Modification and Validation of the RIPASA Score for Diagnosis of Acute Appendicitis
Modification and Validation of the RIPASA Score for Diagnosis of Acute Appendicitis
Purpose: The diagnostic approach of patients with acute appendicitis (AA) remains debated. A
 number of clinical prediction rules (CPRs) exist for diagnosis of AA with variable
 sensitivity, specificity, and diagnostic accuracy, in different ethnic populations. Among
 these, the Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) score was shown to have a
 high sensitivity though with a poor specificity. The aim of this study is to modify and
 validate the RIPASA score in 4 distinct ethnic groups, and to compare the performance of the
 new score to the original RIPASA and Alvarado scores.

 Methods: This multicenter, international prospective observational study will be conducted in
 6 countries, and will include all eligible patients referred to surgical specialists with
 acute right iliac fossa pain or suspected AA in the participating centres. Patients will be
 categorized into 4 ethnic groups based on the country of origin. The modified RIPASA score
 will be developed in one ethnic group, and along with the original RIPASA and Alvarado
 scores, will be externally validated in the other 3 ethnic groups. Management of patients
 will be prospectively evaluated in a standardized manner. The focus of the analysis will be
 on the performance of the 3 CPRs in different ethnic and gender groups using receiver
 operating characteristic curve analyses.

 Discussion: We expect this study to develop a CPR that can assist surgeons and surgical
 residents to early identify patients with AA in the busy clinical and low-resource settings,
 and to optimize the diagnostic value of the RIPASA and Alvarado scores in different ethnic
 and gender groups.
Introduction Acute appendicitis (AA) is the most common abdominal emergency requiring
 emergency surgery, and its preoperative clinical diagnosis remains a vexing challenge.
 Several clinical prediction rules have been developed to facilitate diagnosis of AA, and to
 predict severity of the disease, nonetheless there has been a controversy regarding the
 benefit of these CPRs in reducing negative appendicectomy rates and costs and improving
 surgical outcomes. Among these, the Alvarado score is the most commonly validated CPR,
 followed by Kalan's modified Alvarado score. The latter CPR is more user friendly and almost
 equally sensitive though less accurate than the original Alvarado score. Both scores are
 however more useful when used as "rule out" rather than "rule in" diagnostic tools,
 particularly in female patients of child-bearing age. Moreover, while numerous reports have
 demonstrated that these scores are reliable Clinical predictors for AA in western countries,
 parallel studies failed to replicate these results in different ethnic populations. This was
 partially ascribed to variations in the characteristics of the evaluated patients, and
 variable interpretation of variables by different clinicians in different settings.

 The Raja Isteri Pengiran Anak Saleha Appendicitis (RIPASA) score, which is based on 15
 clinical and laboratory parameters, has been recently validated by Erdem and colleagues, and
 compared to other three CPRs including the Alvarado score. The RIPASA score presented the
 highest sensitivity (100%, cut-off value of 7.5), whereas it had a poor specificity (28%).
 The diagnostic accuracies of the scoring systems however were almost comparable. In a recent
 meta-analysis conducted by Frountzas et al, culling data from 12 studies, the RIPASA score
 showed superior sensitivity (94% vs 69%) and area under curve (AUC) value (0.94 vs 0.79), and
 a lower specificity (55% vs 77%) compared to the Alvarado score. More importantly, ten out of
 the 12 studies in this analysis were carried out in Asian, Middle Eastern, and Latin American
 patients and evidenced that the RIPASA score consistently outperformed the Alvarado score in
 terms of diagnostic accuracy and sensitivity. On the other hand, none of the studies included
 African patients, and only two studies were conducted in western populations, showing
 conflicting results.

 A recent study has shown that the most reliable laboratory parameters in the diagnosis of AA
 are primarily "neutrophilia" and secondarily "leukocytosis". Nonetheless, different cut-off
 values for these predictors have been suggested in the literature. In a well-designed
 prospective blinded trial, Dueholm et al. demonstrated that the interquartile range (25%-75%)
 of the total white blood cell (WBC) count (x 109/ l) for "No appendicitis" and "Appendicitis"
 was 7.1-11 vs 11-16.3, respectively. The corresponding figures for neutrophils were 60-80%
 and 75-88%, respectively. The authors assessed the diagnostic value of tests combinations,
 and indicated that a diagnostic model using WBC > 11 (x 109/ l) as a cut-off value has the
 highest efficiency, with a negative predictive value of 98%. In contrast, Iyrik et al. showed
 that WBC count of 12 (x 109/ l) and neutrophils of 73% were the optimal cut-off values to
 discriminate between "Appendicitis" and "No appendicitis". Of note, the cut-off value for
 leukocytosis in the RIPASA score is not clearly defined, and the parameter "neutrophilia" is
 not included. Therefore and in light of the current evidence, we would like to introduce some
 modifications to the RIPASA score in order to improve the specificity and to make it simpler,
 reproducible, and applicable to busy clinical settings.

 Methods Hypothesis and objectives The hypothesis is that a better understanding of the
 performance of CPRs in relation to ethnic differences may improve their diagnostic value and
 may have a role in avoiding unnecessary operations, reducing the negative appendicectomy rate
 and improving patient outcomes.

 The primary objective of this study is to develop a modification of the RIPASA score in a
 Latin American population, and to externally validate the modified RIPASA (MODRIS) score in 3
 other ethnic populations (European, African, and South Asian). For comparison, the
 performance of the original RIPASA and Alvarado scores will also be analyzed.

 Secondary objectives are:

 -  To determine the specificity (the ability to diagnose non-appendicitis) and the
 sensitivity (the ability to diagnose acute appendicitis) of each CPR, based on the
 optimal cut-off on the receiver operating characteristic (ROC) curve.

 -  To determine the failure rate for each CPR, defined as the proportion of patients
 stratified to the "low-risk" group who do have appendicitis (reciprocal of the negative
 predictive value).

 -  To assess the postoperative outcomes, including negative appendicectomy rate, in
 patients who are classified as "low-risk" by each CPR. Accordingly, an algorithm will be
 proposed for management of low-risk patients in each ethnic group.

 Study setting and participants For this prospective multicentre cohort study, recruitment of
 the study subjects will take place in the participating centres in 6 countries during the
 study period November 1st 2019 to May 31th 2020. Patients will be stratified according to the
 country of origin into four ethnic groups: "African" originating from Nigeria and Sudan,
 "Latin American" originating from Mexico, "South Asian" originating from India and Pakistan,
 and "European" originating from Spain.

 Ethics and informed consent This study is conducted in accordance with the declaration of
 Helsinki. Participation in the study does not oppose a risk greater or different from the
 general surgical treatment of patients with RIF pain. To ensure data anonymity, no patient
 identifiable information will be collected by the main data manager. The study protocol was
 approved by the medical ethics committee of the trial coordinating centre (Soba University
 Hospital, Sudan, ID: 201903311). In other countries, local lead investigators were
 responsible for arranging research ethics committee or institutional approval locally, as
 appropriate. The study has been registered in the ClinicalTrials.gov database (ID:
 NCT04207645).

 Patient management and follow-up During the study period, the decision to operate on patients
 will depend on the surgeon's judgement, imaging findings, or both, and not any appendicitis
 scoring results. With the exception of the main investigators, all researchers who are
 involved in the data collection will be blinded to the three CPRs under evaluation. This is
 to ensure that predictors are assessed blinded to outcome. The clinical data of patients will
 prospectively be collected during the initial evaluation using standardized case report
 forms. These include demographics, clinical findings, laboratory investigations, imaging
 studies, operative details, and postoperative course. All patients, including those who are
 managed conservatively, will be followed up for 1 month to assess for postoperative adverse
 events or whether they required a subsequent operation.

 The patients will be dichotomized into two groups: "No appendicitis" group comprises patients
 who are managed conservatively, underwent negative appendicectomy, or have diagnoses other
 than AA, and "Appendicitis" group comprises patients who have histologically confirmed AA.

 Brief centre survey:

 At each participating centre, a consultant surgeon has completed a brief survey regarding the
 service characteristics and the clinical pathway of management of patients with RIF pain in
 their hospital.

 Definitions:

 -  Acute appendicitis is strictly defined as presence of acute inflammation, i.e
 polymorphonuclear infiltration in the muscularis propria of the appendix.

 -  Complicated appendicitis: defined as histologically or intraoperatively diagnosed
 gangrenous appendicitis, perforated appendicitis, and appendicitis with an abscess or
 periappendicular mass.

 -  Negative urinalysis: absence of Red cells, WBCs, or bacteria.

 -  30-day adverse events: these include wound infection, intraabdominal/pelvic abscess,
 unscheduled postoperative imaging, reintervention, readmission, or unexpected adverse
 postoperative event within 30 days of surgery on index admission.

 Predictors change:

 -  Omission of the "Rovsing's sign" and the "foreign national identity card". The former
 clinical sign is subjective and time consuming, and latter parameter has been included
 by the authors as there was a high percentage of foreign nationals who do not have free
 access to medical services in emergency settings. These circumstances are not applicable
 to many other countries. Furthermore, omitting the "foreign national identity card"
 parameter in two previous studies did not adversely affect the results.

 -  Including "neutrophil percentage" as a predictor in the new CPR, which has a good
 predictive value (0.91), with a fair sensitivity (0.71). We hypothesize that this
 addition will bolster the diagnostic accuracy.

 -  A total of 14 candidate predictors will be used to construct the MODRIS score.

 Sample size calculation The study population comprises a development and internal validation
 cohort (Latin American group), and 3 external validation cohorts (European, South Asian, and
 African groups). In each of the 4 groups, the sample size calculation will be based on a
 planned interim analysis that will be carried out at the start of the trial, and will involve
 the first 200 patients. The patients of this internal pilot study will be included in the
 validation cohorts. In the Latin American group, the number of final candidate predictors
 will be determined based on calculation of the number of events, and this is to verify an
 events-per-variable rate greater than 20. In each of the external validation cohort, an
 algorithm based on a binary logistic regression model, recently described by Palazon-Bru et
 al., will be used to estimate the required sample size for external validation of the MODRIS
 score. This method uses smooth curves rather than risk categorization, thereby providing
 greater validity to the results. Based on the results of the survey, it is anticipated that
 centres in each geographical region (5-11 centres per region) will capture a total of 60-200
 patients with RIF pain per month. Recruitment will continue in each region until the
 estimated sample size is reached.

 Statistical analysis Statistical analysis will be performed using SPSS version 22.0 (IBM
 corp., Armonk, NY, USA) and R 3.5.1 (Foundation for Statistical Computing, Vienna, Austria).
 Normal distribution of data will be assessed using visual inspection of histograms. Normally
 distributed data will be presented as mean with standard deviation (SD) and non-normally
 distributed data will be presented as median with interquartile range (IQR). Categorical
 variables will be presented as counts and proportions. Comparisons between groups will be
 performed using both parametric and non-parametric tests as appropriate. A two-sided
 significance level of P < 0.05 will be considered statistically significant. Missing data
 will be explored and if the percentage exceeds 10 % a multivariate imputation with chained
 equations will be performed.

 Development and internal validation of the MODRIS score: four continuous predictors (age,
 temperature, WBC count, and neutrophil percentage) will be transformed into basic cubic
 splines to determine the functional form of these predictors regarding the outcome risk. All
 candidate predictors, including all splines transformations of the continuous predictors,
 will be included in a logistic regression model and then a backward elimination method based
 on the likelihood ratio test (P < 0.25) will be applied to select the final predictors. In
 addition, gender will be included as a variable and interaction term for all symptoms and
 signs. The model will be adapted to a scoring system using the Framingham Heart Study
 methodology. The MODRIS score will be internally validated through a bootstrap technique with
 1000 random samples. Discrimination will be assessed by calculation of area under the
 receiver-operator characteristic curve, whilst calibration will be obtained through the
 construction of smooth curves.

 External validation: the MODRIS score will be externally validated in 3 ethnic groups.
 Simultaneously, discrimination of the RIPASA and Alvarado scores will be determined, and the
 DeLong test will be used to compare the difference between the AUCs of the 3 CPRs. The ROC
 analyses will be used to calculate the optimal cut-off value for the 3 CPRs in each ethnic
 group. The specificity, sensitivity, and negative predictive value will also be calculated.
 Based on the optimal cut-off value, patients will be stratified into "low risk" and "high
 risk" groups. An ideal CPR would achieve the highest specificity while maintaining a negative
 predictive value of ≥ 95% in the low-risk group. The postoperative outcomes of "low risk"
 groups will be compared between CPRs. In addition, gender-specific analysis will be carried
 out to assess the performance of the CPRs in each gender group.

 Discussion The current study aims to externally validate the MODRIS score, and to compare it
 to the original RIPASA and the widely used Alvarado score in 3 distinct ethnic groups, using
 a large, prospective international cohort. Although several previous studies have validated
 the latter two CPRs, most were either underpowered or had a retrospective design.

 In a recent multicentre study in Europe validating 12 CPRs for AA, the Adult Appendicitis and
 Appendicitis Inflammatory Response (AIR) scores were found to be the best performers.
 Nevertheless, both scores require C-reactive protein (CRP) measurement for their calculation.
 We did not include CRP level in the MODRIS score which makes it particularly useful in
 low-resource settings with limited access to diagnostic investigations. Although it
 correlates well with the severity of the disease and postoperative complications, a single
 CRP reading has only a modest positive predictive ability for AA, and its incorporation as an
 adjunctive test in the modified Alvarado score did not improve the diagnostic accuracy of the
 scoring system. Moreover, the MODRIS score maintains the advantages of the RIPASA score such
 as it requires calculation only at a single point in time, does not require special clinical
 experience, and includes the gender factor, thereby ensuring a lower false-positive rate of
 AA in female patients compared to Alvarado score.

 Implications for clinical practice Previous reports have indicated that AA in developing
 countries with limited resources has a different disease profile compared to that described
 in the developed world. It is associated with prolonged delays to definitive surgical care,
 significant morbidity, and poor outcome, which are partially ascribed to a much wider range
 of differential diagnoses of RIF pain than in the developed world, resulting in failure to
 early diagnose the condition. In another aspect, Scarborough et al. compared the
 postoperative outcomes of African and White American patients undergoing appendicectomy for
 AA. The analysis showed that the black race was independently associated with increased
 incidence of serious and overall postoperative complications. The authors suggested that
 blacks may suffer a delay in either diagnosis or management of appendicitis relative to
 whites. Clinical prediction rules have been advocated by several authors as one of the
 suggested strategies to improve outcomes of AA by facilitating clinical decision-making among
 junior doctors. Optimizing the diagnostic value of CPRs in different ethnic groups may help
 to improve the quality and safety of care and effectiveness of the management of patients
 suspected for AA, particularly in African patients and in resource-constraint environments.

 Limitations By the very nature of the multicentre design of the study and the variable
 clinical and laboratory assessment of patients in different centres, inter-observer
 variability is expected to present in the dataset and this may impact the internal validity
 of the study. However, efforts were made to minimise this inherent bias by recruiting centres
 from a limited number of countries, which are likely to follow a similar clinical pathway of
 management of AA. Data collection will be carried out using standardized forms designed to be
 completed at the patient's bedside, to reduce measurement and recall bias. Another limitation
 of the study is that the follow-up is limited to 30 days after the index hospital admission.
 It is possible that a proportion of patients who are managed conservatively may subsequently
 undergo appendicectomy either at other hospitals or beyond the 30-day follow-up. Furthermore,
 although we are trying to achieve high levels of case ascertainment, it is possible that a
 small number of eligible patients may be missed during the study period.
Inclusion Criteria:

 -  all consecutive patients age ≥ 16 years, who are referred to the on-call surgeon's
 team with acute right iliac fossa (RIF) pain or suspected acute appendicitis, will be
 included.

 Exclusion Criteria:

 -  history of previous appendicectomy

 -  previous abdominal surgery in the last 90 days

 -  history of chronic abdominal pathology (e.g. ovarian cyst, colitis .. etc)

 -  history of inguinal hernia

 -  pregnancy