter then collected additional demographic information and details on priapism history (i.e. age of onset, frequency and duration of priapism episodes, and prior treatments). One in 5 patients were randomly asked to return within 2–4 weeks to assess test-retest reliability of the instrument. The questionnaire was pre-tested on 30 eligible patients to ensure understanding and acceptability of the questions. Once it was deemed that the questionnaire was understandable and acceptable, it was administered to the remainder of the recruited patients.

Outcome measurements

As in the original study, criterion-oriented validity was assessed by evaluating the PIP’s ability to distinguish between patient subgroups based on priapism activity (≥1 year or < 1 year since last episode), priapism severity (duration of episodes), and ED prevalence. Active priapism was defined as having at least one priapism episode without spontaneous remission within the past year; spontaneous remission was defined as no active priapism episodes at least within the past year. The purpose of this distinction was to evaluate the performance of the instrument comparing findings when the disorder was active or in remission. Priapism of high severity was defined as priapism episodes lasting > 2 hours while low severity was defined as priapism episodes lasting ≤2 hours. ED was classified as present (mild to severe) and not present (none) based on the specified ranges of the IIEF questionnaire scores [17]. Content validation was assessed based on patient descriptive rating of the items using terms such as high, medium or low importance or high, medium or low clarity.

Statistical analysis

The study sample comprises 100 patients, representing all eligible patients during the time frame of the study. Means ± standard deviations (SD) as well as medians with interquartile range (IQR) were calculated. Continuous data were compared using the Wilcoxon rank sum nonparametric test. Categorical data were compared using the Chi Square or Fisher’s Exact test as appropriate. Internal consistency coefficients for the total PIP questionnaire and the 3 subscales (domains) were generated using Cronbach’s α. Cronbach’s α was calculated with acceptable values ranging from 0.70 to 0.95. Test-retest analysis was performed using paired t-tests and McNemar Chi-square test. With 100 patients the study had 84% power to detect relatively small effect sizes (i.e. good precision) ≥ 0.6 [18]; power ≥80% to detect differences in proportions ≥27 percentage points [19]; and power = 86% to detect Chronbach’s α>0.7 compared to a null hypothesis = 0.5 [20]. A p value of < 0.05 was considered statistically significant. Statistical analysis was performed using SAS v9.4 (SAS Institute, Cary, NC).

Ethics statement

This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethics Committee, University of the West Indies, Mona, Kingston, Jamaica (IRB No. ECP 20, 16/17), and individual consent was obtained from each patient.

Results

Demographics and priapism characteristics

A total of 100 sickle cell disease patients with a history of priapism completed the questionnaire. Of these, 86.8% had Hemoglobin SS disease, 6.6% had Hemoglobin Sβ-thal disease, and 6.6% had Hemoglobin SC disease.

Patients were stratified into active (54) and remission (46) priapism groups based on whether they experienced a priapism episode within the past year. Patients in the active priapism group were younger (p = 0.011), had a shorter duration of disease (p = 0.023), and had more frequent priapism episodes (p = 0.036) than the remission group (Table 1). No significant differences were seen between the two groups for age of onset of priapism, priapism severity or ED rates.

Table 1

Demographic and clinical characteristics of active and remission priapism patients.

	Active Priapism (n = 54)	Remission Priapism (n = 46)	P-Value
Median Age, yrs (IQR)	26.5 (22–33)	32 (24–42)	0.011
Marital Status, n (%)			0.192
Married	4 (10.3)	8 (21.1)
Unmarried	35 (89.7)	30 (78.9)
Hemogloblin Status, n (%)			0.259
HbSS	38 (90.5)	28 (82.4)
HbSβ	3 (7.1)	2 (5.9)
HbSC	1 (2.4)	4 (11.8)
Priapism History, yrs median (IQR)
Age of Onset	17 (14–22)	20.0 (14.5–25)	0.186
Overall Duration	7.5 (4–14)	10.5 (6–22)	0.023
Episode Frequency, n (%)			0.036
Daily (1–7 episodes/wk)	20 (43.5)	8 (21.6)
Monthly (<4 episodes per month)	26 (56.5)	29 (78.4)
Episode Duration, n (%)			0.867
≤2 hrs (“very minor”)	30 (58.8)	21 (55.3)
2–5 hrs (“minor”)	19 (37.3)	16 (42.1)
>5 hrs (“major”)	2 (3.9)	1 (2.6)
Erectile Dysfunction, n (%)	19 (38.8)	22 (48.9)	0.323

Questionnaire outcomes

Patients uniformly completed the questionnaire within 15 minutes with no difficulties. For criterion-oriented validity, we demonstrated the ability of both the total and subscale dimensions of this instrument to distinguish between subgroups, finding uniformly higher scores for active priapism and existent ED relative to their converse conditions, but no statistically significant difference for priapism severity. The active priapism group had a significantly higher total PIP score, and higher QoL, SF and PW scores than that of the remission group (all p ≤0.005) (Table 2).

Table 2

A Priapism Impact Profile (PIP) questionnaire criterion-oriented validity of domains based on comparison of patient subgroups.

Patient Subgroups	Priapism Activity, median (IQR)			Priapism Severity, median (IQR)			Erectile Dysfunction, median (IQR)
	Active (n = 54)	Remission (n = 46)	P value	High (n = 3)	Low (n = 86)	P value	Present (n = 41)	Absent (n = 59)	P value
Total PIP Score	37 (25–48)	21 (16–27)	0.0003	30 (19–48)	27 (18–42)	0.623	36 (19–50)	23 (18–33)	0.026
Quality of Life	13 (9–18)	7 (6–10)	0.0001	10 (7–19)	10 (6–16)	0.589	13 (8–19)	8 (6–11)	0.004
Sexual Function	10 (6–15)	5 (5–10)	0.005	9 (5–16)	7 (5–13)	0.220	11 (5–18)	6 (5–10_	0.008
Physical Wellness	12 (7–15)	7 (3–10.5)	0.001	10 (6–15)	9 (6–14)	0.556	10.5 (5–15)	9 (5.5–12)	0.147

Considering each of the individual PIP questions separately, the instrument was able to distinguish between subgroups in the entire sample with most questions exhibiting significantly higher scores for active priapism and presence of erectile dysfunction but not priapism severity (Table 3).

Table 3

PIP questionnaire criterion-oriented validity of questions 1–12 based on comparison of patient subgroups.

Items	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12
Priapism Activity, median (IQR)
Active	4 (2–6)	4 (2–5)	2 (1–3)	3 (1–5)	2 (1–4)	2 (1–3)	2 (1–4)	1 (1–2)	1 (1–3)	4 (2–6)	5 (3–6)	2 (1–4)
Remission	4 (2–5)	1 (1–3)	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–3)	2 (1–4)	3 (1–6)	1 (1–3)
p value	0.172	<0.0001	0.005	0.0005	0.010	0.057	0.003	0.578	0.441	0.002	0.002	0.157
Priapism Severity, median (IQR)
High	4 (2–6)	3 (1–6)	2 (1–3)	2 (1–5)	2 (1–4)	2 (1–3)	2 (1–3)	1 (1–2)	1 (1–3)	3 (1–5)	6 (2–6)	1 (1–4)
Low	4 (2–6)	2 (1–5)	1 (1–3)	2 (1–3)	1 (1–3)	1 (1–2)	1 (1–3)	1 (1–1)	1 (1–3)	3 (1–6)	4 (3–6)	1 (1–3)
p value	0.908	0.510	0.488	0.307	0.642	0.064	0.306	0.113	0.646	0.409	0.165	0.438
Erectile Dysfunction, median (IQR)
Present	5 (3–6)	4 (2–6)	2 (1–4)	3 (1–5)	2 (1–4)	2 (1–3)	2 (1–4)	1 (1–2)	2 (1–4)	3 (1–6)	6 (2–7)	2 (1–4)
Absent	3 (2–4)	2 (1–4)	1 (1–2)	2 (1–3)	1 (1–2)	1 (1–2)	1 (1–2)	1 (1–1)	1 (1–2)	3 (1–4)	4 (2–6)	1 (1–3)
p value	0.007	0.008	0.0002	0.039	0.044	0.047	0.125	0.001	0.0004	0.295	0.167	0.131

See S1 File for the original Priapism Impact Profile Questionnaire

The PIP questionnaire had fairly good content validity, with patients assigning medium or high “clarity” or “importance” by an average of 82.8% and 69.2%, respectively, over all 12 questions (Table 4). The PIP questionnaire had excellent reliability. The item-total Cronbach’s α reliability coefficient for the total PIP score was 0.926. Individual PIP domains had α coefficients of 0.8577 for QoL, 0.925 for SF, and 0.778 for PW (Table 5).

Table 4

Content validity utilizing patient evaluation of Item importance and clarity.

	Number Rating Item as Medium or High/Number of Respondents to the Item
	Q1	Q2	Q3	Q4	Q5	Q6	Q7	Q8	Q9	Q10	Q11	Q12
Importance (%)	89/99 (89.9)	75/96 (78.1)	61/97 (62.9)	68/97 (70.1)	64/97 (66.0)	58/96 (60.4)	62/96 (64.6)	59/96 (61.5)	61/97 (62.9)	70/95 (73.7)	81/97 (83.5)	51/91 (56.0)
Clarity (%)	90/95 (94.7)	83/94 (88.3)	76/97 (78.4)	77/95 (81.1)	78/93 (83.9)	77/93 (82.8)	58/91 (63.7)	71/93 (76.3)	82/93 (88.2)	81/91 (89.0)	86/93 (92.5)	64/ 87 (73.6)

Table 5

Cronbach’s alpha reliability coefficients for PIP score, QoL, SF, and PW to demonstrate good item-domain/total instrument interrelatedness.

	Cronbach’s Alpha coefficients
Quality of Life	0.8570.790–0.881 (removing Q4 causes largest decrease)
Sexual Function	0.9250.897–0.927 (removing Q5 causes largest decrease)
Physical Wellness	0.7780.609–0.761 (removing Q11 causes largest decrease)
Total PIP	0.9260.915–0.929 (removing Q3 causes largest decrease)

Twenty patients completed the questionnaires a second time at an interval up to 1 year after initial completion. We compared retest vs. initial responses with respect to the individual 12 questions (S1 Table in S1 File); the Total PIP score and QOL, SF, and PW domains (S2 Table in S1 File); and the proportion who assigned medium-to-high importance or medium-to-high clarity to each of questions 1–12 (S3 and S4 Tables in S1 File, respectively). No comparisons were statistically significant with the exception of the question 3 importance, where medium-to-high importance was assigned by 90% of the 20 patients in their initial responses vs. 65% of retest responses (p = 0.05). Over all 12 questions, the average percentage of medium-to-high importance was 79.7% in initial response, and 77.5% in retest response (S5 Table in S1 File), and medium-to-high clarity was 89.9% in initial response and 92.8% in retest response (S6 Table in S1 File).

Discussion

In this external validation study, the PIP, a novel instrument developed to assess the general health-related impact of priapism in males, proved to be excellent with respect to validity and reliability among this Jamaican population with SCD. The generation of such a patient reported outcome tool is a milestone in the management of SCD males with priapism considering the burden of the disease in these males and the dearth of assessments of the quality of life impact associated with priapism.

With respect to criterion-oriented validity, the instrument was able to discriminate between patients with active and remitted disease, with the former having predictably higher scores. This was consistent with findings from the preliminary study [15]. Median total PIP scores in our study for active and remitted disease were 37 and 21, respectively compared to 45.5 and 21.5 in the preliminary study. The instrument was also able to significantly discriminate between patient groups based on erectile function. Patients with more severe ED had higher scores and greater bother, which was consistent with the preliminary study [15]. Most patients in the study had priapism episodes of low severity (≤2 hours duration), however, there was no difference in priapism severity scores between patients with active or remitted disease. Whereas in the preliminary study, the PIP was able to distinguish between patient groups based on disease severity score, we were not able to demonstrate this in our study. It is logical to believe that priapism episodes of greater than 2-hour duration would cause great distress due to prolonged episodes of pain. We suggest that patients in our study may have developed coping strategies which allowed them to have adjusted to the chronic pain leading to less distress and bother and lower PIP scores. Studies on patients with SCD with chronic pain have demonstrated that coping strategies were predictors of adjustment and influenced psychological distress [21]. Our study did not evaluate coping strategies in enrolled patients.

The content validity demonstrated in the original study was validated in our population of patients with SCD. All questions in our study were rated as having medium or high clarity and importance by 82.8% and 69.2% of patients, respectively. This compares favorably to 93% and 78% of patients, respectively, in the preliminary study [15]. Several questions, inclusive of questions 3, 6 and 12 were rated as having lower importance than in the original study. The differences in these responses could be attributed to cultural differences and communication norms between the study populations.

The instrument’s internal consistency (Cronbach’s α), which is a reliability measure of item intercorrelation, was 0.926 in our study. This was similar to the findings in the preliminary study where the Cronbach’s α was 0.9 [15]. We defined an acceptable Cronbach’s α as 0.7 to 0.95 and both studies have acceptable reliability measures. The test-retest reliability was excellent in our population. Unfortunately, some of the patients returned with delays of up to 1 year for retesting due to socio-economic factors.

Instruments have been used in the SCD population to assess quality of life in general [22-27]. The WHOQOL-Bref and the Short form-36 (SF-36) questionnaires which have applicability in diverse clinical settings are instruments that have been used to assess quality of life in SCD [22,27]. Other instruments such as the Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) and the Sickle Cell Impact Measurement Scale (SIMS) have also been used. Very few of the instruments used to assess quality of life in SCD are validated in this population [26]. The PIP is the only instrument that has been designed to primarily assess quality of life in priapism only. The PIP therefore serves as a new quality of life tool in the management of patients with priapism in SCD.

The PIP will be very useful in the clinical setting in any patient with recurrent priapism. It should ideally be used as a routine screen for all patients and those with high scores should be referred for psychological assessment and treatment. The tool will also be useful during treatment to assess the impact of treatment on quality of life, sexual function and physical wellness by observing changes in scores with time. Additionally, the PIP will give more insight in the natural history of priapism in sickle cell disease by observing changes in scores over time and during various active phases of the disease.

Several strengths of this study are noteworthy. The study comprises a rather large sample size of patients with SCD-associated priapism, which is uncommon in many literature reports for this disease state. In addition, given the strict inclusion criteria for our study population, the findings are informative for SCD- associated priapism differentiated from other causes of priapism. In addition, the external validation of the instrument in a culturally distinct population, differing from the original study population, is important. This validation suggests the comprehensiveness of this instrument and its potential universality in further use.

Several limitations require mentioning. The study represented a single-institution analysis and therefore results may not be generalizable to all patients with SCD. Due to the cross-sectional design of the study, the instrument was limited in assessing changes in QOL with time. Recall bias could be an important bias inherent in this type of study, considering that the data relied on patient recall. In addition, patients with acute complications of SCD were excluded from the study, hence the generalizability of our results to patients with acute illnesses is uncertain. Data on the presence of complications of SCD were not collected, hence the presence of these may have been confounders in the evaluation of QOL. In addition, the questionnaire was restricted to adult males so we cannot comment on its performance in non-adults with priapism. We validated the PIP in a Jamaican population including men only with SCD- associated priapism, so validation is needed in a non-SCD population. We believe that a process of adaptation of the questionnaire in the future is prudent, considering the cultural differences between the two study populations. This process of adaptation will bear in mind culture discourse norms in Jamaica and may change the perception of the importance of some of the questions as well as the severity of priapism.

Conclusion

In conclusion, our study presents the first external validation study of the novel PIP questionnaire using a population of men with SCD in Jamaica. The instrument demonstrated sound psychometric performance, suggesting that it offers practical utility in the management of priapism. Specifically, it may be used by the clinical practitioner for assessing the baseline health-related impact of priapism in the afflicted individual. It is conjectured that the instrument will prove useful in assessing the effectiveness of existing and novel therapies in the management of priapism. Ongoing investigation including clinical trials is warranted to determine its use in monitoring outcomes in priapism associated with SCD and possibly other etiologies of priapism.

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4 Aug 2021

PONE-D-21-19408

External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease

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Reviewer #1: The study team is to be commended on conducting an important study to further validate an instrument to measure priapism. The approach and analysis to analyze the psychometric properties was excellent. I have a few suggestions to present the work more clearly.

Table 2 – flip the columns and rows

Table 3 – not helpful, can you publish the actual PIP questions? If yes, then I would consider as a separate table. As is this table is confusing and would need a legend. I see it is included as supplemental; I would include in the main manuscript.

Table 4 – also not helpful and not really clearly presented. It looks like there were several items that scored low in level of importance. Was there discussion about eliminating these items? This should be discussed in the discussion section.

Table 5 – can you include a more typical presentation of the factor analysis results? Internal consistency, were there specific items that look like they could have been eliminated? Since an item analysis wasn’t presented I am not sure.

Could the team sit down together and discuss how to revise the tables to maximize their presentation of the results?

Great results.

Discussion:

P1 – “Landmark”, can you tone this down a little bit?

Overall the discussion is acceptable, not exciting, but acceptable. Can you include a little more on how this scale could be useful in a clinical setting? Would this become a routine screen? What would be the result of the screen? Referral to who? How would this help patients? I know it is an important instrument and would be beneficial to healthcare providers, but perhaps a paragraph on incorporating into the clinic setting and how it would help improve male’s lives would be beneficial to the reader.

Reviewer #2: In their original article entitled: “External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease”, Morrison et al. evaluated the validity and reliability of the priapism impact profile (PIP) in assessing the general health-related impact of priapism in a cohort of patients with sickle cell disease (SCD). Priapism is a frequent complications of SCD, and is known to alter the quality of life and can lead to erectile function. Assessing the impact of priapism in the course of SCD patients is thus of high importance. The PIP was originally designed and tested only once at the Johns Hopkin hospital in the United States. An external validation of this tool and preferably in the different setting was much needed.

To assess the validity of the PIP, Morrison et al. administered the questionnaire to 100 SCD patients recruited from a sickle cell clinic in Kingston, Jamaica. Patients were divided into active and remission priapism groups. The PIP tool was able to distinguish between subgroups with respect to active priapism, presence of erectile dysfunction, but not for priapism severity. Also, the PIP questions were rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively. Based on these results, the authors advocated for the possible use of the PIP for the clinical management of Priapism and for the assessment of priapism therapies. Morrison et al. used a comprehensive and reproducible method to collect and analyze data, their results are well organized and presented, and the conclusions they made derived directly from their findings. I thus recommend the article by Morrison et al. for publication in PLOS ONE, subject to addressing the following minor comments:

Comment 1: The aim for this study was to assess the validity and the reliability of the PIP tool. The authors emphasized more on the validity of the tool, but did not clearly stated whether the tool was reliable or not. Please the reliability of the tool should be clearly mentioned in the results section.

Comment 2: Also, the reliability score (Cronbach’s α) was higher in the original/preliminary study (0.9) as compared to that of the present study (0.78). The authors explained that this difference may possibly be due to some factors such as degree of religiousness, life setting (urban vs rural), and level of noise in the interview area. This also give credit to the effect of the difference with respect to study settings on the reliability of the PIP. The authors should discuss a possibly amendment/adaptation that can be done to the PIP tool for it to suit the Jamaican context.

Comment 3: The PIP tool was able to distinguish difference with respect to priapism severity in the preliminary study performed at the Johns Hopkin Hospital, while it was not able to do so in the present study. In addition to the coping mechanisms as mentioned by the authors, this difference of result may also be due to the cultural difference between the two study settings. Therefore, as mentioned in my previous comment, the authors should discuss a possible adaptation of the PIP instrument to their actual study setting.

Comment 4: P9/L195-196: The active priapism group had significantly higher quality of life score as compare to the remission group. Does this finding means that according to the PIP tool patients with active priapism have better quality of life as compared to patients in remission? This finding should be clarified and discussed by the authors as well.

Comment 5: the authors found that 69.2% of patients rated questions from the PIP as having medium to high importance. This means that nearly 30% of the participants think that some questions are not important. The authors should discuss how they think the questions that were rated as having a lower importance (Q3, Q6, Q12) can be edited/improved to suit the Jamaican context.

Reviewer #3: The sickle cell population has been misunderstood over 100 years in America despite its many potentially life threatening complications as well as morbidities that negatively affects quality of life. The authors have taken time to develop a much needed disease specific quality of life instrument to measure the effects of one unique but frequently encountered complication of priapism in this population. The PIP is a brief instrument and it measures quality of life , sexual function and physical Wellness they have defined and developed within the PIP instrument. The study measures its reliability responsiveness and to detect important changes within subgroups. The original PIP was developed without shortcuts using the standard 5 step QOL instrument development in 2011 tested throughout 2014 which showed that it was reliable and valid then. The authors took the time to do a an externally validation in 100 in collaboration with a large sickle cell center in Jamaica. A PIP questionnaire this cohort of adult patients with sickle cell disease having both active and remitted remittent priapism in Kingston Jamaica. Although the number of subjects evaluated are small compared to other conditions such as diabetes, cancer, this is a catastrophic complication of adults and males with sickle cell disease and very important to establish QOL instruments that can be utilized to assess with drug study development , routine care, and with third payer parties. resulted in 100 patients to successfully test PIP validity.

The authors conducted the research with purpose and it is very important that we document quality of life issues among individuals with sickle cell disease.

In the discussion section the authors appropriately pointed out the advantages and limitations of the study in that it is a single institution analysis the cronbach alpha was on the low end and that they did not evaluate various treatments and acute complications which could have included blood therapy which may have even modified their results. However the patients gave their input and It was important and lined up with how they felt about the appropriateness of the instrument questions . Also mentioned that the study was limited only to the adult male population but they noted this occurs also in younger pediatric and adolescent sickle cell populations. This disease specific instrument targeting a very narrow specific complication in sickle cell patients is much needed .There are new pipeline therapies for which some have already been FDA approved. As such, this type of instrument is much needed.

Minor suggestions:

1. Table 3. Label under the Items column needs to be consistent for the reader by subgroup.

Active vs.Remisssion under the severity median column and under erectile dysfunction. Or I maybe reading it wrong. Please clarify.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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27 Sep 2021

September 22, 2021

Dr. Ambrose Wonkam

Academic Editor

PLOS One

Dear Dr. Wonkam,

RE: PONE-D-21-19408 External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease

Thank you for reviewing the submitted manuscript and considering our work for publication. We note the comments of the reviewers and seek to address each individually in the document herein. Please see our responses to each comment below.

Reviewer 1

Reviewer #1: The study team is to be commended on conducting an important study to further validate an instrument to measure priapism. The approach and analysis to analyze the psychometric properties was excellent. I have a few suggestions to present the work more clearly.

1. Table 2 – flip the columns and rows

Response

Thank you for your comments. The table was amended (See table 2 in results).

2. Table 3 – not helpful, can you publish the actual PIP questions? If yes, then I would consider as a separate table. As is this table is confusing and would need a legend. I see it is included as supplemental; I would include in the main manuscript.

Response

The PIP questionnaire was submitted with the original documents but will be uploaded again with the resubmission. A footnote will be included below the table directing readers to the S1 File with the PIP questionnaire. The table has also been reformatted to be reader-friendly.

3. Table 4– also not helpful and not really clearly presented. It looks like there were several items that scored low in level of importance. Was there discussion about eliminating these items? This should be discussed in the discussion section.

Response

Table 4 has been reformatted so that it is reader-friendly. The authors do not believe that the items that scored lower should be eliminated. We instead believe it is prudent that a process of adaptation of the questionnaire may be carried out considering cultural norms in Jamaica. This may allow the questionnaire to be more understandable for patients. (Please see lines Paragraph 1, page 20 of the discussion)

4. Table 5 – can you include a more typical presentation of the factor analysis results? Internal consistency, were there specific items that look like they could have been eliminated? Since an item analysis wasn’t presented I am not sure.

Response

Based on the Reviewer’s comment Table 5 has been revised to show the range for the change in Cronbach’s alpha associated with deleting each of the component questions one at a time as well as the overall Cronbach’s alpha for each domain. None of the items when deleted gave a large enough change to Cronbach’s alpha to justify eliminating it.

5. Could the team sit down together and discuss how to revise the tables to maximize their presentation of the results?

Response

We thank the reviewers for these comments and have made changes to the tables for ease of reading. Table 5 had corrections made to the content. We apologize as the results erroneously presented earlier represented analysis of early incomplete data. We herein report the correct analyses with the finalized data for Table 5.

6. Great results.

Discussion:

P1 – “Landmark”, can you tone this down a little bit?

Response

We have replaced the term “landmark” with “milestone.” The authors believe that the novelty of the instrument, being the first of its kind and its potential use a tool in management of priapism warrants its description as a milestone achievement. (Please see paragraph 1, page 17)

7. Overall the discussion is acceptable, not exciting, but acceptable. Can you include a little more on how this scale could be useful in a clinical setting? Would this become a routine screen? What would be the result of the screen? Referral to who? How would this help patients? I know it is an important instrument and would be beneficial to healthcare providers, but perhaps a paragraph on incorporating into the clinic setting and how it would help improve male’s lives would be beneficial to the reader.

Response

The PIP will be very useful in the clinical setting in any patient with recurrent priapism. It should ideally be used as a routine screen for all patients and those with high scores should be referred for psychological assessment and treatment. The tool will also be useful during treatment to assess the impact of treatment on quality of life, sexual function and physical wellness by observing changes in scores with time. Additionally, the PIP will give more insight in the natural history of priapism in sickle cell disease by observing changes in scores over time and during various active phases of the disease. (Please see paragraph 2, page 19)

Reviewer 2

In their original article entitled: “External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease”, Morrison et al. evaluated the validity and reliability of the priapism impact profile (PIP) in assessing the general health-related impact of priapism in a cohort of patients with sickle cell disease (SCD). Priapism is a frequent complication of SCD, and is known to alter the quality of life and can lead to erectile dysfunction. Assessing the impact of priapism in the course of SCD patients is thus of high importance. The PIP was originally designed and tested only once at the Johns Hopkin hospital in the United States. An external validation of this tool and preferably in the different setting was much needed.

To assess the validity of the PIP, Morrison et al. administered the questionnaire to 100 SCD patients recruited from a sickle cell clinic in Kingston, Jamaica. Patients were divided into active and remission priapism groups. The PIP tool was able to distinguish between subgroups with respect to active priapism, presence of erectile dysfunction, but not for priapism severity. Also, the PIP questions were rated as having medium or high clarity and importance by an average of 82.8% and 69.2% of patients, respectively. Based on these results, the authors advocated for the possible use of the PIP for the clinical management of Priapism and for the assessment of priapism therapies. Morrison et al. used a comprehensive and reproducible method to collect and analyze data, their results are well organized and presented, and the conclusions they made derived directly from their findings. I thus recommend the article by Morrison et al. for publication in PLOS ONE, subject to addressing the following minor comments:

Comment 1: The aim for this study was to assess the validity and the reliability of the PIP tool. The authors emphasized more on the validity of the tool, but did not clearly stated whether the tool was reliable or not. Please the reliability of the tool should be clearly mentioned in the results section.

Response

The reliability measure (Cronbach’s alpha) is described in reference to Table 5 – please see lines 195-196. An addition was made to the results section stating that the PIP questionnaire had excellent reliability.

Comment 2: Also, the reliability score (Cronbach’s α) was higher in the original/preliminary study (0.9) as compared to that of the present study (0.78). The authors explained that this difference may possibly be due to some factors such as degree of religiousness, life setting (urban vs rural), and level of noise in the interview area. This also give credit to the effect of the difference with respect to study settings on the reliability of the PIP. The authors should discuss a possibly amendment/adaptation that can be done to the PIP tool for it to suit the Jamaican context.

Response

The authors again apologize for the incorrect Cronbach’s alpha score that was reported in the initial submission of this manuscript (please see response #5 to Reviewer 1). This result was based on analysis of older incomplete data. The current value is 0.926 which is acceptable and very consistent with the prior study.

Comment 3: The PIP tool was able to distinguish difference with respect to priapism severity in the preliminary study performed at the Johns Hopkin Hospital, while it was not able to do so in the present study. In addition to the coping mechanisms as mentioned by the authors, this difference of result may also be due to the cultural difference between the two study settings. Therefore, as mentioned in my previous comment, the authors should discuss a possible adaptation of the PIP instrument to their actual study setting.

Response

The authors agree that cultural differences between the study populations could account for the differences in the perception of severity of priapism between the two groups. We agree that a process of adaptation of the questionnaire should be considered for the future; basing the adaptation on cultural discourse norms. (Please see paragraph 1, page 20 of the discussion)

Comment 4: P9/L195-196: The active priapism group had significantly higher quality of life score as compare to the remission group. Does this finding mean that according to the PIP tool patients with active priapism have better quality of life as compared to patients in remission? This finding should be clarified and discussed by the authors as well.

Response

The higher quality of life score in the active priapism cases translated to poorer quality of life and greater distress in these patients. Please see the explanation in the methods, lines 91-93- “Higher scores indicate greater severity within each domain.”

Comment 5: the authors found that 69.2% of patients rated questions from the PIP as having medium to high importance. This means that nearly 30% of the participants think that some questions are not important. The authors should discuss how they think the questions that were rated as having a lower importance (Q3, Q6, Q12) can be edited/improved to suit the Jamaican context.

Response

The authors agree that cultural differences between the study populations could account for the differences in the perception of severity of priapism between the two groups. We agree that a process of adaptation of the questionnaire should be considered for the future; basing the adaptation on cultural discourse norms. (Please see paragraph 1, page 20 of the discussion)

Reviewer 3

The sickle cell population has been misunderstood over 100 years in America despite its many potentially life-threatening complications as well as morbidities that negatively affects quality of life. The authors have taken time to develop a much-needed disease specific quality of life instrument to measure the effects of one unique but frequently encountered complication of priapism in this population. The PIP is a brief instrument and it measures quality of life, sexual function and physical Wellness they have defined and developed within the PIP instrument. The study measures its reliability responsiveness and to detect important changes within subgroups. The original PIP was developed without shortcuts using the standard 5 step QOL instrument development in 2011 tested throughout 2014 which showed that it was reliable and valid then. The authors took the time to do a an externally validation in 100 in collaboration with a large sickle cell center in Jamaica. A PIP questionnaire this cohort of adult patients with sickle cell disease having both active and remitted remittent priapism in Kingston Jamaica. Although the number of subjects evaluated are small compared to other conditions such as diabetes, cancer, this is a catastrophic complication of adults and males with sickle cell disease and very important to establish QOL instruments that can be utilized to assess with drug study development, routine care, and with third payer parties resulted in 100 patients to successfully test PIP validity.

The authors conducted the research with purpose and it is very important that we document quality of life issues among individuals with sickle cell disease.

In the discussion section the authors appropriately pointed out the advantages and limitations of the study in that it is a single institution analysis the cronbach alpha was on the low end and that they did not evaluate various treatments and acute complications which could have included blood therapy which may have even modified their results. However the patients gave their input and It was important and lined up with how they felt about the appropriateness of the instrument questions. Also mentioned that the study was limited only to the adult male population but they noted this occurs also in younger pediatric and adolescent sickle cell populations. This disease specific instrument targeting a very narrow specific complication in sickle cell patients is much needed. There are new pipeline therapies for which some have already been FDA approved. As such, this type of instrument is much needed.

Minor suggestions:

Comment 1. Table 3. Label under the Items column needs to be consistent for the reader by subgroup.

Active vs. Remisssion under the severity median column and under erectile dysfunction. Or I maybe reading it wrong. Please clarify.

Response

Table 3 presents the criterion-oriented validity of questions 1-12 based on subgroups of priapism activity (active and remission), priapism severity (high and low) and erectile dysfunction (absent and present).

Submitted filename: response-to-reviewers.docx

Click here for additional data file.

30 Sep 2021

External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease

PONE-D-21-19408R1

Dear Dr. Morrison,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Ambroise Wonkam

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

7 Oct 2021

PONE-D-21-19408R1

External validation of the priapism impact profile in a Jamaican cohort of patients with sickle cell disease

Dear Dr. Morrison:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

Professor Ambroise Wonkam

Academic Editor

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