Faculty of Medicine Ramathibodi Hospital Mahidol ... · peritonitis from a perforated appendicitis....

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Faculty of Medicine Ramathibodi Hospital,

Mahidol University

RACE 699 Dissertation

Doctor of Philosophy Programme in Clinical Epidemiology

(International Programme)

Title: Ramathibodi Appendicitis Score (RAMA-AS): A useful tool for

diagnosis of appendicitis

Name student Chumpon Wilasrusmee, MD

ID RACE/D 5336192

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CONTENTS

CHAPTER 1 .............................................................................................................................. 811

BACKGROUND & RATIONALE .......................................................................................... 811

1.1 Research Questions ...................................................................................................... 912

1.2 Research Objectives ..................................................................................................... 912

CHAPTER 2 ............................................................................................................................ 1114

LITERATURE REVIEW ...................................................................................................... 1114

2.2 Definitions ................................................................................................................. 2528

2.2.1 Appendicitis . ........................................................................................................... 2528

2.2.2 Migration of pain ...................................................................................................... 2528

2.2.3 Pain aggravated by coughing .................................................................................. 2528

2.2.4 Rebound tenderness. ................................................................................................ 2528

2.2.5 Rigidity. ..................................................................................................................... 2528

2.2.6 Abdominal pain ........................................................................................................ 2528

2.2.7 Vomiting. ................................................................................................................... 2528

2.2.8 Polymorphonuclear leukocytosis ............................................................................ 2528

2.2.9 Rovsing sign .............................................................................................................. 2528

2.2.10 Appendectomy .......................................................................................................... 2528

2.2.11 Negative appendectomy ........................................................................................... 2629

2.3 Conceptual framework ................................................................................................. 2730

CHAPTER 3 ............................................................................................................................ 3033

METHODOLOGY ................................................................................................................. 3033

3.1 Study design and setting .......................................................................................... 3033

3.2 Study subjects ........................................................................................................... 3134

3.3 Variables and Measurement ................................................................................... 3134

3.4 Data Collection ......................................................................................................... 3538

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3.5 Sample size estimation ............................................................................................. 3639

3.6 Cost effectiveness analysis of RAMA-AS ............................................................... 4144

3.7 Implementation of RAMA-AS and impact analysis .............................................. 4346

3.8 Ethics considerations ................................................................................................ 4447

3.9 Budget ........................................................................................................................ 4750

3.11 Time Frame ................................................................................................................ 4750

ACKNOWLEDGEMENT ...................................................................................................... 4851

TABLES ................................................................................................................................... 5558

A) Case record forms .................................................................................................... 7982

D) Dummy tables ....................................................................................................... 102106

B) Informal sheet & consent form ........................................................................... 108112

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TABLE OF CONTENTS

Table 1. Characteristics of studies that had developed prediction scores for

appendicitis…………………………………………………………………………54

Table 2. Risk of bias assessment……………………………………………………61

Table 3. Describe performances of predictive models of appendicitis……………..64

Table4. Describe variables that were included in the derive phase of predictive scores

of appendicitis………………………………………………………………………67

Table 5 Data from pilot study in 60 patients who was consulted for management of

abdominal pain and suspected of appendicitis at surgical unit of Ramathibodi

Hospital………………………………………………………………………………69

Table 6 Risk of bias assessment for clinical prediction rule of appendicitis……..…70

Table 7 Sample size estimation…………………………………………….……….75

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FIGURE OF CONTENTS

Figure 1: Identification of studies for inclusion……………………………………..77

Figure 2 Flow of patients and process of data collection……………………………78

Figure 3 Diagram of data analysis…………………………………………………..79

Figure 4 Decision tree of the RAMAAS model in diagnosis of appendicitis………80

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TITLE RAMATHIBODI APPENDICITIS SCORE (RAMA-AS): A

USEFUL TOOL FOR DIAGNOSIS OF APPENDICITIS

Chumpon Wilasrusmee, MD

Section of Clinical Epidemiology and Biostatistic, Ramathibodi Hospital

Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol

University

Email: [email protected]

Supervisors

Ammarin Thakkinstian, Ph.D.

Section for clinical Epidemiology and Biostatistics, Faculty of Medicine,

Ramathibodi Hospital, Mahidol University, Bangkok


Assist. Professor Dr. Patarawan Woratanarat

Department of Orthopedics, Faculty of Medicine Ramathibodi Hospital,

Mahidol University

Section for clinical Epidemiology and Biostatistics, Faculty of Medicine,

Ramathibodi Hospital, Mahidol University, Bangkok


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Panuwat Lertsitthichai, MD

Department of Surgery, Faculty of Medicine Ramathibodi Hospital, Mahidol

University


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CHAPTER 1

BACKGROUND & RATIONALE

Appendicitis is one of the most important clinical causes among acute abdominal

pain, with an incidence of 110/100,0001. Although many attempts have been made to

improve the diagnostic accuracy, false positive and false negative rates remain

common with rates of negative appendectomy of 15% to 26%2 3 and perforated

appendectomy of 10% to 30%4.

Several scoring systems have been developed for diagnosis of appendicitis with

interesting results nevertheless these systems have been less routinely applied in

general practice. We therefore performed a systematically review how those scores

had been developed and validated, and how their performances were. This review of

14 relevant studies suggested that 5 to 14 variables were included in the models with

the common variables were migration of pain, nausea/vomiting, and duration of pain

for clinical signs; rebound tenderness, RLQ tenderness, and elevated temperature for

symptoms. Most studies (64.3%) created prediction scores based on univariate results

or non-statistical models. The discrimination coefficient C statistics were 0.79 (95%

CI: 0.67, 0.90) for the derive studies and 0.84(0.77, 0.92) for the internal validation

studies. In addition, the pooled C statistics were 0.74 (95%CI, 0.69, 0.79) for external

validation of Alvarado scores. Our review suggested that qualities of research

methods for scoring systems of appendicitis were varied.

Although there are several diagnostic scoring systems available, applying them to the

general population might be questionable due to improper methods used for creating

scores. The more appropriate scores with internal and external validations are still

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required. We therefore conduct a cross-sectional study with aims at developing

Ramathibodi appendic score (RAMA-AS) using proper methods for creating and

validating a good clinical decision rule (CDR) in diagnosis of appendicitis.

1.1 Research Questions

Primary research question

1.1.1 What are variables contained in the RAMA-AS and how to calculate the

RAMA-AS?

1.1.2 Can the RAMA-AS perform well in classifying appendicitis from non-

appendicitis patients?

1.1.3 Will the RAMA-AS work well in internal and external settings?

Secondary research questions

1.1.4 Does our RAMA-AS work better than previous CDRs in diagnosis of

appendicitis?

1.1.5 Is our RAMA-AS cost-effective when compared with imaging diagnostic

including ultrasonography (US), computerized tomography (CT), and

magnetic resonance imaging (MRI) and diagnostic laparoscopy?

1.1.6 Will the RAMA-AS be used by physicians’ and help them to improve

outcomes in the diagnosis of appendicitis?

1.2 Research Objectives

Primary Objectives

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1.2.1 To develop a RAMA-AS for diagnosis of appendicitis.

1.2.2 To internally and externally validate RAMA-AS

Secondary objectives

1.2.3 To compare the performance of the RAMA-AS with previous scoring systems

including RIPASA score, Appendicitis Inflammatory response score, Alvarado

score, Fenyö-Lindberg score, Ohmann score, Eskelinen score, Simple scoring

system, Practical score of Ramirez and Deus, and Teicher score.

1.2.4 To compare the cost effectiveness of the RAMA-AS to diagnostic imaging

including US, CT, and MRI and diagnostic laparoscopy in the diagnosis of

appendicitis.

1.2.5 To develop RAMA-AS software which can simply classify appendicitis and

non-appendicitis patients.

1.2.6 To assess whether use of the RAMA-AS will be able to reduce diagnosis

imaging including US, CT, and MRI in real clinical practice.

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CHAPTER 2

LITERATURE REVIEW

2.1 A Systematic review of scoring systems for diagnosis of appendicitis

Appendicitis is one of the most important clinical causes among acute

abdominal pain, with an incidence of 110/100,0001. Although many attempts have

been made to improve the diagnostic accuracy, false positive and false negative rates

remain common with rates of negative appendectomy of 15% to 26%2 3 and

perforated appendectomy of 10% to 30%4. Several scoring systems have been

included computer-based models and algorithms that had been developed with good

performances at the initial evaluation, but fair when applied to general populations.

Nevertheless, these scoring systems have been occasionally applied in general routine

practice, because of a lack of accuracy in validation studies5. The drawback of the

negative appendectomy (i.e., false positive) was less life threatening than a false

negative which could be as worse as mortality from appendiceal perforation and

peritonitis from a perforated appendicitis. As a result, the aggressive surgical

approach was frequently applied when the situation was in doubt which resulted in

removal of normal appendices. In order to reduce the aggressive management,

diagnostic tests for appendectomy are required to improve performance in

discriminating those patients who require prompt surgical intervention from the

patients who need only observation without a risk of complication of appendicitis.

Imaging modalities have been used to improve diagnostic accuracy. However,

there are some disadvantages including cost, less accessible particularly in developing

countries, lack of radiologists, examiner-dependent efficacy (e.g., ultrasound),

potential harmful ionization (e.g., computerized tomography, CT), and low

performance in low or high prevalence of disease. Clinical scoring systems by

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synthesizing clinical information have been developed and should be useful for those

countries where imaging is less accessible. The scores are derived by incorporating

physical examination, clinical signs and symptoms in a mathematical equation.

Currently, there are a number of diagnostic scores constructed by many camps using

various statistical methods1 6-40. Some scores have been validated either internally8 39

or externally7-9 11 15 16 21 27 30 37-39 41 whereas some scores have been applied without

validation18 33. Performances of those scores varied from fair to good in validation

phases, but some scores were still questionable. We therefore conducted a systematic

review which aimed at exploring score performances in both development and

validation phases. Strengths and limitations of previous diagnostic scores were

critically appraised. Lessons from this review will help to identify the most valid

model/s or lead to create the new model if required. This model can be later applied in

general settings in developing countries where resources are limited.

Methods

Search strategy

We searched Medline from 1949 and EMBASE from 1974 to March 2012 to

identify relevant articles published in English. Search terms were included as follows:

appendicitis, gangrenous appendicitis, phlegmon, perforated appendicitis, abdominal

pain, score, scoring system, prediction score, prediction model, diagnostic score,

assessment tool, ultrasonogram, ultrasonography, computer tomography, accuracy,

negative appendectomy, sensitivity, specificity, likelihood ratio, false positive, false

negative, true positive, true negative, ROC, AUC. The search strategies are described

in the appendix.

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Study selection

Studies were reviewed based on titles and abstracts. If a decision could not be

made, full articles were retrieved. Observational studies (cohort, case-control, or

cross-sectional) published in English were selected if they met with the following

criteria: suspected adult appendicitis, considered more than one risk factor in the

prediction score, had the outcome as appendicitis versus non-appendicitis, applied any

equation (e.g., Logistic regression, Bayesian method, or non-mathematical-

investigator opinion based) to build up the prediction model, and reported each

model’s performance (i.e., calibration and discrimination parameters).

Data extraction

The general characteristics of studies (i.e., author, journal, publication year,

type of participants, ethnicity, study design, number of subjects, rate of negative

appendectomy, percent of complicated appendicitis, and specific objective/s (i.e.,

develop or validate score, or both)) were extracted. If the diagnostic model was firstly

developed, specific information about model building (i.e., type of statistical model,

predictive factors, creating scores using coefficients or exponential of coefficients)

were extracted. Calibration (a ratio of expected versus observed value (E/O ratio)),

and discrimination parameters (i.e., the concordance statistic (C-statistic)) along with

95% confidence interval (CI) were also extracted. These parameters were calculated if

the study did not directly report, but did provide summary data which allowed for

calculations. For studies which aimed at a validated model, the type of validations

(internal, external, or both) and results were also recorded. If authors had modified

the previous prediction models, the following aspects were recorded: whether any of

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the original included variables were removed or modified; and whether new predictive

factors were added.

Risk of bias assessment

The risk of bias assessment tool was developed based on a user’s guide for

clinical prediction rule42, which considered both derivation and validation phases.

Four domains were considered for the derivative phase, i.e., selection bias

(representative of spectrum), information bias (ascertainment of outcome

measurements, blinding outcome assessment, number of predictors, assessment

predictors without knowledge of outcome, proportion of important predictors),

confounding bias (used multi-variate regression analysis, created score properly), and

other issues (sample size, clinically sensible). For the validation phase, only 3

domains were considered, i.e., selection bias (representative of spectrum), information

bias (ascertainment of outcome measurement, blinded assessment of outcome,

accurate interpretation), and other issue (i.e., follow up). Each item was classified as

yes (low risk of bias), no (high risk of bias), and unclear if there was insufficient

information to judge (Table 1).

Two reviewers (CW and TA) had independently extracted data and assessed

risk of bias for all included studies. Any disagreement was discussed with the third

party (AT) to resolve.

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Statistical analysis

Model performances were described separately by derivative and validation

phases. Calibration (O/E ratio) and discrimination (C-statistic) coefficients along with

their 95% CIs were estimated for each study. A meta-analysis was applied to pool O/E

and C-statistic using the equations as described in the appendix. Heterogeneity was

assessed using Q statistic and a degree of heterogeneity I2 was estimated. If it was

present (p value <0.10 or I2 > 25%), a random-effect model was used to pool data,

otherwise a fixed-effect model was applied. All analyses were performed using

STATA version 12.0.

Results

Description of studies

We identified 440 studies of which 37 studies met our inclusion criteria and

thus were eligible for the review, see Figure 1. The characteristics of these studies

have been described in Table 2. Among those 37, 10 studies7 11 15 16 18 21 27 28 37 43 had

aimed only at derived prediction scores or modified the previous prediction models

(hereafter called derived studies), 4 studies8 33 38 39 had derived and internally and

externally validated in the same studies, whereas 23 studies had only aimed at

internal9 30 and external1 6 10 12-14 17 19 20 22-26 29 31 32 34-36 40 validations.

Among 14 derived studies7 8 11 15 16 18 21 27 28 33 37-39 43, all studies focused on

adult patients, and most studies included patients with suspected appendicitis who

received operation or their conditions were being observed whereas 3 studies33 37 39

included only patients who received operations. Ten models7 8 11 15 16 18 27 33 37-39 43

were developed in Caucasian populations while three models11 21 28 were in Asian

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populations. The models were mostly constructed based on cohorts either

retrospective7 33 39 or prospective cohorts.8 15 16 18 21 27 28 38 43

Among 23 studies that aimed only for validation, 20 studies had validated

models on patients with suspected appendicitis whereas 3 studies had focused on

operated patients. Most study designs were prospective cohorts. Fifteen studies were

done in Caucasian while 8 studies were done in Asian populations.

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Risk of bias assessment

Risk of bias assessments was performed and results have been described in

Table 3. Among 14 derivative studies, 8/14 (57.1%) studies had recruited consecutive

patients with chief complaints of abdominal pain, or randomly sampled patients from

a well defined population frame of abdominal pain; whereas the remaining studies had

recruited a specific group of patients who had at least a few clinical signs and

symptoms. Most studies (92.9%) had confirmed the diagnosis of appendicitis by

histology without mention of whether histology was performed without blinding

clinical information. The numbers of predictors used in the prediction models were

covered and appropriated (i.e., low risk of bias) if authors considered and used

predictors from all categories which were demographic, clinical signs, symptoms, lab,

and imaging data; otherwise this item was graded as high risk of bias. Ten out of

fourteen (71.4%) studies clearly listed all categories of predictors where the remaining

studies considered only a few categories. Only 5/14 (35.71%) studies stated clearly

how they measured or collected predictors in the way that assessors were blinded

from knowledge of the final diagnosis of appendicitis, lab, and imaging findings,

whereas 57.14% of studies used predictors which were not blinded or assessed with

knowledge of possible diagnosis of appendicitis.

Eleven out of fourteen studies (78.7%) had performed statistical estimations or

tests for all predictors, whereas 3/14 (21.3%) studies did not apply any statistical

method. However, only 5/14 (35.7%) studies had applied multivariate regression by

simultaneously including significant predictors in the models, and used coefficients or

relative risks suggested from regression models to create scores, whereas the

remaining studies created prediction scores based on univariate results or non-

statistical models.

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Twelve (85.7%) studies had sufficient numbers of subjects for either appendicitis or

total subjects considered based on a rule of thumb (1 predictor per 10 appendicitis

subjects or 20-30 per total subjects). Some studies (71.4%) included predictors that

seemed to be clinically sensible, the scores were easy to apply and also had suggested

a course of clinical action.

For validation studies, 21/25 (84%) studies were less likely for selection bias.

An ascertainment of diagnosis of appendicitis was clearly defined in 24/25 (96%)

studies. All studies did not mention whether diagnosis of appendicitis was masked

from clinical data. Thirteen out of twenty five (52%) studies clearly described that

interpretation of the rule was not influenced by information of final diagnosis of

appendicitis, while 24% was influenced by diagnosis of appendicitis and 24% did not

mention it. Only 6 (24%) studies had followed up all included patients.

Score development

Among 14 derivative studies, 5 categories of predictive variables were

considered in the models including demographic data, clinical signs, clinical

symptoms, laboratory results, and imaging (Table 4). Among 2 demographic

variables, gender was the more commonly included in the model compared with age

(42.9% vs 14.3%). Ten symptom variables were considered in which nausea (9/14,

64.3 %) was the most commonly included in the model followed with migration of

pain, pain at presentation, or duration of pain (all were 46.2%). Nine clinical signs

were considered and the most common variables used were rebound tenderness

(76.9%), followed with right lower quadrant (RLQ) tenderness (61.5%), and RLQ

guarding (53.9%) or elevated temperature (53.9%). Among 10 clinical symptoms,

nausea/vomiting (53.9%) followed with migration and duration of pain (46.4%) were

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the most commonly included in the predictive models. Most studies (84.6%)

considered at least one lab variable. Among these, rising white blood cell count

(76.9%) was the most commonly used followed with left shift of polymorphonuclear

cell (46.2%). Only a few studies used radiological data (e.g. ultrasonography and

abdominal radiograph) in creating scoring systems.

As described in Table 2, these prediction scores were developed using

statistical modeling in 5 studies8 15 27 38 39 whereas 9 studies7 11 16 18 21 28 33 37 43 did not

apply statistical modeling. Among 5 studies with statistical modeling, 4 studies8 15 27

38 applied multivariate logistic regression and 1 study39 used discriminant analysis.

Scoring schemes of these models were created based on regression coefficients of the

logit or discriminant regression models. Among 9 studies that did not apply statistical

models, a univariate analysis (e.g., Chi-square test, relative risk) and estimated

diagnostic parameters (e.g., likelihood ratio, sensitivity, specificity) were used for

assessing associations in 6 studies whereas 3 studies did not apply any statistical

analysis tests.

Model performances

The models’ performances using C-statistics and O/E calibration coefficients

were extracted from individual studies, if reported, otherwise they were estimated

using summary data reported in the articles, see Table 5. Among 10 studies where the

calibration coefficient O/Es were available, the O/Es were very similar across studies

with the overall pooled O/E of 1 (95% CI: 0.97, 1.03). Contrastingly, the

discrimination coefficient C statistics varied from poor (0.54) to excellent (0.97)

discrimination with the pooled C statistic of 0.79 (95% CI: 0.67, 0.90). The C

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statistics were very varied among 2 studies15 38 (i.e., ranged from 0.59 to 0.97) with

appropriate statistical methods to derive prediction scores.

Six out of 14 prediction models had internally validated their prediction

scores, but only 5 had data available. The discrimination coefficient C statistics

ranged from 0.61 to 0.92 with the pooled C statistic of 0.84 (0.77, 0.92). Pooling

within subgroups according to appropriateness of derived predictive scores suggested

similar results with the C statistics of 0.81 (95%CI = 0.65, 0.97) and 0.88 (95%CI =

0.85, 0.91) for appropriate and inappropriate derived predictive scores, respectively.

Twenty-three studies had been conducted which aimed at external validation

of 14 prediction models. The Alvarado score7 was frequently validated in 14 studies6 8

10 12 13 19 20 23 26 29 31 32 35 38 followed by Fenyo model in 3 studies14 17 38. The study by

Tzanakis et al38 had externally validated 8 previous models, and thus was a major

contributor of data in poolings. Most studies created diagnostic scores using

predictive factors according to the original scores. Data used for validations were 15

Caucasian1 12-14 17 20 22 23 25 29-31 34 40 43 and 8 Asian6 10 19 24 26 32 35 36 population studies.

Fourteen studies had externally validated Alvarado scores. All eight variables

(i.e., migration of pain, anorexia, nausea/vomiting, elevated temperature, rebound

tenderness, RLQ tenderness, increase WBC, and PMN left shift) were included in the

external validated models with the pooled E/O and pooled C-statistic of 0.99 (95%CI,

0.91 to 1.09) and 0.74 (95%CI, 0.69, 0.79), respectively. The Alvarado score was also

modified by two subsequent studies which excluded the shift to left of PMN because

this data was unavailable in a routine laboratory 21 41, or replaced it with a few other

variables (i.e. cough test, Rovsing’s sign, rectal tenderness)41.This made the score

performance change from 0.80 (95%CI, 0.73, 0.86) to 0.76 (95%CI, 0.60, 0.92) with

PMN exclude, and even worst for replacing PMN with a few more variables with the

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C-statistic of 0.54 (95%CI, 0.45, 0.63). External validation of other scoring systems

was performed in 9 models with the pooled statistic of 0.81 (95%CI: 0.77, 0.84), but

this was mainly contributed to by Tzanakis, et al38 which had validated 7 models. (In

the above paragraph you stated 8 models.) Pooling external validated studies

according to appropriate and inappropriate original model construction resulted in the

C statistics of 0.80 (95% CI: 0.65, 0.94) and 0.77 (95%CI: 0.74, 0.81), respectively.

Discussion

We have reviewed performances of diagnostic models for appendicitis. Most

models yielded relatively fair to good performances in discrimination with the pooled

C-statistic of 0.84 (95%CI 0.77, 0.91) in settings where the models were developed

and 0.78 (95%CI 0.74, 0.82) in settings where the models were applied. However,

only one third of scores were appropriately derived based on regression models.

For those models with good to excellence external performances (C-statistic

≥0.8), 10 variables were commonly included in the models, which were migration of

pain, anorexia, nausea/vomiting, duration of pain, elevated temperature, rebound

tenderness, right lower quadrant tenderness, guarding, increased white blood cells,

and left shift of PMN. These models were originally developed using proper

statistical modeling (i.e., logistic regression) in only 2/23 studies whereas the rest had

used results of diagnostic parameters or univariate analysis (i.e., Chi-square test)

without proper rationale for weighting in prediction scores.

The Alvarado score , developed by Alvarado et al7 since 1986, was the most

popular prediction model for diagnosis of appendicitis which aimed at identifing

patients who should go to operation or observe. The model was originally developed

using data from 277 Caucasians to assess the association between 8 predictive factors

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and appendicitis. These predictive factors included localized tenderness at the right

lower quadrant (RLQ) of abdomen, migration of pain, elevation of temperature,

nausea/vomiting, anorexia/acetone in urine, rebound tenderness at RLQ of abdomen,

leukocytosis, and shift to the left of polymorphonuclear cell (PMN). The diagnostic

parameters (i.e., sensitivity, specificity and accuracy) were estimated for each

individual predictive factor and used for creating the predictive score. The

discrimination ability C-statistic was 0.80 (95%CI, 0.73, 0.86) in the derivative phase

which dropped to 0.74 (95%CI, 0.69, 0.79) after external validation.

Since the PMN is unavailable in a routine laboratory 21 41, it was excluded

from the model which yielded a bit lower performance in the derived phases (C-

statistics 0.80 vs 0.76), but it was far worst if it was replaced with a few clinical

variables (i.e. cough test, Rovsing’s sign, rectal tenderness; C-statistics 0.80 vs 0.54).

The E/O ratio is commonly used to measure the closeness of the predicted and

the observed values. The C-statistic is usually applied to measure how well the model

will assign a higher probability of having an event to an appendicitis group and a

lower probability to a non-appendicitis group44. The association between diagnostic

factors and appendicitis derived from the derived data may occur by chance. This

problem is prominent in situations in which there is a relatively small sample size

compared with the diagnostic factors included in the model. With a small sample size,

it is more likely to select unimportant variables, but omit some important variables

from the model34. Conversely, a very large sample size is more likely to include

statistically important variables without clinical importance. The number of subjects

with events should be at least 10 and safer with 20 or larger per one risk factor to

derive a valid model as for simulation studies35 36. For the results of our review, the

number of variables included in the model varied from 4 to 18 variables, so the

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required number of appendicitis cases should therefore be at least 40 to 180 subjects,

and 80 to 360 subjects to be safer. Six out of 14 derived studies9 11 18 21 27 37 had their

number of appendicitis cases less than the required numbers by including 5 to 14

variables with total appendicitis cases of 43 to 261 patients.

Although the performances of predictive scores in the derived phase, internal,

and external phases were good (C-statistic = 0.79, 0.84, and 0.78, respectively),

applying these scores to a general population was less confident because most scores

were created inappropriately. Most studies (64.3%) derived predictive scores using

univariate analyses or estimated diagnostic parameters and used results from these

analyses to create scores. The rationale of choosing a method for creating the

predictive score was not clearly described. In addition, these scores were based on

univariate analyses and thus confounding bias might be present.

Differences in the distribution of risk factors across populations may also

affect the generalizability of the model to different populations. The C-statistics

derived from external validation usually tend to be lower than the C-statistics derived

from internal validation. Our results suggested that the pooled C-statistic from

external validations had slightly lower C-statistic than from internal validation.

However, pooling of external validations was dominated by the Tzanakis, et al38

study which had used the same subjects to validate 9 scoring systems. Excluding this

study from pooling resulted in the C-statistic of 0.75 (95%CI 0.74, 0.82).

Our review suggested that the research methods and reporting of research

findings in diagnostic scoring systems of appendicitis showed discrepancy. Some

research groups have advocated and developed research methods and reporting

recommendations for conducting research in this area.45 46 In addition, a user’s guide

for reading and use of evidence for this area has been also developed42 to improve

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research methods, reporting, and use of evidence of prediction scores. We have

modified and used this tool for our study. The type of studied subjects, study design,

validity of measurements for outcome and diagnostic factors, and use of statistical

methods were mainly reported in most of the model developments. However, only

50% (7/14) of the derived studies had developed scores and were internally tested in

the same studies. Most studies (64.3%) had created scores without applying statistical

modeling. None of the studies reported calibration parameters and only 9 (39.1%)

studies in external validation performed discrimination analysis and reported the C-

statistic. The models seemed to be clinically sensible in 71.4% (10/14 studies) which

were simple and easily interpretable.

In conclusion, although there are several diagnostic scoring systems for

appendicitis, applying them to a general population might be questionable due to

improper methods used for creating scores and lack of external validations. The more

appropriate scores with internal and external validations are still required.

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2.2 Definitions

2.2.1 Appendicitis is inflammation of the appendix, which is the small, finger-

shaped pouch attached to the beginning of the large intestine on the lower-

right side of the abdomen. Appendicitis is a medical emergency, and if left

untreated, the appendix may rupture and cause a potentially fatal infection.

2.2.2 Migration of pain to the right lower quadrant pain starting either centrally

in the epigastric area, or in the whole abdomen then eventually migrating

down to the right lower abdomen.

2.2.3 Pain aggravated by coughing patient was asked to cough and any

worsening of pain was recorded.

2.2.4 Rebound tenderness elicited in the right lower quadrant when a hand

pressing the abdomen for 10-15 seconds was suddenly withdrawn.

2.2.5 Rigidity involuntary contraction of the abdominal muscles in the absence

of diagnostic evidence from an attribute.

2.2.6 Abdominal pain abdominal pain (not only right lower quadrant)

2.2.7 Vomiting one or more episodes.

2.2.8 Polymorphonuclear leukocytosis study as a total count 10,000/mm3

with polymorphs 75%.

2.2.9 Rovsing sign named by the Danish surgeon, Niels Thorkild Rovsing, and it

is a sign of suspected appendicitis. If palpation on the left lower abdominal

quadrant results in more pain in the right lower quadrant, the patients have

a positive Rovsing sign and may have appendicitis.

2.2.10 Appendectomy a surgical procedure to remove the appendix.

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2.2.11 Negative appendectomy histological of normal appendix was found from

appendectomy that was done for the purpose of treatment after the

diagnosis of appendicitis.

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2.3 Conceptual framework

RAMA-AS

Validation: Evidence of reproducible accuracy Internal (narrow) Validation External (broad) Validation

- Bootstap - Thammasat University Hospital - Chonburi Hospital

Introduce the software to RCST Evidence that the RAMA-AS: - Change physician practice -Improves patients outcomes - Reduces costs from imagings

Important Parameter - Demographic data: age, sex. - Symptom: migration of pain, anorexia, nausea. - Sign: elevated temperature, guarding of RLQ, rebound tenderness. - Lab: Increase WBC, PMN left shift, CRP.

Derivative phase: Identification of risk factors with appropriated model and predictive power

Economic analysis - Cost effectiveness - Cost utility

RAMA-AS Software development

Impact analysis

Pilot implementation - Faculty of Medicine Ramathibodi Hospital - Thammasat University Hospital

28

Clinical decision in the diagnosis of appendicitis is based on clinician experience

which is the integration of patient history, physical examination, and investigation.

Scoring system in diagnosis of appendicitis is a clinical decision rule which quantifies

the individual contributions that various parameters of patient history, physical

examination, and basic investigation results make toward the diagnosis of

appendicitis. This will pave the way to use a formal test, simplify, and increase the

accuracy of clinicians in the assessment of appendicitis. Development and validation

of RAMA-AS will involve 3 steps as shown: creating the clinical decision rule or

scoring system, validating the rule, and assessing the impact of the rule on clinical

behavior.

Derivative phase

The creating of a scoring system will involve the identification of parameters

with predictive power. All predictive parameter will be included and clearly

identified. Assessment of appendicitis will be done by a pathologist who is blinded to

the assessing parameters as well as the assessor for the parameters will be blinded

from the pathological diagnosis of appendicitis.

Validation phase

This phase will test the reproducible accuracy of RAMA-AS which will be

divided into 2 studies. Internal validation is a narrow validation which will apply the

RAMA-AS in a similar clinical setting and population as the derivative phase.

External validation is a broad variation which will apply the RAMA-AS in multiple

clinical settings with varying prevalence of appendicitis.

Impact analysis

This phase aims to find the evidence that RAMA-AS changes clinicians’

behavior and improves outcomes regarding the diagnosis of appendicitis.

29

Variables and appendicitis

Important parameters in the diagnosis of appendicitis will be divided into 4

groups: demographic data, symptoms, clinical signs, and laboratory results. Two

demographic variables that were commonly used in previously developed appendicitis

scoring systems were age and gender. Ten symptom variables were considered in

which nausea/vomiting, followed with migration and duration of pain were the most

commonly included in the predictive models. Nine clinical signs were considered with

the most common variable used was rebound tenderness, followed with right lower

quadrant (RLQ) tenderness and RLQ guarding or elevated temperature. Most of the

scoring systems considered at least one lab variable. Among these, rising white blood

cell count was the most common used followed with left shift of polymorphonuclear

cell.

All important parameters from previous systematic reviews will be included

in the derivative phase. Included predictive parameters in RAMA-AS must be

clinically sensible, easy to use, and suggest a course of action.

30

CHAPTER 3

METHODOLOGY

3.1 Study design and setting

The study will consist of 3 parts as follows:

Part I: Development and validation of RAMA-AS

Part II: Cost effectiveness analysis

Part III: Implementation of RAMA-AS

Part I: Development and validation of RAMA-AS

3.1.1 Study design and setting

The study design will be a cross-sectional study of patients who present with

abdominal pain and are suspected of appendicitis at the emergency department

between January 2013 to May 2014 will be included in this study.

Setting:

Development and internal validation of RAMA-AS: A Single center study

prospective cohort study in the Faculty of Medicine Ramathibodi Hospital,

Mahidol University from January 2013-May 2014.

External validation: Patients who were suspected to have appendicitis at the

Faculty of Medicine, Thammasart University and surgical unit at Chonburi

Hospital will be tested by using the RAMA-AS from June 2014-Decmber 2015

31

3.2 Study subjects

Inclusion criteria:

‐ Patients age 18-60 years

‐ Present at Emergency unit or Surgical outpatient department, Faculty of

Medicine Ramathibodi Hospital with right-side abdominal pain within 7 days

‐ Are suspected of having appendicitis by have at least one of the following

symptoms and signs:

o Symptoms: right lower abdominal pain, migration of abdominal pain,

anorexia, nausea, vomiting

o Signs: fever, right lower quadrant tenderness, guarding, rebound

tenderness, and decrease bowel sound

‐ Agree to participate and give consent to the study

Exclusion criteria

- Patients who cannot give the history of illness by themselves

- Patients who have severe underlying diseases and moribund such as severe

myocardial infarction and terminal illness

- Patients who have palpable abdominal mass

- Patients who are diagnosed as tumor or malignancy of appendix

- Patients who have metastatic tumor to the appendix

3.3 Variables and Measurement

3.3.1 Outcome of interest

3.3.1.1 Appendicitis

Acute appendicitis is a histo-pathological diagnosis which is diagnosed according to

the following criteria48:

32

‐ Macroscopic finding: intravascular injection of serosa, fibrinous, purulent

film, edematous, hemorrhagic, necrotic changes of the wall, and blood or pus

on opening of the appendix.

‐ Microscopic finding: focal or expanded erosion, ulceration, abscess.

Histological criteria for acute appendicitis is an inflammatory reaction with

polymorphonuclear leucocytes in the mucous layer of the appendix and edema.

3.3.1.2 Complicated appendicitis will be defined by a surgeon and/or pathologists

follows:

- The surgeon clearly identifies the perforation.

- A peritoneal swab or fluid culture grows at least one definite bowel organism

- The histopathologist identifies a perforation in association with gangrene or

full thickness necrosis.

3.3.1.3 Negative (non) appendicitis

Negative appendicitis is a histological normal appendix that is found from

appendectomy. For non-surgical patient, a negative clinical findings will be assessed

by telephone follow up at 1 month. If the patient cannot be contacted by telephone, we

will attempt to contact via express mail.

3.3.2 Predictive Variables

There are 4 domains of predictive variables as follows:

33

3.3.2.1 Demographic variables

-Age: age will be recorded as years at diagnosis. Appendicitis is most frequently

found in the age more than 40 years old with the mean and median age of 31.3 and 22

years, respectively.

-Sex: sex will be recorded as males or females. Male are more slightly prominent than

female with the ratio of 1.2 to 1.3:1.

3.3.2.2 Clinical symptoms

All clinical data will be assessed by residents at ER clinic or surgical

outpatient department. These are included:

-Onset of pain will be recorded as insidious or sudden. Onset is a description of

speed/manner onset of pain. Sudden onset of pain is occurred abruptly and severe

while insidious onset of pain is occurred in mild degree and gradually.

- Duration of pain is time since pain occurs until patient arrives to the hospital.

-Right lower quadrant (RLQ) abdominal pain will be recorded as present or absent.

-Migration of pain will be recorded as present or absent. In appendicitis, pain starts

either in epigastric area, centrally, or in the whole abdomen then eventually migrating

down to the right lower abdomen.

-Anorexia will be recorded as present or absent. Anorexia is loss of appetite,

especially as a result of disease.

-Aggravation of pain with cough will be recorded as present or absent. Patient will be

asked to cough and any worsening of pain will be recorded.

-Nausea will be recorded as present or absent. Nausea is sensation of unease and

discomfort in the upper stomach with an involuntary urge to vomit.

-Vomiting will be recorded as present or absent. Vomiting is a forceful expulsion of

the contents of one's stomach through the mouth and sometimes the nose.

34

-Dysuria will be recorded as present or absent. Dysuria is painful or difficult

urination.

Diarrhea will be recorded as present or absent. Diarrhea is the condition of having

three or more loose or liquid bowel movements per day.

Clinical signs will be recorded as present or absent.

-Fever: temperature >37.8c by oral route

-Tenderness at RLQ: pain when a hand pressing at right lower quadrant part of

abdomen especially at McBurney's point (the point over the right side of the abdomen

that is one-third of the distance from the anterior superior iliac spine to the umbilicus

(the belly button). This point roughly corresponds to the most common location of the

base of the appendix where it is attached to the cecum.

-Rebound tenderness: elicited in the right lower quadrant when a hand pressing the

abdomen for 10-15 seconds was suddenly withdrawn.

-Abdominal guarding: the tensing of the abdominal wall muscles to guard inflamed

organs within the abdomen from the pain of pressure upon them. The tensing is

detected when the abdomen wall is pressed. Abdominal guarding is also known as

'défense musculaire'.

-Rovsing sign: palpation on the left lower abdominal quadrant results in more pain in

the right lower quadrant.

-Per rectal examination tenderness: Pain at suprapubic area or within rectum after

rectum examination and exerts pressure on the peritoneum of the cul-de-sac of

Douglas.

3.3.2.3 Laboratory results

-Increased white blood cell count: a total white blood cell count 10,000/mm3.

-Polymorphonuclear leukocytosis: a polymorphonuclear count 75%.

35

-Normal urinalysis will be recorded as normal or abnormal.It is useful to rule out the

urinary tract cause of abdominal pain.

All data will be measured as described above.

In order to standardize data collection process, the quality control process will

be started by training the first and second year surgical residents. The manual of data

collection will be clear with detailed explanations including definition of signs,

symptoms, and laboratory tests, methods of examination, and follow up at

appointment or telephone follow up. Double data entering froms the case record form

will be used.

3.4 Data Collection

Case record form (see appendix A)

Case record forms (CRF) will be consist of 6 parts, which are log sheet,

demographic data, clinical sign, clinical symptom, laboratory data, and outcome parts,

see appendix A. The CRFs will be prepared at Section for Clinical Epidemiology and

Biostatistics, Faculty of Medicine, Ramathibodi Hospital and distributed by them to

all research sites.

Training

Surgical residents will be trained about this research project, informed consent,

and assessment for all parameters that will be used in the diagnosis of appendicitis at

the beginning of this project and retrained every rotation at general the surgical unit.

Research assistants will be trained for data collection, queries, and check for all

variables that will be used in the diagnosis of appendicitis at the beginning of the

project and retrained every 6 months.

36

The manual of data collection is shown in the appendix B.

Data flow, queries, quality control, and project monitoring

Consecutive cases of suspected appendicitis (as described in inclusion criteria)

will be included at the emergency or out-patient surgical unit. The first or second year

surgical residents and a research assistant who have passed the protocol training will

be responsible for data collection.

The outcome of having appendicitis and variables including age, sex, onset of

pain, duration of pain, progression of pain, right lower quadrant (RLQ) abdominal

pain, migration of pain, anorexia, aggravation of pain with cough, nausea or vomiting,

dysuria, diarrhea, fever (temperature >37.8 c by oral route), tenderness at RLQ,

rebound tenderness, guarding, Rovsing sign, tenderness at RLQ during per rectal

examination, increased white blood cell count, polymorphonuclear leukocytosis,

normal urinalysis, and CRP will be collected prospectively in consecutive cases for

the development and validation of RAMAAS.

The flow of patients and process of data collection is shown in figure 3.

3.5 Sample size estimation

The sample size calculation is estimated based on estimation proportion of

appendicitis. The prevalence of appendicitis in patient with abdominal pain and

suspected appendicitis was 37.8%47 . A confidence interval width and type I error are

set at ± 5% for both. The estimated sample size is

n= /

1.96 ∗ 0.38 1 0.380.05

= 362

37

Taking into account for missing data of 5% yields 380 subjects that are required to

include in the study. As such, the expected numbers of appendicitis are 155 subjects.

A total of 8-10 variables are expected to use for generate the scores. Using the

rule of thumb, 10 subjects with appendicitis are required for 1 variable associated with

appendicitis in the analysis to generate the clinical prediction score. Approximately 80

and 100 subjects with appendicitis will be need for 8 and 10 parameters, respectively.

As such, a total sample size of 380 should be covered considering requirement of

patients according to the rule of thumb.

For external validation, we will include 114 (30% of derived subjects) for each of 2

hospitals.

Statistical analysis

3.5.1 Data management

Databases will be created based on the case record forms (CRFs) by using

EPIDATA program version 3.1. The principal investigator will check for the

completeness of CRFs before data entry. Double data entry will be done by

independent staff and typing errors will be validated in two data sets. Data checking

and cleaning will be done monthly with clarification of missing, unclear, or un-

sensible data. A safe area will be used to keep data. Only principle investigators,

supervisors, and the data manager will be able to access the data. Real time back up of

data will be done automatically at the DMU server to prevent data loss.

3.5.2 Derivative phase

Descriptive data

38

Mean and standard deviation (SD) or median and range will be used for

describing continuous data while frequency or percentage will be used for categorical

data. The baseline characteristics of patients will be compared between appendicitis

and non-appendicitis groups using independent t test (or Mann-Whitney test) and chi

square (or exact test) for continuous and categorical data, respectively.

Univariate analysis

The whole data sets collect at Ramathibodi Hospital will be used for the

derivative phase. Simple logistic regression analysis will be used to define the

explanatory variables that influence the diagnosis of appendicitis. Three groups of

variables will be analyzed as follows:

‐ Demographic parameters: age and sex

‐ Clinical symptom parameters: onset of pain, duration of pain, progression

of pain, right lower quadrant (RLQ) abdominal pain, migration of pain,

anorexia, aggravation of pain with cough, nausea or vomiting, dysuria,

diarrhea

‐ Clinical sign parameters: fever (temperature >37.8 c by oral route),

tenderness at RLQ, rebound tenderness, guarding, Rovsing sign,

tenderness at RLQ during per rectal examination

‐ Laboratory parameters: increased white blood cell count,

polymorphonuclear leukocytosis, and normal urinalysis

The maximum likelihood function will be used to estimate the parameter and

the simple with logit. Likelihood ratio (LR) test will be used to test the association

between variable and appendicitis.

Multivariate analysis

39

‐ Model selection

Parameters whose p values are less than 0.20 in the univariate analysis will be

simultaneous considered in the multivariate analysis. Multiple logistic regression

analysis will be used to estimate effect size and select the variable that should remain

in the model. The LR test will be applied to select variables in the model with

forward or back ward elimination to find the final parsimonious model.

‐ Goodness of fit

Exploration for goodness of fit will be done to define whether the model fits

well with data (predicted and observed values are close). Model goodness of fit will

be explored using chi square test. The Hosmer-Lemeshow test will be used to assess

the goodness fit of the models. In addition, a calibration coefficient oi-ei or oi/ ei

along with their 95% confidence intercal (CI) will be estimated. Pearson chi-square

residual, residual sum square, and deviance residual will be calculated if the model

does not fit well with data. Outliers will be identified and assessed affect on prediction

values and coefficients.

‐ Creation prediction score

The coefficients or odds ratio of the final parsimonious model will be used to

create prediction score (RAMA-AS). Each parameter will be weighted differently

according to its coefficient. The score will be calculated by “sum up” coefficients or

odds ratio. The receiver operating curve (ROC) analysis will be used to calibrate the

cutoff point of the scores. Diagnostic parameters (i.e., sensitivity, specificity,

likelihood ratio positive (LR+) and negative) will be estimated for each distinct value

of the scores.

Two cut-off points will be attempted to identify. The first cutoff will have

high sensitivity which will refer to complicated appendicitis and the second cutoff

40

will have high specificity for acute appendicitis. As a result, 3 diagnostic zones rule

out (high sensitivity) and rule in (high specificity), and non-appendicitis will be

generated. An area under curve or C statistic will be also estimated.

3.5.3 Validation phases

Internal validation

The bootstrap technique with 200 replications will be applied for internal

validation of the RAMA-AS 46 48. For each bootstrap sample, the RAMA-AS scores

will be created for each patient and then will be fitted in logistic model. The

discrimination parameter C statistic will be estimated. In addition, calibration

coefficient of observe(O)/predicted value (E) will be estimated. Further more, the

correlation between the O and E values of appendicitis will be assessed using the

Somer’D correlation, called Dboot. Calibration of the model will be then assessed by

subtracting the original Somer’D correlation from the mean Dboot. Discrimination of

the model will be assessed by comparing the original C statistic versus an average C

statistic from the bootstraps.

External validation

Data from a prospective cross sectional study at Department of Surgery,

Faculty of Medicine, Thammasart University and/or surgical unit at Chonburi

Hospital will be used to validate the generalized capability of RAMA-AS. The

RAMA-AS will be calculated for each patient. The ROC curve analysis will be

applied to estimate C-statistic. Then, the original C statistic (from boostrap internal

validation) and this C statistic (external validation) will be compared.

41

Comparison of RAMA-AS and previous scores

Fourteen scoring systems from the previous systematic review in chapter 2

will be compared with RAMA-AS. Calibration (O/E ratio), discrimination (C-

statistic) coefficients along with their 95% CIs, and AUC will be estimated for each

study. Comparison of O/E ratio, C-statistic, and AUC will be performed to evaluate

the performance of RAMA-AS.

The sensitivity, specificity, positive predictive value, negative predictive

value, and accuracy will be analyzed for each scoring system. To compare the

diagnostic performance of RAMA-AS and the previously proposed scoring system,

the area under the ROC curve (AUC) will be calculated for each scoring system. The

AUC of each scoring system will be compared using chi square method, with p value

< 0.05 considered statistically significant.

3.6 Cost effectiveness analysis of RAMA-AS

Society cost will be calculated from direct and indirect costs. Direct medical

costs (include medicine, medical supplies, laboratory and imaging tests, hospital

charges, and nursing care) and indirect non-medical cost (travel costs, food,

accommodation and opportunity lost from providing informal care and visits of

relatives and friends at hospital and home) will be collected. The incremental cost

effectiveness ratio (ICER) will be calculated by comparing a difference of cost

between outcomes predicted by RAMA-AS versus non RAMA-AS. RAMA-AS may

reduce the cost of investigation (U/S, CT scan). Utility will be estimated form EQ5D

as recommended by guideline for economic evaluation in Thailand49 ICER will be

calculated by dividing the difference of cost by the difference of utility between

RAMA-AS versus non RAMA-AS.

42

A decision tree will be used to model the important outcomes after patients are

suspected of having appendicitis. The decision tree starts from the patients who are

suspected of appendicitis, but the diagnostic strategy will differ based on whether the

RAMA-AS or routine clinical diagnosis with imaging is used for initial diagnosis. In

the pro RAMA-AS pathway the highly suspicious of appendicitis (say score more

than 7) group will be treated by appendectomy. The final outcome is either true

diagnosis of appendicitis or negative appendectomy. For the inconclusive patients

(score 4 to 7) further investigation by ultrasonography will be used for diagnosis.

Positive ultrasonographic patients will be treated by appendectomy while negative

group will receive further investigation with computer tomography (CT scan).

Positive CT scan patients will be treated with appendectomy while the negative

patients will be discharged (figure 4).

The direct and indirect costs occurred by health care providers and households

will be identified in two pathways: patient questionnaire interviews and data

extraction from hospital records. Ramathibodi, Thammasat and Chonburi Hospitals

will be used for the costing study. The prospective reviews of medical records of all

patients who are suspected of having appendicitis will be performed. The case records

review aims to measure hospital resources used such as clinician's time, type and

number of investigations, disposable equipments, and length of hospital admission.

The valuation of the hospital costs, including capital and overhead costs, for each

individual patient will be determined from each department involved in the services

for patients with suspected appendicitis. Daily event and cost questionnaires will be

used to accumulate patient-specific information and estimation of other household

expenses such as travel costs, food, accommodation and opportunity lost from

providing informal care and visits of relatives and friends at hospital and home

43

including the patient's recovery time to full activity after surgery. The face-to-face

interviews will be performed with patients at the post-operation visit (7-10 days after

surgery). For the patients who are lost to follow up or having longer follow-up period

than 4 weeks, telephone interview will be performed to collect that data. The costs

will be represented in Thai Baht at 2011 value (30 Baht = 1USD). All costs and

outcomes that occur beyond one year will be discounted using the same rate of 3.5%.

Uncertainty analysis

To determine if values within a plausible range for all input variables resulted

in a different conclusion, the probabilistic uncertainty analysis, assigning a beta

distribution for all probability and utility parameters and gamma distribution for all

cost parameters, and generating 1,000 rounds of simulations using Microsoft Excel®

with macro function on all estimated quantities will be carried out. The cost-

effectiveness acceptability curve based on the net benefit approach will also be

provided to present the relationship between the values of the ceiling ratio

(willingness to pay for one unit more of QALY) and probability favoring each

treatment strategy.

In addition, the scores will be converted to Thai utility using a conversion

index as suggested by Sakthong et al49 (appendix C). The calculation is done by

subtracting the relevant coefficients from 1.000. The constant term is used if there is

any dysfunction. The N3 term will be used if any dimension is at level 3.

3.7 Implementation of RAMA-AS and impact analysis

To encourage physician use our RAMA-AS in a routine practice, a computer

algorithm software will be developed. Once it’s developed, we will pilot it at

Ramathibodi and Thammasart hospitals. An accuracy of the RAMA-AS will be

44

collected. In addition, numbers of using it and reasons for using and not using will be

collected and discussed.

We will then introduce and demonstrate our software to the Royal College

Surgeon of Thailand. We will ask for collaboration from about 5-8 hospitals where

physicians are willing to try our software. The software will then be installed and

demonstrate. Data will be collect for assessing accuracy of the RAMA-AS. The

RAMA-AS performance and costs will then be compared with using imagings.

3.8 Ethics considerations

Informed consent if needed

The informed consent is shown in the appendix section.

Submit to the ethic committee for approval

This will be conducted according to the principles of the Helsinki Declaration

and in accordance with the Medical Research Involving Human Subjects Act. The

protocol will be submitted for approval from the ethics committee of Faculty of

Medicine Ramathibodi Hospital, Mahidol University. The principles of respect for

persons, beneficence, nonmaleficence, and justice will be applied in this research.

45

Respect for Persons

This principle of two ethical convictions will be considered. All participants

will be treated as autonomous and second, participants with diminished autonomy will

be protected. They will be treated with dignity and respect. The medical and surgical

care will not be disturbed by this study. This study will not used participants as a

means to an end or in a manner inconsistent with the person's interests or wishes. All

the treatment will be given to participants in the standard quality of care. The decision

of sending participants for investigations, giving medical treatment and surgery will

not be disturbed. The data will be collected to case record form by history taking,

physical examination, and reviewing medical records. Telephone follow up may

disturb participants, so the convenient time of participants will be recorded and used

for contact.

Beneficience

This study will prevent and remove harm as well as promote the good of the

person by minimizing the possible harms or risks and maximizing the potential

benefits. The nonmaleficence which prohibits the infliction of harm, injury, or death

upon others will be applied (the maxim Primum non nocere: “Above all do no harm”).

This study does not disturb the process of care. There is no new therapy or medicine

use in this study.

Justice

Each participant will be treated fairly and equitably, and be given his or her

due. The study will use available resources fairly and distribute them fairly and

equitably. All participants will be treated equally. They have the right to leave the

study at anytime without affecting their quality of care.

46

Protection

This study will assure that participation is voluntary and treated with equality

and fairness. The participants will be informed of all the procedures which will

happen related to patients.

47

3.9 Budget

3.11 Time Frame

Activities January 2013 – May 2015 June 2015 – May 2016 June 2016– May 2017 June 2017

Developing and internal

validation of RAMAAS

-Data collection

-Data analysis

External validation

-Data collection

-Data analysis

Economic analysis

Impact analysis

Data analysis

Presentations

Level ITEMS Cost/Unit Units COST Responsible unit

Study level Data collection

Data management

Research assistance

External monitoring

Software development

300

250

15,000

4,000

50,000

608

608

12

2

1

6,000

152,000

20,000

45,000

8,000

50,000

-Study sites

-Central DMU

-Central coordinating

center

Subject level Laboratory test 120 720 86,400 -Study sites

Total 367,400

48

ACKNOWLEDGEMENT

This study proposal is a part of the dissertation for (Student name’s) training in Ph.D. (Clinical Epidemiology), Faculty of Medicine Ramathibodi Hospital and Faculty of Graduates, Mahidol University.

Funding resource

49

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55

TABLES

Table 1 Risk of bias assessment for clinical prediction rule of appendicitis

i) Derivative phase Domain Item Low risk of

bias

Comments

Selection bias - Was the spectrum of patients representative of the patients who will receive the evaluation in practice? (representative spectrum)

Recruited all consecutive patients with chief complain of abdominal pain, or random samples patients from well define population frame of abdominal pain

Yes

Recruited a specific group of patients (e.g., having at least a few clinical sign and symptoms)

No

Information provided could not classify Y/N Unclear

No information to assess NA

Information bias

Ascertainment of outcome measurement

- Was appendicitis clearly defined and acceptable in this field?

Diagnosed by biopsy

Yes

Diagnose by Surgeon using operation finding

No



- Were those assessing the outcome event blinded to the presence of the predictors?

Appendicitis was proven by biopsy and pathologist was masked to know about clinical information

Yes

Appendicitis was diagnosed by Surgeon without proven by biopsy & surgeon could access to clinical data

No

Information provided could not classify Y/N Unclear Did not mention NA

56

Ascertainment of predictors - Were all important predictors consider to include in the derivation process?

Clearly list all items of predictors and considered number of predictors for each item as demographic(1/2), clinical sign (4/9), symptom (5/10), lab(2/4), and imaging (1/2)

Yes

Did not consider all 4 items and/or numbers of predictors for each item were < a half of overall predictors

No


Did not mention NA

Were assessing of presence of predictors blinded to the outcome event?

Stated clearly how to assess predictors and assessors were blind for knowledge of the final diagnosis of appendicitis, lab, and imaging findings when undertook physical examinations or vice versa

Yes

Physical examination, lab, or imaging was not blind or these predictors were assessed with knowledge of possible diagnosis of appendicitis

no


- Were all important predictors present in a significant proportion of the study population?

Statistic test was applied for all predictors and only statistical (or clinically with reasons) significant predictors were considered to include in the model

Yes

Did not apply statistical test, or rationale for include predictors was not provided

No


Did not mention NA

Confounding bias

- Multivariate regression analysis was applied for derive model.

Applied muitivariate (logistic, Poisson, discriminant) regression using conventional or Bayesian statistical methods, or using recursive partitioning analysis by simultaneously included all predictors in the same model

Yes

Did not apply multivariate regression analysis No


57

- Was score or weight created properly? Score or weight for each predictor was created

based on suggestion from regression model (e.g., coefficient or relative risk)

Yes

Was not based on regression results or weight without proper rationale

No


Did not mention NA

Other issue bias - Were the total sample size and number of events adequate or modeling?

Number of appendicitis and total subjects were sufficient base on a rule of thumb (1 predictor/10 appendicitis or 20-30 total subjects)

Yes

N < 10 appendicitis or n < 20-30 total patients per 1 predictor

No


Did not mention NA

- Does the rule make clinical sensible? Included predictors seem clinically sensible,

easy to use, suggested a course of action

Yes

Included predictor did not make any sense, not easy to calculate, or provided only probability of appendicitis without course of action

No


58

ii) Validation phase

Domain Item Low risk of bias

Comments

Selection bias - Was the spectrum of patients representative of the patients who will receive the evaluation in practice? (representative spectrum)

Recruited all consecutive patients with chief complain of abdominal pain, or random samples patients from well define population frame of abdominal pain

Yes

Recruited a specific group of patients (e.g., having at least a few clinical sign and symptoms)

No



Information bias Ascertainment of outcome measurement

- Was appendicitis clearly defined and acceptable in this field?

Diagnosed by biopsy

Yes

Diagnose by Surgeon using operation finding No



- Were those assessing the outcome event blinded to the presence of the predictors?

Appendicitis was proven by biopsy and pathologist was masked to know about clinical information

Yes

Appendicitis was diagnosed by Surgeon without proven by biopsy & surgeon could access to clinical data

No


- Was there an explicit and accurate interpretation of the predictors and/or the actual rule without knowledge of the outcome.

Clearly described interpretation of the rule was not influenced by information of final diagnosis of appendicitis

Yes

Clinical rule classification was influenced by No

59

diagnose of appendicitis


Did not mention NA

Other issue bias - Was there 100% follow-up of those enrolled? All included patients were included at the

end of study

Yes

Some patients were lost to follow up No


Did not mention NA

60

Table 2. Characteristics of studies that had developed prediction scores for appendicitis

Author Phase

of study

Year Model Study design Type of

participant

Male(%) Ethnicity Appendicitis Non

Appendicitis

Statistical

method

% Negative

appendectomy

%complicated appendicitis

Van way39 D/I 1982 Van way Retrospective

Cohort

Operated

patients

NA Caucasian 360 116 Discrimination

analysis

29.83% 25.30%

Teicher37 D 1983 Teicher Case control Operated

patients

45.50% Caucasian 100 100 Diagnostic

analysis

40%

Alvarado7 D 1986 Alvarado Retrospective

Cohort

Suspected

appendicitis

NA Caucasian 227 50 Diagnostic

analysis

7% 18.77%

Fenyo16 D

1987 Fenyo Prospective

Cohort

Suspected

appendicitis


analysis

18% 14.00%

Christian11 D 1992 Christian Quasi-

experimental

design

Suspected

appendicitis

77.59% Asian 43 15

non-statistical

base

6.5% 6.50%

Eskelinen15 D 1992 Eskelinen Prospective

cohort

Suspected

appendicitis

NA Caucasian 270 1333 Logistic

regression

21.6% 6.74%

Kalan21 D 1994 Modified

Alvarado

Prospective

cohort

Suspected

appendicitis

55.26% Asian 40 9 non-statistical

base

23.68% NA

Ramirez33 D/I 1994 Practical Retrospective Operated 63.00% Caucasian 293 67 Diagnostic 18.61% NA

61

score of

Ramirez and

Deus

Cohort patients analysis

Gallego18 D 1998 Gallego Prospective

Cohort

Suspected

appendicitis


analysis

8.85% 18.23%

Tzanakis38 D/I/E 2005 Tzanakis

Prospective

Cohort

Suspected

appendicitis

56.10 Caucasian 217 504 Logistic

regression

19.20% 10.23%

Lintula27 D 2005 Lintula Prospective

cohort

Suspected

appendicitis

100% Caucasian 43 84 Logistic

regression

13% NA

Malik28 D 2007 Modified

Alvarado

Prospective

cohort

Suspected

appendicitis

55.12% Asian 174 80 non-statistical

base

11.49% 12.07%

Andersson8

D/I/E 2008 Appendicitis

inflammatory

response

score

Prospective

Cohort

Suspected

appendicitis

46.00% Caucasian 191 254 Logistic

regression

11.00% 14.00%

Chong9 D 2010 RIPASA Retrospective

cohort

Operated

patients

57.69% Asian 261 51 Univariate

analysis

16.30% NA

External validation phase

Fenyo17 E 1997 Fenyo Prospective

Cohort

Suspected

appendicitis


analysis

17.5% NA

62

Lamparelli25 E 2000 Mod.

alvarado by

Kalan

Prospective

Cohort

Suspected

appendicitis


analysis

NA NA

Denizbasi13 E 2003 Alvarado Prospective

Cohort

Suspected

appendicitis


analysis

NA NA

AlQahtani6 E 2004 Alvarado Prospective

Cohort

Suspected

appendicitis

59% Asian 121 30 Diagnostic

analysis

12.5% NA

Pruekprasert

32

E 2004 Alvarado Prospective

Cohort

Suspected

appendicitis


analysis,

Discrimination

analysis

NA NA

Enochsson14 E 2004 Fenyo Prospective

Cohort

Suspected

appendicitis

12% Caucasian 330 96 Diagnostic

analysis

NA NA

Sitter34 E 2004 Eskelinen Prospective

Cohort

Suspected

appendicitis


analysis,

Discrimination

analysis

21.6% NA

Tepel1 E 2004 Ohmann Retrospective

Cohort

Suspected

appendicitis


analysis

22% NA

McKay29 E 2007 Alvarado Retrospective

Cohort

suspected

appendicitis


analysis

NA NA

63

Sun35 E 2008 Alvarado Retrospective

Cohort

Suspected

appendicitis

66.2% Asian 213 159 Diagnostic

analysis,

Discrimination

analysis

NA NA

Kurane24 E 2008 Mod.

Alvarado by

kalan

Prospective

Cohort

Suspected

appendicitis


analysis

61.67% NA

Ohmann30 I 2008 ohmann Prospective

Cohort

Suspected

appendicitis


analysis

10.2% 13.4%

Talukder36 E 2009 Mod

Alvarado

malik

Prospective

Cohort

Suspected

appendicitis


analysis

16% NA

Hsieh19 E 2010 Alvarado Retrospective

Cohort

Suspected

appendicitis


analysis,

Discrimination

analysis

NA NA

Pouget-

Baudry31


Cohort

Operated

patients


analysis

NA NA

Lintula43 I 2010 Lintula RCT Suspected

appendicitis


analysis

13% NA

Chong10 E 2011 Alvarado Prospective Suspected 47.9% Asian 101 91 Diagnostic 22.9% 6.1%

64

Chong

(2010)

Cohort appendicitis analysis,

Discrimination

analysis

Inci20 E 2011 Alvarado Prospective

Cohort

Suspected

appendicitis


analysis

13.6% NA

Limpawattan

asiri26


Cohort

Suspected

appendicitis


analysis,

Discrimination

analysis

14.7% NA

Konan23 E 2011 Alvarado Retrospective

Cohort

Operated

patients


analysis,

Discrimination

analysis

NA NA

Kanumba22 E 2011 Mod.

alvarado

kalan

Cross

sectional study

Suspected

appendicitis


analysis

33.1% 62.9%

Yoldas40 E 2011 Lintula Retrospective

Cohort

Operated

patients


analysis,

Discrimination

analysis

NA NA

Castro12 E 2012 Alvarado

Andersson

Retrospective

Cohort

Suspected

appendicitis


analysis,

21% NA

65

Discrimination

analysis

NA: not applicable, D=Derivative, I=Internal validation, E=external validation, Diagnostic=100%, Discrimination analysis=39.13%

66

Table 3. Risk of bias assessment.

Study Phase

Selection

bias Information bias Confounding bias Other issue

Representativ

e spectrum

Ascertainment

of outcome

measurement

Blinded

assess

outcome

No

predic

tors

Predictor

s blinded

outcome

Significant

predictors

Accurate

interpreta

tion

Multivariate

regression

analysis

Created

score

properly

Sample

size

Clinical

sensible

Other

issue

Van way,198239 D N NA NA N N Y - Y Y Y Y -

Teicher,198337 D Y Y NA Y NA Y - N N Y Y -

Alvarado,19867 D Y Y NA Y NA Y - N N Y Y -

Fenyo,1987***16 D Y Y NA Y NA Y - N N Y N -

Christian,199211 D N Y NA N Y N - N N N Y -

Eskelinen,199215 D Y Y NA Y Y Y - Y Y Y Y -

Kalan,199421 D N Y NA N NA Y - N N N Y -

Ramirez,199433 D N Y NA Y NA Y - N N Y N -

Gallego,199818 D Y Y NA Y NA Y - N N Y N -

Tzanakis,200538 D Y Y NA Y Y Y - Y Y Y Y -

Lintula, 200527 D Y Y NA Y Y Y - Y Y Y Y -

Malik,200728 D N Y NA N NA Y - N N Y Y -

Andersson, 20088 D Y Y NA Y Y Y - Y Y Y Y -

67

Chong,20109 D N Y NA Y NA Y - N N Y N -

Van way,198239 I N NA NA - - - N - - - - N

Fenyo,1987***16 I Y Y NA - - - Y - - - - N

Ramirez,199433 I N Y NA - - - N - - - - N

Tzanakis,200538 I Y Y NA - - - Y - - - - Y

Andersson, 20088 I Y Y NA - - - Y - - - - Y

Lintul,201043 I Y Y NA - - - Y - - - - Y

Fenyo, 199717 E Y Y NA - - - N - - - - N

Denizbasi,200313 E Y Y NA - - - Y - - - - NA

AlQahtani,20046 E Y Y NA - - - Y - - - - Y

Pruekprasert,

200432

E Y Y NA - - - Y - - - - Y

Enochsson,

200414

E UN Y NA - - - Y - - - - NA

Sitter,200434 E Y Y NA - - - Y - - - - NA

Tzanakis,200538 E Y Y NA - - - NA - - - - Y

Mckay,200729 E Y Y NA - - - N - - - - NA

Andersson,20088 E Y Y NA - - - NA - - - - Y

Kurane,200824 E Y Y NA - - - Y - - - - NA

Sun, 200835 E Y Y NA - - - N - - - - NA

Talukder,200936 E Y Y NA - - - Y - - - - NA

Hsieh, 201019 E Y Y NA - - - N - - - - NA

68

Pouret-

Baudry,201031

E Y Y NA - - - Y - - - - Y

Chong,201110

E Y

Y

Y

Y

NA

NA

- - - Y

Y

- - - - NA

NA

Inci,201120 E Y Y NA - - - Y - - - - Y

Limpawattan,

201126

E Y Y NA - - - Y - - - - NA

Konan,201123 E N Y NA - - - N - - - - NA

Kanumba,201122 E Y Y NA - - - Y - - - - NA

Yoldas,201140 E N Y NA - - - N - - - - NA

Castro,201212 E Y

Y

Y

Y

NA

NA

- - - Y

Y

- - - - NA

NA

69

Table 4. Describe performances of predictive models of appendicitis

Author, Year

Derived model Internal validation External validation

No. Variable/

event/N O/E C-statistic

No. Variable/

event/N O/E C-statistic Author, Year

No. Variable

/event/N O/E C-statistic

Van way, 198239 4/NA/219 NA NA 4/169/257 1(0.92,1.08) 0.61(0.54,0.68) Tzanakis, 200538 4/87/201 1(0.76,1.24) 0.78(0.72,0.84)

Teicher, 198337 7/100/200 1(0.75,1.25) 0.78(0.72,0.83) - - - Tzanakis, 200538 4/87/201 1(0.69,1.31) 0.86(0.81,0.91)

Alvarado, 19867 8/227/277 1(0.93,1.07) 0.80(0.73,0.86) - - -

Denizbasi, 200313 8/175/221 0.99(0.91,1.09) 0.71(0.63,0.78)

AlQahtani, 20046 8/121/151 1(0.79,1.21) 0.84(0.76,0.93)

Pruekprasert, 200432 8/186/231 1(0.93,1.07) 0.74(0.67,0.81)

Tzanakis, 200538 4/87/201 1(0.69,1.31) 0.83(0.78,0.88)

McKay, 200729 8/48/144 1(0.70,1.30) 0.74(0.66,0.82)

Andersson, 20088 8/76/225 0.99(0.79,1.21) 0.63(0.58,0.68)

Sun, 200835 8/213/372 1(0.90,1.10) 0.65(0.61,0.70)

Hsieh, 201019 8/115/180 1(0.85,1.15) 0.77(0.70,0.83)

Pouget-

Baudry,201031 8/171/233 1(0.92,1.08) 0.68(0.62,0.73)

Chong, 201110 14/101/192 0.99(0.82,1.18) 0.78(0.72,0.84)

Inci, 201120 8/57/66 1(0.89,1.11) 0.75(0.58,0.92)

70

Limpawattanasiri,

201126 8/715/1000 1(0.94,1.06) 0.81(0.78,0.84)

Konan,201123 8/41/82 1(0.69,1.31) 0.84(0.76,0.91)

Castro, 201212 11/340/935 1(0.91,1.09) 0.62(0.60,0.65)

Fenyo, 198716 16/109/259 1(0.75,1.25) 0.91(0.89,0.93) - - -

Fenyo,199717 4/392/1167 1(0.88,1.12) 0.80(0.77,0.82)

Enochsson,200414 4/330/426 1(0.94,1.06) 0.73(0.68,0.78)

Tzanakis, 200538 4/87/201 1(0.65,1.35) 0.88(0.83,0.92)

Christian, 199211 5/43/58 1(0.56,1.44)* 0.87(0.77,0.98)* - - - Tzanakis, 200538 4/87/201 1(0.71,1.29) 0.85 (0.80,0.90)

Eskelinen, 199215 6/572/1333 1(0.93,1.07) 0.59(0.58,0.61) - - - Sitter, 200434 6/662/2359 1(0.90,1.10) 0.82(0.80,0.84)

Tzanakis, 2005 4/87/201 1(0.71,1.28) 0.87(0.83,0.92)

Kalan, 199421

(Modified Alvarado ) 7/40/49 1(0.74,1.26)* 0.76(0.60,0.92)* - - -

Lamparelli, 200025 7/56/84 1(0.80,1.20) 0.82(0.74,0.90)

Kurane, 200824 7/23/60 1(0.49,1.51) 0.81(0.71,0.92)

Kanumba, 201122 7/85/127 0.99(0.72,1.28) 0.92(0.87,0.97)

Ramirez, 199433 7/293/360 1(0.94,1.06) 0.72(0.60,0.84) NA NA NA - - - -

Gallego, 199818 6/101/192 1(0.78,1.23) 0.89(0.85,0.93) - - - - - - -

Ohmann, 199930 - - - 8/235/1254 1(0.44,1.56) 0.87(0.84,0.90) Tepel, 20041 4/113/400 1(0.78,1.20) 0.73(0.68-0.78)

Tzanakis, 200538 4/87/201 1(0.60,1.40) 0.88(0.84,0.93)

Tzanakis, 200538 10/130/303 1(0.45,1.55) 0.97(0.95,0.99) NA NA NA Tzanakis, 200538 10/87/201 - 0.96(0.93,0.99)

Malik, 200728

(Modified Alvarado ) 8/174/254 1(0.93,1.07) 0.54(0.45,0.63) - - - Talukder, 200936 8/84/100 1(0.91,1.09) 0.65(0.52,0.78)

Andersson, 20088 7/115/316 NA 0.87 7/115/316 1(0.43,1.57) 0.89(0.86,0.93) Castro, 201212 11/348/945 0.99(0.91,1.09) 0.55(0.54,0.57)

71

Chong, 20109 NA NA NA 14/101/192 1(0.45,1.55) 0.90(0.85,0.94) Tzanakis, 200538 14/101/192 0.99(0.82,1.18) 0.78(0.72,0.84)

Lintula, 200527 NA NA NA 11/52/96 1(0.64,1.36) 0.92(0.87,0.97) Yoldas, 201140 11/132/156 1(0.92,1.08) 0.79(0.73,0.86)

Pool effect - 1(0.97,1.03) 0.79(0.67,0.90) - 1(0.92,1.07) 0.84(0.77,0.91) - - 0.99(0.98,1.02) 0.78(0.74,0.82)

72

Table4. Describe variables that were included in the derive phase of predictive scores of appendicitis

Study, Year

Demographic data Clinical Symptoms

Age Sex Total Migration of pain

Anorexia Nausea/

vomiting

Duration of pain

Progression of pain

GU symptom

Aggravation with cough,

movement

Pain at presentation

Diarrhea Rigor Total

Van way, 1982 - 1 - - - - - - - 3

Teicher, 1983 2 - - - - - - - - 2

Alvarado, 1986 - - 0 - - - - - - - 3

Fenyo, 1987 - 1 - 9

Christian, 1992 - - 0 - - - - - - - - 2

Eskelinen, 1992 - - 0 - - - - - - - - 2

Kalan, 1994 - - 0 - - - - - - - 3

Ramirez, 1994 - 1 - - - - - - - - 2

Gallego, 1998 - - 0 - - - - - - - - - - 0

Lintula, 2005 - 1 - - - - - - - 3

Tzanakis, 2005 - - 0 - - - - - - - - 2

Malix, 2007 - - 0 - - - - - - 4

Andersson, 2008 - - 0 - - - - - - - - 2

Chong, 2010 2 - - - - - 5

Total 2 6 NA 7 6 9 6 2 1 2 6 2 1 NA

73

Study, Year

Signs Laboratory

Imaging Total

Elevated tempera

ture

Guarding

RLQ

Rebound

tenderness

Rigidity

RLQ tenderness

Rovsing’s sign

rectal tenderness

Pain outside

RLQ

Rectal Mass

R.

side

Total Increase WBC

PMN left shift

Negative UA

CRP

Total Abdominal

radiograph

Ultrasonographic

Total

Van way, 1982 - - - - - - - - - 0 - - - - 0 - - 0 4

Teicher, 1983 - - - - - - - 2 - - - 1 - - 0 7

Alvarado, 1986 - - - - - - 3 - - 2 - - 0 8

Fenyo, 1987 - - 7 - - - 1 - - 0 18

Christian, 1992 - - - - - - - 2 - - - 1 - - 0 5

Eskelinen, 1992 - - - - - - 3 - - - 1 - - 0 6

Kalan, 1994 - - - - - - 3 - - - 1 - - 0 7

Ramirez, 1994 - - - - - - - 2 - - 2 - - 0 7

Gallego, 1998 - - - - - - - 2 - - 2 2 6

Lintula, 2005 - - - - - 4 - - - - 0 - - 0 8

Tzanakis, 2005 - - - - - 4 - 3 - 1 10

Malix, 2007 - - - - 5 - - - 1 - - 0 10

Andersson, 2008 - - - - - - - 2 - 3 - - 0 7

Chong, 2010 - - - - 5 - - 2 - - 0 14

74

Total 9 7 11 2 9 2 2 1 1 NA 9 8 1 2 NA 1 2 NA NA

75

FIGURES

Figure 1: Identification of studies for inclusion

76

Figure 2 Flow of patients and process of data collection

Patient abdominal pain at ER or surgical OPD

Appendicitis

Acute abdomen and suspected appendicitis

Not suspected

appendicitis

Home

Not improve

ER or OPD

- Suspected for appendicitis - Consult surgical service for evaluation and

management

Not suspected

appendicitis

Home telephone follow

up at 1 month

Not improve

Observation or

InvestigationAppendicitis

Surgery

(Appendectomy)

Non‐appendix

Appendicitis Negative finding

77

Figure 3 Diagram of data analysis

Clean and check data

Simple logistic regression analysis ‐age, sex, onset of pain, duration of pain, progression of pain, right lower quadrant (RLQ) abdominal pain, migration of pain, anorexia, aggravation of pain

with cough, nausea or vomiting, dysuria, diarrhea, fever (temperature >37.8 c by oral route), tenderness at RLQ, rebound tenderness, guarding, Rovsing sign, tenderness at RLQ during per rectal examination, increase white blood cell count, polymorphonuclear leukocytosis, normal urinalysis, and CRP ‐Outcome: Appendicitis 0/1

Multiple logistic regression analysis ‐ Parsimonious model

‐ Goodness of fit, residuals, outliers ‐ Receiver operating curve ‐ Cutoff threshold ‐ Sensitivity, specificity, PPV, NPV ‐ Odd ratio, coefficience, generation of scoring system

Internal validation

External validation

Economic analysis ‐ Cost effectiveness ‐ Cost utility

Impact analysis:

‐ pilot study

‐ implement at RCST

78

Figure 4 Decision tree of the RAMAAS model in diagnosis of appendicitis.

79

APPENDICES

A) Case record forms

โครงการศกษา ระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร"

Form 1: Eligible data and preoperative EQ5D

วน/เดอน/ป (พศ.) // HN

ผกรอกขอมล …………………………………….

สถานทเกบขอมล 1. รามาธบด 2. ธรรมศาสตร 3. ชลบร กรณาทาเครองหมายกากบาทหนาเกณฑการคดเลอกถาผ ปวยผานเกณฑคดเลอกขอนน ผปวยทเขารวมการวจยตองผานเกณฑเขารวมการวจยครบทกขอ ดงตอไปน

ปวดทองดานขวาเปนเวลา 7 วน

ไดรบการวนจฉย หรอสงสยวาเปนไสตงอกเสบ

มอายระหวาง 18 ถง 60 ป ไมไดตงครรภ

สามารถอาน และสอสารภาษาไทยได ไมไดรบประทานยาในกลมสเตอรอยด เชน prednisolone หรอยากดภมคมกน เชน methotrexate, cyclophosphamide,

azathioprine, mercaptopurine, anthracycline, mitomycin, Ciclosporin, Tacrolimus ไมเคยไดรบการวนจฉยวา

- เปนผปวยตดเชอ HIV ทมอาการ AIDS เชน cryptococcal meningitis, tuberculosis, pneumocystis carinii infection

- ไมเคยมประวตโรคไตวายระยะสดทาย - ไมเคยมประวตโรคตอตานภมคมกนตนเอง เชน โรค SLE - ไมเปนผปวยภาวะตบแขงทมทองมานรวมดวย - ไมมภาวะอวนผดปกต (BMI > 40 kg/m2) - ไมเปนผปวยทเปนมะเรงชองทองในระยะสดทาย

ในกรณทผ ปวยผานเกณฑเขารวมวจยครบทกขอ ใหขอมลผ ปวยเกยวเนองกบการวจย (Information process and consent form) ยนดทจะเขารวมการวจย และ เซน inform consent ยนด (participants) Participants ID - ไมยนด (non-participants) Non-participants ID -

ลงขอมลในแบบขอมลพนฐาน และคณภาพชวต

ถาผ ปวยยนด เขารวมโครงการ (Patient’s log sheet and preoperative EQ5D)

80


Form 1: Eligible data and preoperative EQ5D

ID -

แบบประเมนคณภาพชวตกอนผาตด (Preoperative EQ5D)

ภาวะการเจบปวยของทานในปจจบนนมผลตอทานในหวขอตอไปนอยางไรบาง

1. การเคลอนไหว 1. ขาพเจาไมมปญหาในการเดน

2. ขาพเจามปญหาในการเดนบาง 3. ขาพเจาไมสามารถไปไหนได และจาเปนตองอยบนเตยง

2. การดแลตนเอง 1.ขาพเจาไมมปญหาในการดแลตนเอง 2.ขาพเจามปญหาในการอาบนาหรอการแตงตวบาง

3.ขาพเจาไมสามารถอาบนาหรอแตงตวดวยตนเองได 3. กจกรรมททาเปนประจา (เชน การทางาน, การเรยนหนงสอ, การทางานบาน การทากจกรรมในครอบครว หรอการทากจกรรมยามวาง) 1.ขาพเจาไมมปญหาในการทากจกรรมททาเปนประจา 2.ขาพเจามปญหาในการทากจกรรมททาเปนประจาอยบาง 3.ขาพเจาไมสามารถทากจกรรมททาเปนประจาได 4. ความเจบปวด/ 1.ขาพเจาไมมอาการเจบปวดหรออาการไมสขสบาย ความไมสขสบาย 2.ขาพเจามอาการเจบปวดหรออาการไมสขสบายปานกลาง 3.ขาพเจามอาการเจบปวดหรออาการไมสขสบายมากทสด 5. ความวตกกงวล/ 1.ขาพเจาไมรสกวตกกงวลหรอซมเศรา ความซมเศรา 2.ขาพเจารสกวตกกงวลหรอซมเศราปานกลาง 3.ขาพเจารสกวตกกงวลหรอซมเศรามากทสด

81


Form 2: Patient’s log sheet

HN Participants ID -

ขอมลผ ปวย

ชอ ........................................ นามสกล ..................................................................................... วน/เดอน/ป เกด (พ.ศ.) // ทอย บานเลขท ............................... หม ............... ซอย .....................................................................

หมบาน ............................................. ถนน ....................................ตาบล/แขวง .................................... จงหวด ............................................. รหสไปรษณย ................................... เบอรโทรศพทบาน .................................................. เบอรโทรศพทเคลอนท ........................................... ญาตทสามารถตดตอไดชอ ...................................... เบอรโทรศพทเคลอนท ...........................................

82


Form 3: Evaluation data

วน/เดอน/ป (พศ) // ID - A) Baseline data and Chief complaint ผกรอกขอมล ......................................................................

กรณาตอบคาถามในขอตางๆดานลางโดยกาเครองหมายกากบาท × ลงในชองสเหลยม 1.อาย กป 2. เพศ 1. ชาย 2. หญง 3. นาหนก (kg) 4. ความสง (cm)

5. วนทนอนโรงพยาบาล (วน/เดอน/ป พศ.) // 6. เวลา .

อาการสาคญ (chief complaint) 1.ปวดทอง 2. อนๆ ระบ ........................................ ชวโมง

7. ลกษณะอาการปวดทอง 7.1 ตาแหนงทเรมปวด 1. Epigastrium 2. Periumbilibal 3. อนๆ ......................

7.2 ลกษณะ 1. Dull aching, constant 2. Colicky 3. อนๆ ...................... 7.3 Migratory pain 1. ม 2. ไมม

7.4 การเรมปวด (onset) 1. คอยๆเปนมากขน 2. ทนททนใด (sudden) 7.5 การเปนมากขนของอาการปวด (progression of pain) 1. ม 2. ไมม 7.6 อาการปวดบรเวณทองดานขวาลางขณะตรวจ 1. ม 2. ไมม

8. ระยะเวลา เรมมอาการปวดทองประมาณ ชวโมงกอนมาโรงพยาบาล

เรมปวดทองทบรเวณดานขวาลางประมาณ ชวโมงกอนมาโรงพยาบาล

9. คลนไส 1. ม 2. ไมม 10. อาเจยน 1. ม 2. ไมม ถาม จานวน ครง ลกษณะ .........................

11. เบออาหาร 1. ม 2. ไมม 12. ปวดราว 1. ม 2. ไมม; ถามราวไปบรเวณ ..........................................

13. ไข 1. ม 2. ไมม ถาม มอาการไขกอนปวดทอง 1. ใช 2. ไมใช 14. ปสสาวะ 1. ปกต 2. ไมปกต ถาไมปกต 1. แสบขด 2. มเลอดหรอสนาลางเนอ 3. อนๆ ............... 15. อจจาระ 1. ปกต 2. ไมปกต ถาไมปกต 1. ถายเหลว 2. ปวดเบง 3. อนๆ .................................. 16. กรณเพศหญง 16.1 ประจาเดอน 1. ปกต 2. ไมปกต ถาไมปกต......................................................................... 16.2 LMP (วน/เดอน/ป พศ.) //; Not remember

16.3 ตกขาว 1. ปกต 2. ไมปกต ถาไมปกต......................................................................... 17. ขยบตว หรอไอทาใหอาการเจบเปนมากขน 1. ใช 2. ไมใช อนๆ .................................................................................................................................................................................... 18. อาการหนาวสน 1. ม 2. ไมม

19. โรคประจาตว (Underlying disease)

19.1 เบาหวาน 1. เปน 2. ไมเปน 19.2 ความดนโลหตสง 1. เปน 2. ไมเปน 19.3 โรคประจาตวอนๆ 1. เปน 2. ไมเปน ระบ ..........................................................

20. แพยา 1. ม 2. ไมม; ถามระบ...............................

21. สบบหร 1. สบ 2. ไมสบ; ประมาณ ..............มวน/วน 22. ดมสรา 1. ดม 2. ไมดม; ประมาณ ..............ขวด/วน

23. ประวตโรคในครอบครว (Family History) 1. ม 2. ไม ถาม ระบ .....

83



B) Physical examination ID - Vital sign: 1. BT . °c 2. PR /min 3. BP / mmHg 4. RR /min HEENT 5. Pale conjunctiva 1. Yes 2. No 6. Icteric sclera 1. Yes 2. No Respiratory tract 7. Breath sound 1. Normal 2. Abnormal; specify …………………………………. Cardiovascular 8. Heart sound 1. Normal 2. Abnormal; specify …………………………………. 9. Heart rate 1. Regular 2. Irregular; specify …………………………………. Abdomen 10. Inspection 1. Normal 2. Abnormal; specify …………………………………………. 11. Bowel sound 1. Normal 2. Decrease 3. Increase; specify site ……………………. 12. Tender 1. Yes 2. No; If yes, site of tender 1. RLQ 2. LLQ 3. RUQ 4. RLQ+LLQ 5. generalized 13. Rebound tenderness 1. Yes 2. No; If yes, site of tender 1. RLQ 2. LLQ 3. RUQ 4. RLQ+LLQ 5. Generalized 14. Guarding 1. Yes 2. No 15. Rigidity 1. Yes 2. No 16. Indirect rebound tenderness (Rovsing’s sign) 1. Positive 2. Negative 17. Psoas’s sign 1. Positive 2. Negative 18. Obturator’s sign 1. Positive 2. Negative Per rectal examination 19. Tender 1. Yes 2. No 3. Not perform; specify ….………………………… Per vaginal examination (Only female) 20. 1. Normal 2. Abnormal 3. Not perform 21. Specify if abnormal …………………………………………………………………. 22. Gynecologic suggestion 1.No Gynecologic condition 2. Gynecologic condition Others

84



C) Laboratory and radiologic results ID - Complete blood cell count 1. WBC (cell/mm3) 2. Hemoglobin (mg %) . 3. Hematocrit (%) 4. Neutrophil (%) 5. Lymphocyte (%) Urinalysis 1. White blood cell count (cells/HF) f- 2. Red blood cell count (cells/HF) f- 3. specific gravity . 4. epithelial cell f- BUN/Cr (mg %) / Blood sugar (mg %) ; not performed Anti HIV 1. Check 2. Don’t check; If check 1. Positive 2. Negative LFT: not performed; if performed, Albumin . g/dL, others .………………………………………… Ultrasound abdomen 1. Done 2. Not done Results 1. Appendicitis 2. Suspected appendicitis 3. Not appendicitis If done specify ………………………………………………………………………………. CT scans 1. Done 2. Not done; Results 1. Appendicitis 2. Suspected appendicitis 3. Not appendicitis If done specify ………………………………………………………………………………. Others Provisional diagnosis …………………………………………………….. Differential diagnosis 1. ………………………………………….. 2. ………………………………………….. 3. …………………………………………..

85

โครงการศกษา ระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร" Form 4: Operative data

ID - เวลาเรม . am/pm สนสด . am/pm ชอ นามสกล วน/เดอน/ป ทผาตด (พศ)//

แพทยผาตด นามสกล 1.แพทยใชทน 2.แพทยประจาบาน 3.ศลยแพทย

Anesthesia 1.GA 2.Spinal block 3. Epidural Scrub 1.Betadine 2.Chlorhexidine ASA classification I II III IV ; specify …………………………………………… Preoperative antibiotics 1.Yes 2.No; If yes please specify Postoperative diagnosis Procedure 1 Incision Type of incision 1.Mcburney’s 2.Lanz 3.Additional midline Incisional length . cm. Subcutaneous fat thickness . cm Findings : Appendix Location 1.Paracecal 2.Retrocecal 3.Pelvic type Erythematous or swelling of appendix 1.Yes 2.No (No = negative appendectomy) Severity of appendicitis : Suppurative : Suppurative appendicitis (No frank pus) 1.Yes 2.No Gangrenous : Gangrenous wall (dark, grayish color) 1.Yes 2.No Ruptured : 1.Yes 2.No Ruptured diagnosis criteria: Hole in appendix 1.Yes 2.No Intraoperative rupture 1.Yes 2.No Frank pus 1.Yes 2.No If frank pus is present; visible wound contamination 1.Yes 2.No Degree of contamination Exudative fluid 1.Yes 2.No; If yes, visible wound contamination 1.Yes 2.No Fecal material 1.Yes 2.No; If yes, visible wound contamination 1.Yes 2.No Phlegmon 1.Yes 2.No Fecalith 1.Yes 2.No Localized abscess formation 1.Yes 2.No Other findings ……………………………………………………………………………………………………….

86

โครงการศกษา ระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร" Form 4: Operative data (cont.)

ID -

Procedures related data Appendiceal stump was secured with 1. Silk 2#0 double ligation 2. Chromic ligation 3. Suture ligation with ………………… 4. Others ………………………… Purse string suture 1. Done 2. Not done Closed suction drain 1. Used 2. Did not use Culture of intra-abdominal fluid 1. Done 2. Not done Others ……………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………… ……………………………………………………………………………………………………………………..

87


Form 5: Postoperative Inpatient data

Participants ID - A) Postoperative pain

- Postoperative day 1 date (dd/mm/yyyy) / /

- Postoperative day 3 date (dd/mm/yyyy) / /

- Use of opioids (morphine) as required yes No if yes,

Day1 dosage …………….mg/day, Day2 dosage……………./day

B) แบบประเมนคณภาพชวต (EQ5D) Postoperative day 3; date (dd/mm/yyyy) / / การผาตดททาใหมแผลผาตดในครงนมผลตอทานในหวขอตอไปนอยางไรบาง




3.ขาพเจาไมสามารถอาบนาหรอแตงตวดวยตนเองได

3. กจกรรมททาเปนประจา (เชน การทางาน, 1.ขาพเจาไมมปญหาในการทากจกรรมททาเปนประจา การเรยนหนงสอ, การทางานบาน, การทากจกรรม 2.ขาพเจามปญหาในการทากจกรรมททาเปนประจาอยบาง ในครอบครว หรอการทากจกรรมยามวาง) 3.ขาพเจาไมสามารถทากจกรรมททาเปนประจาได

4. ความเจบปวด/ 1.ขาพเจาไมมอาการเจบปวดหรออาการไมสขสบาย ความไมสขสบาย 2.ขาพเจามอาการเจบปวดหรออาการไมสขสบายปานกลาง 3.ขาพเจามอาการเจบปวดหรออาการไมสขสบายมากทสด

5. ความวตกกงวล/ 1.ขาพเจาไมรสกวตกกงวลหรอซมเศรา ความซมเศรา 2.ขาพเจารสกวตกกงวลหรอซมเศราปานกลาง 3.ขาพเจารสกวตกกงวลหรอซมเศรามากทสด

88


Form 5: Postoperative Inpatient data (Cont.)

Participants ID - Discharge date (dd/mm/yyyy) / / C) การประเมนภาวะแทรกซอนหลงผาตด Postoperative day ; date (dd/mm/yyyy) / / สรปผลการวนจฉย 1. ตดเชอ 2. ไมตดเชอ โดยพบเกณฑของการตดเชอทแผลผาตดดงตอไปน

Infection occur within 30 days after the operative procedure AND Involves only skin and subcutaneous tissue of the incision AND one of the following 1. Purulent drainage from the superficial incision 2. Culture of fluid or tissue from the superficial incision positive 3. At least one of below sign or symptoms : pain or tenderness, localized swelling, redness, or heat PLUS

The superficial incision is deliberately opened by surgeon Opened date / /

ในผปวยทพบวามการตดเชอทแผลผาตด (SSI) Temperature at diagnosis of SSI . °C; WBC (cell/mm3)

Use of antibiotics: 1. Intravenous 2. Oral 3. None 1. Ceftriazone + Metronidazole 2. Ciprofloxacin + Metronidazole 3. Augmentin 4. Others, specify …………………………………………………………………… ผ ปวยไดรบการเยบปดแผลภายหลงจากการวนจฉยวามการตดเชอทแผลผาตด (resuture) 1. Yes 2. No If yes, resuture date (dd/mm/yyyy) / /

ภาวะแทรกซอนอนๆ (Other complications)

Pneumonia 1. Yes 2. No

Intraabdominal infection 1. Yes 2. No

Wound hematoma 1. Yes 2. No

Urinary tract infection 1. Yes 2. No

Thrombophlebitis 1. Yes 2. No

อนๆ 1. Yes 2. No ถาม.......................................

89


Form 6: Follow up 1 (Day 7-10 after discharge)

Participants ID - Follow up 1. Yes 2. No; date / /

A) ภาวะแทรกซอนหลงผาตด สรปผลการวนจฉย 1. ตดเชอ 2. ไมตดเชอ โดยพบเกณฑของการตดเชอทแผลผาตดดงตอไปน

Infection occur within 30 days after the operative procedure AND Involves only skin and subcutaneous tissue of the incision AND With one of the following 1. Purulent drainage from the superficial incision 2. Culture of fluid or tissue from the superficial incision positive 3. At least one of below sign or symptoms : pain or tenderness, localized swelling, redness, or heat PLUS

The superficial incision is deliberately opened by surgeon Opened date / /

Use of antibiotics: 1. Intravenous 2. Oral 3. No; If yes: 1. Ceftriazone + Metronidazole 2. Ciprofloxacin + Metronidazole 3. Augmentin 4. Others, specify……………………………. ในผปวยทพบวามการตดเชอทแผลผาตด

Temperature at diagnosis of SSI . °C WBC (cell/mm3)

ผ ปวยไดรบการเยบปดแผลภายหลงจากการวนจฉยวามการตดเชอทแผลผาตด (resuture) 1. Yes 2. No If yes, resuture date (dd/mm/yyyy) / /





Urinary tract infection 1. Yes 2. No

Thrombophlebitis 1. Yes 2. No

อนๆ 1. Yes 2. No ถาม.................................

90

ผลการประเมนทางโทรศพทในกรณทผปวยไมไดมาตรวจตดตาม 1. แผลไมมลกษณะบวมแดง 2. อาการเจบแผลลดลง 3. แผลแหงไมมนาเหลอง หรอหนองออกจากแผล 4. ไมไดไปพบแพทยทใด ถามเกณฑดงกลาวครบทกขอ ใหสรปวาผ ปวยไมมการตดเชอทแผลผาตด ถามเกณฑไมครบใหแนะนาผ ปวยใหมาตรวจตดตาม สรปผลการวนจฉยจากการประเมนทางโทรศพท 1. ตดเชอ 2. ไมตดเชอ 3. ไมชดเจน แนะนาใหมาตรวจ

สรปผลการวนจฉยในกรณทผ ปวยมาตรวจตามคาแนะนา 1. ตดเชอ 2. ไมตดเชอ





Urinary tract infection 1. Yes 2. No Thrombophlebitis 1. Yes 2. No อนๆ 1. Yes 2. No ถาม......................................

91

โครงการศกษา ระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร" Form 6: Follow up 1 (Day 7-10 after discharge)

Participants ID - Follow up date (dd/mm/yyyy) / / B) ผลการตรวจชนเนอ (Pathological examination)

Appendicitis 1. Complicated 2. Not complicated If complicated; 1. Gangrenous 2. Ruptured

C) ตนทนทางออมทเกดกบผปวยและญาต (Indirect cost) ชวงนอนโรงพยาบาล พกฟนและการตรวจตามนดครงท 1 C1 ตนทนทางออมทเกด ชวงผปวยนอนโรงพยาบาล

คาเดนทางไปและกลบโรงพยาบาลของผปวย บาท มญาตมาดแลในระหวางทนอนรกษาในโรงพยาบาลครงนหรอไม ม ไมม

ถาผปวยมญาตดแลใหลงขอมลดานลาง

- คาเดนทางไปและกลบโรงพยาบาลของญาต บาท/ครง; จานวนครงทมาโรงพยาบาล ครง - มญาตดแลทงหมดจานวน คน/วน

ญาตตองดแลผปวยโดยรวมทงหมด วน ญาตใชเวลาในการดแลโดยเฉลยตอวน 1.มากกวาครงวน หรอเตมวน 2. ครงวน หรอนอยกวาครงวน

ญาตคนท 1 ทดแลผ ปวยในโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท



- คาอาหารสวนทเพมขนจากปกตของญาต ในการดแลผปวยระหวางนอนโรงพยาบาล จานวนมอทตองเสยเพม มอ /คน จานวน คน คาใชจายในการรบประทานอาหารทตองเสยเพมประมาณ บาท/มอ/คน

- คาทพกของญาต เสย ไมเสย เสยคาทพกทงหมดจานวน คน คนละประมาณ บาท

C2 ตนทนทางออมทเกด ชวงผปวยพกฟน

ผ ปวยสามารถกลบไปทากจวตรประจาวนไดตามปกตหลงไดรบการรกษา วน ผปวยสามารถกลบไปทางานไดตามปกตหลงไดรบการรกษา วน

มญาตมาดแลในระหวางท ผปวยพกฟน หรอไม ม ไมม ถาผปวยมญาตดแลใหลงขอมลดานลาง

92



Participants ID - Follow up date (dd/mm/yyyy) / / C2 ตนทนทางออมทเกด ชวงผปวยพกฟน (ตอ)

- มญาตดแลทงหมดจานวน คน/วน

ญาตตองดแลผปวยโดยรวมทงหมด วน

ญาตใชเวลาในการดแลโดยเฉลยตอวน 1.มากกวาครงวน หรอเตมวน 2. ครงวน หรอนอยกวาครงวน ญาตคนท 1 ทดแลผ ปวยในโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท



C3 ตนทนทางออมทเกดจากการมาตรวจตดตามครงน (follow up) การเดนทาง มา โรงพยาบาล คาเดนทางของผ ปวย บาท การเดนทาง กลบ คาเดนทางของผ ปวย บาท คาอาหารสวน ทเพมขนของผปวย จากชวตปกต ในการมาโรงพยาบาลครงน ตองรบประทานอาหารทงหมด มอ คาใชจายในการรบประทานอาหารของผปวยประมาณ บาทตอมอ โดยปกตผปวยมคาใชจายในการรบประทานอาหารประมาณ บาทตอมอ คาทพกในกรณทเดนทางมาตรวจจากทไกล คาทพกประมาณ บาท

- มญาตมาดวยทงหมดจานวน คน ญาตคนท 1 ทพาผ ปวยมาโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท

ญาตคนท 2 ทพาผ ปวยมาโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท


- คาเดนทางไปและกลบ ของญาตในกรณทไมไดมากบผปวยประมาณ บาท - คาอาหาร สวนทเพมขน ของญาตทกคน จากคาใชจายปกต ทงหมดประมาณ บาท - คาทพกของญาตในกรณทเดนทางมาตรวจจากทไกล คาทพกประมาณ บาท

93



Participants ID 1 - Follow up date (dd/mm/yyyy) / /

สาหรบผปวยทไมไดมาตรวจตดตามนด วนทสมภาษณ (dd/mm/yyyy) / ผลการประเมนทางโทรศพทในกรณทผปวยไมไดมาตรวจตดตาม 1. แผลไมมลกษณะบวมแดง 2. อาการเจบแผลลดลง 3. แผลแหงไมมนาเหลอง หรอหนองออกจากแผล 4. ไมไดไปพบแพทยทใด ถามเกณฑดงกลาวครบทกขอ ใหสรปวาผ ปวยไมมการตดเชอทแผลผาตด ถามเกณฑไมครบใหแนะนาผ ปวยใหมาตรวจตดตาม สรปผลการวนจฉยจากการประเมนทางโทรศพท 1. ตดเชอ 2. ไมตดเชอ 3. ไมชดเจน แนะนาใหมาตรวจ

สรปผลการวนจฉยในกรณทผ ปวยมาตรวจตามคาแนะนา 1. ตดเชอ 2. ไมตดเชอ





Urinary tract infection 1. Yes 2. No Thrombophlebitis 1. Yes 2. No อนๆ 1. Yes 2. No D) ผลการตรวจเพาะเชอ Operative culture Abdominal fluid culture positive negative; colony count * 10˄), results…………………………… Subcutaneous layer culture positive negative; colony count * 10˄), results…………………………… Incision before closure (DPC): positive negative; colony count * 10˄), results…………………………… Incision of DPC at day 4: positive negative; colony count * 10˄), results……………………………. SSI: positive negative; colony count * 10˄), results……………………………..

E) ตนทนทางออมทเกดกบผปวยและญาต (Indirect cost) ในการตรวจตามนดครงท 2 (follow up) การเดนทาง มา โรงพยาบาล คาเดนทางของผ ปวย บาท การเดนทาง กลบ คาเดนทางของผ ปวย บาท คาอาหารสวน ทเพมขนของผปวย จากชวตปกต ในการมาโรงพยาบาลครงน ตองรบประทานอาหารทงหมด มอ คาใชจายในการรบประทานอาหารของผปวยประมาณ บาทตอมอ โดยปกตผปวยมคาใชจายในการรบประทานอาหารประมาณ บาทตอมอ

94

คาทพกในกรณทเดนทางมาตรวจจากทไกล คาทพกประมาณ บาท - มญาตมาดวยทงหมดจานวน คน



95



Participants ID 1 - Follow up date (dd/mm/yyyy) / / C) ตนทนทางออมทเกดกบผปวยและญาต (Indirect cost) ในการตรวจตามนดครงท 2 (follow up) (ตอ) ญาตคนท 3 ทพาผ ปวยมาโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท


D) แบบประเมนคณภาพชวต (EQ5D) 1 month date (dd/mm/yyyy) / /

ภาวะการเจบปวยของทานในปจจบนนมผลตอทานในหวขอตอไปนอยางไรบาง




3.ขาพเจาไมสามารถอาบนาหรอแตงตวดวยตนเองได 3. กจกรรมททาเปนประจา (เชน การทางาน, การเรยนหนงสอ, การทางานบาน การทากจกรรมในครอบครว หรอการทากจกรรมยามวาง) 1.ขาพเจาไมมปญหาในการทากจกรรมททาเปนประจา 2.ขาพเจามปญหาในการทากจกรรมททาเปนประจาอยบาง

3.ขาพเจาไมสามารถทากจกรรมททาเปนประจาได

4. ความเจบปวด/ 1.ขาพเจาไมมอาการเจบปวดหรออาการไมสขสบาย ความไมสขสบาย 2.ขาพเจามอาการเจบปวดหรออาการไมสขสบายปานกลาง 3.ขาพเจามอาการเจบปวดหรออาการไมสขสบายมากทสด

5. ความวตกกงวล/ 1.ขาพเจาไมรสกวตกกงวลหรอซมเศรา ความซมเศรา 2.ขาพเจารสกวตกกงวลหรอซมเศราปานกลาง 3.ขาพเจารสกวตกกงวลหรอซมเศรามากทสด

96


Form 8: Additional follow up

Participants ID - Follow up date (dd/mm/yyyy) / /

สาเหตของการมาตรวจตดตามครงน 1. สงสยตดเชอ 2. Pain 3. Others; specify…………………………………..

ผลการตรวจ SSI no SSI ตนทนทางออมทเกดจากการมาตรวจตดตามครงน (follow up)

การเดนทาง มา โรงพยาบาล คาเดนทางของผ ปวย บาท

การเดนทาง กลบ คาเดนทางของผ ปวย บาท คาอาหารสวน ทเพมขนของผปวย จากชวตปกต ในการมาโรงพยาบาลครงน ตองรบประทานอาหารทงหมด มอ

คาใชจายในการรบประทานอาหารของผปวยประมาณ บาทตอมอ โดยปกตผปวยมคาใชจายในการรบประทานอาหารประมาณ บาทตอมอ คาทพกในกรณทเดนทางมาตรวจจากทไกล คาทพกประมาณ บาท

- มญาตมาดวยทงหมดจานวน คน ญาตคนท 1 ทพาผ ปวยมาโรงพยาบาลครงน เพศ 1. ชาย 2. หญง อาย ป ประกอบอาชพหรอไม 1.ไม 2.ประกอบอาชพ โดยมรายไดเฉลยเดอนละ บาท




97

B) Manual of data collection คมอการเกบขอมล

การศกษาระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร"

สถานท ลกษณะผปวย รายละเอยดงานทตองทา ผรบผดชอบ หองตรวจผปวยทแผนกฉกเฉนหรอหนวยตรวจผปวยนอกศลยกรรม

- ผปวยทกรายทมอาการปวดทองดานขวาภาวะไสตงอกเสบ - ผปวยทสงสยภาวะไสตงอกเสบ

- เชคเกณฑการเขารวมการวจย (Form 1) โดยผปวยตองผานเกณฑทกขอ

- ชวนผปวยเขารวมโครงการ โดยใหขอมลผปวยทผานเกณฑตามรายละเอยดใน

ใบ Information sheet - ถาผปวยไมเขารวม ไมตองสมภาษณตอ ใหเกบ Form 1 ไวในแฟม - ถาผปวยยนดเขารวมโครงการใหสมภาษณคณภาพชวตของผปวยกอนการผาตด

Form 1 Page 2 (Preoperative EQ5D) โดยซกถาม ผปวยถง

ผลกระทบของอาการปวดทองตอภาวะสขภาวะของผปวย - ลงขอมลใน log sheet (Form 2) - ลงขอมลใน Evaluation data (Form 3 A,B,C)

แพทยผรบผดชอบ หรอพยาบาล

หองผาตด ผปวยทไดรบการผาตดเนองจากสงสยภาวะไสตงอกเสบ

- กรอกขอมลผาตด ใน Form 4: Operative data;Page1-2 ASA classification ใหใชขอมลของวสญญ และเกณฑ

การจดกลมจากใบบนทกของวสญญ ลกษณะแผลผาตดแบบ Mc Burney เปนการลงแผลตามแนว external

oblique aponeurotic sheath Lanz แผลตามแนวผวหนง (Langer line)

เชคความครบถวน ของเกณฑการวนจฉยภาวะไสตงอกเสบแบบมเนอตาย

หรอมการแตกทะล โดยถามทงเนอตายและการแตกทะลใหวนจฉยเปนแบบแตกทะล

Finding Procedure related data

- เกบ Form เขาแฟมงานวจย

แพทยผาตด และพยาบาลหองผาตด (ตอ)

DMU & site

organization

unit

- รวบรวมแฟมวจยผปวยทเขาโครงการใหมตอนเชาทกวน - Assign ID - ตรวจความครบถวนของขอมล Form 1-4 ตดตอประสานงานกบแพทยหรอ

พยาบาลทรบผดชอบ หากขอมลไมครบถวน - หากขอมลครบถวน ถายสาเนา และสงขอมลเขา DMU - เตรยมแฟมพรอม Forms การประเมนหลงผาตด

ผชวยวจย

หอผปวยใน ผปวยหลงผาตด - เกบขอมลหลงผาตดวนท 1

- ประเมนความเจบปวด Form 5 Part A โดยอธบายพรอมใหดรป วา 0 คอไมมอาการเจบปวดเลย และ 100 คออาการ

ผชวยวจย IPD

98

เจบปวดมากทสดในชวต และใหผปวยเลอก

99

สถานท ลกษณะผ ปวย รายละเอยดงานทตองทา ผ รบผดชอบ หอผ ปวยใน (ตอ) ผ ปวยหลงผาตด (ตอ) - เกบขอมลหลงผาตดวนท 3

- ประเมนความเจบปวด Form 5 Part A - ภาวะสขภาวะ Form 5 Part B (Postoperative EQ5D)

ผชวยวจย IPD (ตอ)

- ประเมนภาวะแทรกซอนหลงการผาตด วนท 3-7 Form 5: Part C

เกณฑการวนจฉยการตดเชอ

- สาหรบกลมเยบปดแผลทนท ใหประเมนวนทๆผปวยกลบบาน

(หรอกอน 1 วน)

- สาหรบกลมเยบปดแผลในภายหลง ใหประเมนวนวนทๆเยบปด

แผล

- ในกรณทมการตดเชอทแผลผาตด กรอกขอมลเพมในสวนการตดเชอ กรอกวนทๆ เปดและปดแผล ในกรณทมการเปด หรอเยบ

ปดแผล ถาไมมใหตอบ No

แพทยผ รกษา

DMU & site organization unit

- รวบรวมแฟมวจย และตรวจความครบถวนของขอมล Form 1-5

- ตดตอประสานงานกบแพทยหรอพยาบาลทรบผดชอบ หากขอมลไมครบถวน - หากขอมลครบถวน ถายสาเนา และสงขอมลเขา DMU

- เตรยมความพรอมการตดตามผปวย แฟมพรอม Form 6: การตดตามครงท 1 โทรแจงผปวยใหมาตรวจตามนด


FU 1: หองตรวจผ ปวยนอก

ผ ปวยหลงผาตด วนท 7-10 ผชวยวจยกลางพาผ ปวยเขาพบแพทย ผชวยวจย

- ประเมนการตดเชอทแผลผาตด Form 6: Part A

- ในกรณทมการตดเชอทแผลผาตด

- กรอกขอมลเกณฑการตดเชอ - ลงขอมลผลการตรวจชนเนอ Form 6: Part B

แพทยผประเมน

- ผชวยวจยสมภาษณผปวย ตนทนทางออมทเกดกบผปวยชวงนอนโรงพยาบาล

ชวงพกฟน และการตรวจตดตามครงท 1 Form 6: Part C1,C2,C3


- ถาหากผปวยไมมาตามนด ใหแจง PI ของ site เพอสมภาษณอาการทางโทรศพท และกรอก Form 6: Part A


100

สถานท ลกษณะผ ปวย รายละเอยดงานทตองทา ผ รบผดชอบ

FU 2: หองตรวจผ ปวยนอก

ผ ปวยหลงผาตด วนท 30-35

- ประเมนการตดเชอทแผลผาตด Form 7

- ในกรณทมการตดเชอทแผลผาตด Part A

- กรอกขอมลเกณฑการตดเชอ - การเยบปดแผลในภายหลง

- ผลการเพาะเชอ Part B

- ตนทนทางออม Part C

- ภาวะสขภาวะ Part D

- ในกรณทผปวยไมไดมาตรวจตดตาม สมภาษณทางโทรศพท - อาการตดเชอทแผล และกรอก Form 7: Part A

- ภาวะสขภาวะผปวย Form 7: Part D

แพทยผประเมน

หองตรวจผ ปวยนอก

หรอใน

ผ ปวยทมาตรวจนอกเหนอจาก

protocol เนองจากมการตดเชอ หรออนๆ

- ใหผชวยวจยแจงแพทยทเกยวของ และ PI

- กรอกขอมล Form 8:

- ผลการตรวจ - ขอมลคาใชจายทางออมจากการมาตรวจครงน


DMU & site organization unit

- ผชวยวจยรวบรวมขอมล - คาใชจายทางตรง (direct cost) ของผปวยตงแตเขา

โรงพยาบาลถงการมาตรวจครงสดทาย - ตรวจความเรยบรอยของขอมล Form 1-Form 7/8

- สงแฟมขอมลทงหมดให PI ตรวจกอนสง DMU


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C) Calculating utility from EQ-5D

Dimension Level UK Thai Constant - 0.081 0.202

Mobility Level 1 0 0 Level 2 0.069 0.121 Level 3 0.314 0.432

Self care Level 1 0 0 Level 2 0.104 0.121 Level 3 0.214 0.242

Usual activities Level 1 0 0 Level 2 0.036 0.059 Level 3 0.094 0.118

Pain/discomfort Level 1 0 0 Level 2 0.123 0.072 Level 3 0.386 0.209

Anxiety/depression Level 1 0 0 Level 2 0.071 0.032 Level 3 0.236 0.11

N3 - 0.269 0.139

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D) Dummy tables 1. Patients’ characteristic in appendicitis and non-appendicitis group

Parameters Appendicitis Non-appendicitis P value

Age (years) <40 ≥40

Sex M F

Onset of pain Sudden insidious

Migration of pain Presence Absence

Duration of pain < 48 hours ≥ 48 hours

Anorexia present absence

Aggravation of pain with cough present absence

Nausea present absence

Vomiting present absence

Dysuria present absence

Diarrhea present absence

Fever (T>37.8oC) present absence

Tender at RLQ present

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absence

Abdominal guarding present absence

Rovsing sign present absence

PR tenderness present absence

Increase WBC present absence

PMN leucocytosis present absence

RLQ=right lower quadrant, PR=per rectal examination, WBC=white blood cell,

PMN=polymorphonuclear

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2. Factors associated with appendicitis: multiple logistic regression analysis

Parameters Coefficient SE P value OR (95%CI)





Fever (T>37.8oC) present absence

Tender at RLQ present absence

Abdominal guarding present absence

Increase WBC present absence

PMN leucocytosis present absence



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3. Scoring scheme: steps used to calculate RAMA-AS

Parameters Scoring Score for individual





Total score ..…….. Low risk

Moderate risk High risk

………….. <X

X to Y ≥Y



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4. Percentage of having appendicitis according to RAMA-AS category in derivative and validation phases

Score Probability of appendicitis

Derivative Validation

Group LR+ (95%CI)

PPV Group LR+ (95%CI)

PPV

AP Non-AP AP Non-AP

Low

Moderate

High

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5. ROC curve for predicting appendicitis

6. Comparison RAMA-AS with other scoring systems.

Scoring system No. variable/event/N O/E C-statistic

RAMA-AS

Alvarado

RIPSA

AIRS

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B) Informal sheet & consent form

คาแนะนาผปวย (Information Sheet)

โครงการศกษาระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร"

ผรบผดชอบโครงการ ศ. จมพล วลาศรศม

สถานทตดตอ ภาควชาศลยศาสตร คณะแพทยศาสตรโรงพยาบาลรามาธบด

มหาวทยาลยมหดล เลขท 270 ถ.พระราม6 เขตราชเทว กทม. 10400 หมายเลข

โทรศพท 02-201-1527, 089-798-6337

การวจยนมวตถประสงคเพอศกษาศกษาระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด

อะเพนดไซทส สกอร"

ไสตงอกเสบเฉยบพลนเปนหนงในภาวะฉกเฉนทางศลยกรรมทพบมากทสดโดยมอตราความชก

ประมาณหนงในเจด อบตการณประมาณ 110 ตอ 100,0001 ซงหลายการศกษาไดทาการศกษาเกยวกบความ

ถกตองในการวนจฉย อตราผลลบบวก และผลลบลวง โดยทวไปอตราของการผาตด negative appendectomy

15% - 26%2,3 และอตรา perforate appendectomy 10% - 30%4

ในหลายระบบการใหคะแนนเพอวนจฉยโรคไสตงอกเสบไดมการพฒนาอยอยางตอเนองและมผลลพธ

ทนาสนใจ อยางไรกตามระบบการใหคะแนนยงนามาใชนอยในทางเวชปฏบตทวไป ดงนนผวจยจงดาเนนการ

พฒนาอยางเปนระบบ โดยพฒนาและตรวจสอบระบบคะแนนทใชในปจจบน จากการทบทวนวรรณกรรมท

เกยวของ 14 การศกษาไดแนะนาตวแปรทใชในการวนจฉยตงแต 5 – 14 ตวแปร โดยทวไปตวแปรตวแปรทใช

มากคอ migration of pain, nausea/vomiting, duration of pain, rebound tenderness, RLQ tenderness,

และ elevated temperature

การศกษาสวนใหญ (64.3%) เปนระบบคะแนนทใชจากผลจากการทาแบบจาลองแบบ univariate

หรอการแบบจาลองแบบไมใชสถต สาหรบคา coefficient C statistics เทากบ 0.79 (95% CI: 0.67, 0.90)

สาหรบการศกษาแบบ derive และ 0.84(0.77, 0.92) สาหรบการศกษาแบบ internal validation ในสวนของ

คา C statistics เทากบ 0.74 (95%CI, 0.69, 0.79) สาหรบการศกษาแบบ external validation ของระบบ

คะแนน Alvarado โดยการศกษาและคณภาพของระบบคะแนนแตละระบบจะคอนขางมความแตกตางกน

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ถงแมจะพบวามการใชระบบคะแนนตางๆ มากมายในประชากรทวไป แตยงคงมความสงสยอยถง

ความถกตองของวธการทใชปฏบตวาเหมาะสมหรอไม ซงการตรวจสอบทาง internal และ external

validations ยงคงมความจาเปนเพอตรวจสอบความถกตองของระบบคะแนนตางๆ ในการวนจฉยโรคไสตง

อกเสบ ดงนนผวจยจงไดทาการศกษาแบบ cross-sectional เพอพฒนาระบบคะแนน Ramathibodi appendic

score (RAMA-AS) ทเหมาะสมและสรางระบบคะแนนทถกตองเพอการวนจฉยทมประสทธภาพในการตดสนใจทางคลนกทดทใชวนจฉยโรคไสตงอกเสบ

หากพบวามฉกเฉนสามารถตดตอนพ จทพล ไดตามเบอรโทรศพททใหไว

ผวจยขอรบรองวา ทานจะไดรบการดแลรกษา และปฏบตทเทาเทยมกน ขนตอนการผาตด อปกรณท

ใชสาหรบเยบแผล ยาปฏชวนะทใชหลงผาตด ตลอดการดแลรกษาอนๆ จะเทาเทยมกนไมวาทานจะถกสมให

ไดรบการปดแผลวธไหนกตาม ทานมอสระในการตดสนใจเขารวมโครงการ ทานมสทธทจะปฏเสธไมเขารวม

โครงการวจยได หรอเมอเขาโครงการแลวกสามารถทจะถอนตวจากโครงการตอมาไดทกเมอ โดยการปฏเสธ หรอ

การถอนตวน จะไมมผลตอการรกษาพยาบาลใดๆทงสน นอกจากน ผวจยขอยนยนวา ชอ-นามสกล ตลอดจน

ขอมลการรกษาทงหมดของทาน จะถกเกบเปนความลบ งานวจยนไดรบความเหนชอบจากคณะกรรมการ

จรยธรรมการวจยในมนษย จากสถาบนวจยหลก คณะแพทยศาสตรโรงพยาบาลรามธบด และ คณะแพทยศาสตรโรงพยาบาลธรรมศาสตร ตลอดจนสถาบนวจยรวมอนๆ และไดรบแหลงทนสนบสนนจาก

คณะกรรมการวจยแหงชาต ทานจะไดรบคาทดแทนการเสยเวลา สาหรบมาตรวจตามนดครงละ 200 บาท

จานวน 2 ครง

คณะผวจย ขอขอบคณในความรวมมอของทาน ทจะทาใหงานวจยครงนดาเนนลลวงไปไดดวยด

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ใบยนยอมของอาสาสมคร (Consent form)

โครงการวจยเรอง ระบบคะแนนเพอชวยวนจฉยภาวะไสตงอกเสบ "รามาธบด อะเพนดไซทส สกอร"

วนทใหคายนยอม วนท ………………เดอน ……………………พ.ศ………………………

กอนทจะลงนามในใบยนยอมใหทาการวจยน ขาพเจาไดรบการอธบายจากผวจยถงวตถประสงคของการวจย วธการวจย อนตรายหรออาการทอาจเกดขนจากการวจย รวมทงประโยชนทจะเกดขนจากการวจยอยางละเอยด และมความเขาใจดแลว ซงผวจยไดตอบคาถามตางๆทขาพเจาสงสยดวยความเตมใจ ไมปดบง ซอนเรน จนขาพเจาพอใจ และเขารวมโครงการนโดยสมครใจ

ขาพเจามสทธทจะบอกเลกการเขารวมการวจยนเมอใดกได ถาขาพเจาปรารถนาโดยไมเสยสทธในการรกษาพยาบาลทจะเกดขนตามมาในโอกาสตอไป

ผวจยรบรองวาจะเกบขอมล เฉพาะเกยวกบตวขาพเจาเปนความลบและจะเปดเผยไดเฉพาะในรปทเปนสรปผลการวจย

การเปดเผยขอมลเกยวกบตวขาพเจาตอหนวยงานตางๆ ทเกยวของกระทาไดเฉพาะกรณจาเปนดวยเหตผลทางวชาการเทานนและจะตองไดรบคายนยอมจากขาพเจาเปนลายลกษณอกษร

ในการวจยครงน จะมการเพาะเชอจากแผลกอนทจะทาการเยบแผล 1 ครง โดยไมกอใหเกดอาการเจบปวดแตอยางใด

ผวจยรบรองวาหากเกดภาวะแทรกซอนใดๆ ทมสาเหตจากการวจยดงกลาว ขาพเจาจะไดรบการรกษาพยาบาลอยางไกลชด

ขาพเจายนยอมใหผ กากบดแลการวจย ผตรวจสอบ คณะกรรมการจรยธรรมการวจยในคน และคณะกรรมการทเกยวของกบการควบคมยา สามารถเขาไปตรวจสอบบนทกขอมลทางการแพทยของขาพเจา เพอเปนการยนยนถงขนตอนโครงการวจยทางคลนก โดยไมลวงละเมดเอกสทธ ในการปดบงขอมลของการสมครตามกรอบทกฎหมายและกฏระเบยบไดอนญาตไว

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ขาพเจาไดอานขอความขางตนแลว และมความเขาใจดทกประการ และไดลงนามในใบยนยอมน ดวยความเตมใจ

ในกรณทขาพเจาไมสามารถอานหนงสอได ผวจยไดอานขอความในใบยนยอมนใหขาพเจาฟงจนเขาใจดแลว ขาพเจาจงลงนามในใบยนยอมนดวยความเตมใจ

ขาพเจาสามารถตดตอผวจยไดท ภาควชาศลยศาสตร คณะแพทยศาสตร มหาวทยาลยธรรมศาสตร

โรงพยาบาลธรรมศาสตรเฉลมพะเกยรต เลขท 95 หม 8 ต.คลองหนง อ.คลองหลวง จ.ปทมธาน 12120 โดย

บคคลทรบผดชอบเรองน คอ นพ. บญยง ศรบารงวงศ หมายเลขโทรศพท 02-926-9523 ในเวลาราชการ และ

โทรศพทเคลอนท 0819960365

ลงนาม…………………………………ผ ยนยอม

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Faculty of Medicine Ramathibodi Hospital Mahidol ... · peritonitis from a perforated appendicitis....

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