Platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis

Agostino Colli; Juan Cristóbal Gana; Jason Yap; Thomasin Adams‐Webber; Natalie Rashkovan; Simon C Ling; Giovanni Casazza

doi:10.1002/14651858.CD008759.pub2

. 2017 Apr 26;2017(4):CD008759. doi: 10.1002/14651858.CD008759.pub2

Platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis

Agostino Colli ^1,^✉, Juan Cristóbal Gana ², Jason Yap ³, Thomasin Adams‐Webber ⁴, Natalie Rashkovan ⁵, Simon C Ling ⁶, Giovanni Casazza ⁷

Editor: Cochrane Hepato‐Biliary Group

PMCID: PMC6478276 PMID: 28444987

Abstract

Background

Current guidelines recommend screening of people with oesophageal varices via oesophago‐gastro‐duodenoscopy at the time of diagnosis of hepatic cirrhosis. This requires that people repeatedly undergo unpleasant invasive procedures with their attendant risks, although half of these people have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Platelet count, spleen length, and platelet count‐to‐spleen length ratio are non‐invasive tests proposed as triage tests for the diagnosis of oesophageal varices.

Objectives

Primary objectives

To determine the diagnostic accuracy of platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology. To investigate the accuracy of these non‐invasive tests as triage or replacement of oesophago‐gastro‐duodenoscopy.

Secondary objectives

To compare the diagnostic accuracy of these same tests for the diagnosis of high‐risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.

We aimed to perform pair‐wise comparisons between the three index tests, while considering predefined cut‐off values.

We investigated sources of heterogeneity.

Search methods

The Cochrane Hepato‐Biliary Group Controlled Trials Register, the Cochrane Hepato‐Biliary Group Diagnostic Test Accuracy Studies Register, the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index ‐ Expanded (Web of Science) (14 June 2016). We applied no language or document‐type restrictions.

Selection criteria

Studies evaluating the diagnostic accuracy of platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices via oesophago‐gastro‐duodenoscopy as the reference standard in children or adults of any age with chronic liver disease or portal vein thrombosis, who did not have variceal bleeding.

Data collection and analysis

Standard Cochrane methods as outlined in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews.

Main results

We included 71 studies, 67 of which enrolled only adults and four only children. All included studies were cross‐sectional and were undertaken at a tertiary care centre. Eight studies reported study results in abstracts or letters. We considered all but one of the included studies to be at high risk of bias. We had major concerns about defining the cut‐off value for the three index tests; most included studies derived the best cut‐off values a posteriori, thus overestimating accuracy; 16 studies were designed to validate the 909 (n/mm³⁾/mm cut‐off value for platelet count‐to‐spleen length ratio. Enrolment of participants was not consecutive in six studies and was unclear in 31 studies. Thirty‐four studies assessed enrolment consecutively. Eleven studies excluded some included participants from the analyses, and in only one study, the time interval between index tests and the reference standard was longer than three months.

Diagnosis of varices of any size. Platelet count showed sensitivity of 0.71 (95% confidence interval (CI) 0.63 to 0.77) and specificity of 0.80 (95% CI 0.69 to 0.88) (cut‐off value of around 150,000/mm³ from 140,000 to 150,000/mm³; 10 studies, 2054 participants). When examining potential sources of heterogeneity, we found that of all predefined factors, only aetiology had a role: studies including participants with chronic hepatitis C reported different results when compared with studies including participants with mixed aetiologies (P = 0.036). Spleen length showed sensitivity of 0.85 (95% CI 0.75 to 0.91) and specificity of 0.54 (95% CI 0.46 to 0.62) (cut‐off values of around 110 mm, from 110 to 112.5 mm; 13 studies, 1489 participants). Summary estimates for detection of varices of any size showed sensitivity of 0.93 (95% CI 0.83 to 0.97) and specificity of 0.84 (95% CI 0.75 to 0.91) in 17 studies, and 2637 participants had a cut‐off value for platelet count‐to‐spleen length ratio of 909 (n/mm³)/mm. We found no effect of predefined sources of heterogeneity. An overall indirect comparison of the HSROCs of the three index tests showed that platelet count‐to‐spleen length ratio was the most accurate index test when compared with platelet count (P < 0.001) and spleen length (P < 0.001).

Diagnosis of varices at high risk of bleeding. Platelet count showed sensitivity of 0.80 (95% CI 0.73 to 0.85) and specificity of 0.68 (95% CI 0.57 to 0.77) (cut‐off value of around 150,000/mm³ from 140,000 to 160,000/mm³; seven studies, 1671 participants). For spleen length, we obtained only a summary ROC curve as we found no common cut‐off between studies (six studies, 883 participants). Platelet count‐to‐spleen length ratio showed sensitivity of 0.85 (95% CI 0.72 to 0.93) and specificity of 0.66 (95% CI 0.52 to 0.77) (cut‐off value of around 909 (n/mm³)/mm; from 897 to 921 (n/mm³)/mm; seven studies, 642 participants). An overall indirect comparison of the HSROCs of the three index tests showed that platelet count‐to‐spleen length ratio was the most accurate index test when compared with platelet count (P = 0.003) and spleen length (P < 0.001).

DIagnosis of varices of any size in children. We found four studies including 277 children with different liver diseases and or portal vein thrombosis. Platelet count showed sensitivity of 0.71 (95% CI 0.60 to 0.80) and specificity of 0.83 (95% CI 0.70 to 0.91) (cut‐off value of around 115,000/mm³; four studies, 277 participants). Platelet count‐to‐spleen length z‐score ratio showed sensitivity of 0.74 (95% CI 0.65 to 0.81) and specificity of 0.64 (95% CI 0.36 to 0.84) (cut‐off value of 25; two studies, 197 participants).

Authors' conclusions

Platelet count‐to‐spleen length ratio could be used to stratify the risk of oesophageal varices. This test can be used as a triage test before endoscopy, thus ruling out adults without varices. In the case of a ratio > 909 (n/mm³)/mm, the presence of oesophageal varices of any size can be excluded and only 7% of adults with varices of any size would be missed, allowing investigators to spare the number of oesophago‐gastro‐duodenoscopy examinations. This test is not accurate enough for identification of oesophageal varices at high risk of bleeding that require primary prophylaxis. Future studies should assess the diagnostic accuracy of this test in specific subgroups of patients, as well as its ability to predict variceal bleeding. New non‐invasive tests should be examined.

Plain language summary

Platelet count, spleen length, and platelet‐to‐spleen length ratio for the diagnosis of oesophageal varices in people with liver disease

Background

Hepatic cirrhosis is a severe disease with scars and nodules on the liver tissue. As a result, the normal function of the liver is impaired. Whatever the cause of cirrhosis, changes in the structure of and blood flow within the liver increase pressure in the portal vein (called portal vein hypertension), which is the vein that drains blood from the bowels to the liver. Portal hypertension induces dilatation (extension) of veins within the wall of the oesophagus (food pipe or gullet), which often rupture (break) with severe bleeding. Thus, when liver cirrhosis is diagnosed, an oesophago‐gastro‐duodenoscopy (OGD) is recommended to detect the presence of oesophageal varices (areas of abnormal dilatation of veins). During OGD, a small camera at the end of a tube is inserted down the oesophagus from the mouth and pictures are relayed back to a screen. Large varices or red signs on even small varices show high risks of rupture and bleeding. If high‐risk varices are found, treatment with beta‐blockers is effective in reducing the risk of bleeding. Three simple non‐invasive tests could be used to identify people with liver diease at high risk of having oesophageal varices: platelet count ‐ a simple laboratory test on a blood sample by which the number of platelets (a blood element ensuring coagulation) is measured; length (maximal diameter) of the spleen measured during ultrasound examination of the abdomen; and ratio of platelet count to spleen length.

Study characteristics

We searched scientific databases for clinical studies comparing platelet count, spleen length, or platelet count‐to‐spleen length ratio versus oesophago‐gastro‐duodenoscopy in detecting the presence of varices in children or adults with chronic liver disease or portal vein thrombosis (narrowing of the portal vein). The evidence is current to June 2016.

Key results

We found 25 studies with 5096 participants assessing the use of platelet count to diagnose the presence of varices and grade the risk of bleeding, and comparing platelet count versus oesophago‐gastro‐duodenoscopy in adults with cirrhosis: 13 studies with 1489 participants assessed the diagnostic ability of spleen length, and 38 studies with 5235 participants assessed the diagnostic ability of platelet count‐to‐spleen length ratio. Platelet count‐to‐spleen length ratio was the most accurate and could be used to identify people with liver disease who were at high risk of having oesophageal varices. Particularly, in people with hepatic cirrhosis among whom 580 out of 1000 people are expected to have oesophageal varices, only 41 (7% of 580) people will be missed as having varices and will have no appropriate preventive treatment or follow‐up. Thus, if platelet count‐to‐spleen length ratio is lower than 909 (n/mm³)/mm (the most used threshold), the presence of oesophageal varices can be excluded. Thus, it is possible to reduce the number of endoscopic examinations needed to find a person with oesophageal varices. On the contrary, this ratio is not accurate enough to replace endoscopy for identification of high risk of bleeding oesophageal varices.

Quality of the evidence

All but one study had problems of risk of bias involving mainly the definition of positive or negative index tests (platelet count, spleen length, and their ratio), which should be defined before and not after data analyses, and blinding of test results to the endoscopists who performed oesophago‐gastro‐duodenoscopy. Hence, these problems could impair the accuracy estimates of the three tests.

Summary of findings

Background

Oesophageal varices in portal hypertension

Portal hypertension commonly accompanies advanced liver disease and often gives rise to life‐threatening complications, including haemorrhage from oesophageal and gastrointestinal varices. Prevalence of cirrhosis in high‐income countries ranges from 0.4% to 1.1% of the population (Bellentani 1994; Quinn 1997); up to two thirds of people with cirrhosis will develop gastro‐oesophageal varices (Pagliaro 1992; D'Amico 1999; Jensen 2002). The incidence of oesophageal varices among people with compensated cirrhosis is around 5% per year (Merli 2003; Groszmann 2005), and the cumulative incidence among people with well‐defined compensated cirrhosis seems lower: 44% at 10 years and 53% at 20 years (D'Amico 2014). Gastro‐oesophageal varices are an extension of oesophageal varices; isolated gastric varices in the absence of oesophageal varices are rare and usually are associated with splenic vein thrombosis (Garcia‐Tsao 2007). As varices grow larger, they become more likely to rupture and bleed (Lebrec 1980; NIEC 1988). Haemorrhage from ruptured oesophageal varices is one of the most common causes of gastrointestinal bleeding and is the most common cause of death among individuals with cirrhosis (D'Amico 2006 a; Garcia‐Tsao 2007). Studies conducted by the Northern Italian Endoscopic Club have shown that bleeding over two years occurs at a frequency of up to 30% from large varices compared with 5% to 18% from small varices (NIEC 1988; Zoli 1996; D'Amico 1999). Variceal bleeding is a medical emergency that, in spite of recent progress, is associated with mortality of 10% to 20% at six weeks. Up to 30% of initial bleeding episodes are fatal, and bleeding recurs among 70% of survivors (Graham 1981; NIEC 1988; Sharara 2001; D'Amico 2003; Bambha 2008). However, primary prophylaxis with non‐selective beta blockers or endoscopic variceal banding lowers the incidence of first variceal haemorrhage, especially from medium to large varices (Garcia‐Tsao 2008; de Franchis 2015). Detection of oesophageal varices allows one to define the bleeding risk and to identify progression to decompensated cirrhosis associated with further complications and a poor prognosis requiring more intense follow‐up (D'Amico 2006 b; D'Amico 2014).

Current North American European and Asian Pacific guidelines for detection and management of oesophageal varices recommend performance of oesophago‐gastro‐duodenoscopy to screen for oesophageal varices at the time hepatic cirrhosis is diagnosed (Garcia‐Tsao 2007; Sarin 2008; ASGE Standards of Practice Committee 2012). However, the point prevalence of oesophageal varices requiring prophylaxis is only about 15% to 25%, and most people undergoing screening oesophago‐gastro‐duodenoscopy do not have varices or have varices that do not require treatment. Moreover, oesophago‐gastro‐duodenoscopy is an invasive procedure that often requires sedation and may be associated with serious, even rare, complications and with frequent unexpected hospital admissions (Silvis 1976; Wolfsen 2004; Geraci 2009; Leffler 2010). Therefore, a cost‐effective triage pathway must be developed to select people who will benefit from oesophago‐gastro‐duodenoscopy screening. A recent consensus conference (de Franchis 2015) identified individuals with chronic liver disease who could safely avoid screening endoscopy because their risk of oesophageal varices was very low when liver stiffness was measured by transient elastography < 20 kPa and a platelet count > 150,000 per mm³. However no systematic review supports this recommendation (de Franchis 2015).

A non‐invasive test can play the role of a triage test if it can serve to accurately rule out the presence of varices without missing effective treatments, and hence to reduce the use of endoscopy, reserving its use for people with positive results. A non‐invasive test may even be more accurate than the reference standard, that is, oesophago‐gastro‐duodenoscopy, which is limited by interobserver reliability, which is poor even for the definition of the presence of varices and for assessment of their size and volume (Winkfield 2003). In such a case, the non‐invasive test could replace the reference standard. However, for a non‐invasive test to replace oesophago‐gastro‐duodenoscopy as the preferred diagnostic test for varices, it should accurately demonstrate the presence of varices while providing qualitative information that currently can be gained only from endoscopy. It is important to note that the non‐invasive test should be able to predict the risk of variceal bleeding with as much or greater accuracy than oesophago‐gastro‐duodenoscopy

Many non‐invasive tests have been proposed for the diagnosis of oesophageal varices. This systematic review is one of five that have examined the diagnostic utility of these tests (Gana 2010a; Gana 2010b; Gana 2010c; Colli 2014b).

Target condition being diagnosed

Oesophageal varices

Oesophageal varices of any size were diagnosed. Oesophageal varices are dilated blood vessels within the wall of the oesophagus that develop when resistance to blood flow through the liver is increased as the result of cirrhosis or portal vein obstruction. Large oesophageal varices are associated with greater risk of bleeding than are smaller varices. Red marks (or red signs) on varices diagnosed during oesophago‐gastro‐duodenoscopy have also been associated with increased bleeding risk (JSPH 1980; NIEC 1988; Garcia‐Tsao 2007; Garcia‐Tsao 2008). Medium varices were classified as large varices, as suggested by the American Association for the Study of Liver Diseases, because recommendations for management of medium‐sized varices are the same as for large varices (Garcia‐Tsao 2007).

Index test(s)

Platelet count, spleen length, and platelet count‐to‐spleen length ratio

If non‐invasive tests predict the presence of oesophageal varices with sufficient accuracy, then oesophago‐gastro‐duodenoscopy can be limited to patients identified to be at high risk of varices. Certain blood tests and imaging modalities and calculations based on their results have shown a promising correlation with oesophageal varices. Of these, the most frequently studied non‐invasive tests are platelet count and ultrasound measurements of spleen length. Increased spleen length in patients with chronic liver disease is almost always caused by increased portal pressure (Pockros 2002; Liangpunsakul 2003). Thrombocytopenia may be the result of splenic pooling of platelets due to portal hypertension, immune‐mediated mechanisms, or reduced thrombopoietin synthesis (Peck‐Radosavljevic 2000; Giannini 2003a; Peck‐Radosavljevic 2007). Integrating platelet count and spleen length in a ratio provides a measure of the degree of thrombocytopenia that may result from hypersplenism. This review aims to evaluate the diagnostic accuracy of platelet count, spleen length, or platelet count‐to‐spleen length ratio in predicting the presence of oesophageal varices.

Clinical pathway

At the time of diagnosis of hepatic cirrhosis of whatever aetiology, an oesophago‐gastro‐duodenoscopy is recommended to detect the presence of oesophageal varices and to define the risk of their rupture and bleeding while providing an overall prognostic assessment. In the case of high‐risk varices (large varices or presence of red marks), primary prophylaxis with a non‐selective beta‐blocker or endoscopic banding ligation of varices has been demonstrated to be effective and hence is recommended (D'Amico 1999; Imperiale 2001; Gluud 2007; Gluud 2012). If oesophago‐gastro‐duodenoscopy reveals no varices, a repeated examination is recommended in three years. If low‐risk varices are seen (small varices without red marks), then oesophago‐gastro‐duodenoscopy should be repeated in two years. If small varices are associated with red signs or with Child‐Pugh score B‐C (Pugh 1973), non‐selective beta‐blocker prophylaxis is recommended (Garcia‐Tsao 2007; Garcia‐Tsao 2008; ASGE Standards of Practice Committee 2012; de Franchis 2015).

Prior test(s)

The diagnosis of liver cirrhosis usually is based on clinical judgement derived from history, laboratory testing, physical examination, imaging, liver histology, or a combination of these. No prior test is recommended by the guidelines before screening with oesophago‐gastro‐duodenoscopy of oesophageal varices when the diagnosis of cirrhosis is made.

Role of index test(s)

The possible role of platelet count, spleen length, and platelet count‐to‐spleen length ratio involves screening people with a diagnosis of cirrhosis for the presence of varices, sparing oesophago‐gastro‐duodenoscopy in people with negative results. Furthermore, these non‐invasive tests could even be so accurate in detecting high‐risk varices (large varices or presence of red marks) for which primary prophylaxis is recommended that they could replace oesophago‐gastro‐duodenoscopy.

Alternative test(s)

Some non‐invasive tests other than platelet count, spleen length, and platelet count‐to‐spleen length ratio have been proposed for the diagnosis of oesophageal varices, such as serum markers for liver fibrosis, transient elastography, or imaging with ultrasound computed tomography, magnetic resonance, or capsule endoscopy (Colli 2014b).

We will examine some of these tests in future planned reviews (Gana 2010a; Gana 2010b; Gana 2010c).

Rationale

Effective prevention of the first variceal haemorrhage (primary prophylaxis) in adults with medium or large varices can be achieved via non‐selective beta‐blockers or endoscopic variceal ligation (D'Amico 1999; Imperiale 2001; Gluud 2007). Therefore, both North American (Grace 1998; Adams 2004; Garcia‐Tsao 2007; Garcia‐Tsao 2008) and European guidelines (Jalan 2000; Garcia‐Tsao 2008; EASL 2011; Tripathi 2015; NICE 2016) recommend endoscopy at the time of diagnosis of cirrhosis and at intervals thereafter to identify at‐risk patients who might benefit from prophylactic treatment. These guidelines require that patients repeatedly undergo an unpleasant invasive procedure with its attendant risks, although half have no identifiable oesophageal varices 10 years after the initial diagnosis of cirrhosis. Oesophago‐gastro‐duodenoscopy requires appropriate sedation and analgesia (Cotton 2006) and is associated with an overall complication rate of 0.13% and a mortality rate of 0.004% (Silvis 1976).

Two cost‐effectiveness studies suggested avoidance of surveillance oesophago‐gastro‐duodenoscopy and treatment with non‐selective beta‐blockers for all people with cirrhosis, irrespective of the presence or size of varices (Saab 2003; Spiegel 2003). A third cost‐effectiveness analysis suggested that this non‐selective strategy should be reserved for people with decompensated liver disease (Arguedas 2002). Those conflicting cost‐effectiveness recommendations do not recognise that non‐selective beta‐blockers do not prevent the development of oesophageal varices (Groszmann 2005). Therefore, oesophago‐gastro‐duodenoscopy remains the recommended test for the diagnosis and prognosis of oesophageal varices (Garcia‐Tsao 2007; Garcia‐Tsao 2008).

In view of the invasive nature and costs of oesophago‐gastro‐duodenoscopy, a non‐invasive test with adequate accuracy could serve as a screening test. Such a test would assist in triaging people before oesophago‐gastro‐duodenoscopy, and, if varices of sufficient risk of bleeding are present, primary prophylaxis will be recommended to prevent variceal haemorrhage. Non‐invasive tests for varices, if sufficiently accurate in detecting high‐risk varices, could even replace oesophago‐gastro‐duodenoscopy, which is still the preferred test for diagnosing oesophageal varices. For these reasons, we aimed (1) to assess the ability of platelet count, spleen length, and platelet count‐to‐spleen length ratio to triage people for oesophago‐gastro‐duodenoscopy investigation, and (2) to determine whether this approach could replace oesophago‐gastro‐duodenoscopy.

Objectives

Primary objectives

To determine the diagnostic accuracy of platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices of any size in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of their aetiology. To investigate the accuracy of these non‐invasive tests as triage or replacement of oesophago‐gastro‐duodenoscopy. We considered separately studies with adult participants and studies with paediatric participants.

Secondary objectives

To compare the diagnostic accuracy of platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of high‐risk oesophageal varices in paediatric or adult patients with chronic liver disease or portal vein thrombosis, irrespective of aetiology.

We aimed to perform pair‐wise comparisons between the three index tests, while considering predefined cut‐off values, as reported in the 'Index test' section.

We investigated the following sources of heterogeneity.

Chronic liver disease compared with portal vein thrombosis.
Prevalence of oesophageal varices in the study group (≥ 50% versus < 50% for any varices; > 25% versus ≤ 25% for high‐risk varices).
Severity of liver disease Child A (> 50% versus ≤ 50%).
Different aetiologies (hepatitis C virus (HCV)‐associated cirrhosis versus cirrhosis of all causes).

Methods

Criteria for considering studies for this review

Types of studies

We aimed to include studies that, irrespective of publication status and language, evaluated the diagnostic accuracy of platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices with oesophago‐gastro‐duodenoscopy as the reference standard. We considered studies of cross‐sectional cohort design including people with clinical suspicion of portal hypertension as well as studies of participant‐control design that compared people with oesophageal varices versus matched controls (Colli 2014a). We excluded studies that analysed data only per varix rather than per participant unless participant data were made available by study authors.

Participants

Participants included paediatric or adult patients of any age with chronic liver disease or portal vein thrombosis, irrespective of aetiology, severity of disease, and duration of illness, in whom the presence or absence of varices was confirmed by oesophago‐gastro‐duodenoscopy. The review focused on diagnostic questions related to patients who have not yet suffered gastrointestinal bleeding from oesophageal varices. Patients with a previous surgical portal‐systemic shunt procedure or insertion of a transjugular intrahepatic portal‐systemic shunt (TIPS), previous ligation or sclerotherapy of oesophageal varices, previous history of upper gastrointestinal portal hypertensive bleeding, or previous primary prophylactic therapy of variceal haemorrhage make up a distinct group for whom the diagnosis or natural history of oesophageal varices has been modified. These patients were not the focus of this review, hence we excluded studies that included such patients unless investigators presented data in such a way as to allow this patient group to be isolated from other included patients.

Index tests

Platelet count is obtained from a complete blood count, a readily available automated clinical test. A platelet count cut‐off value less than 150,000/mm³ is considered thrombocytopenia.
Spleen length is usually obtained through evaluation of the patient's abdomen by ultrasound scan (USS). Interobserver agreement when spleen length is determined with USS is considered excellent. For adults, the upper limit of spleen length is 130 mm, beyond which the spleen is generally considered enlarged. Spleen length of 110 mm is regarded as a sensitive cut‐off for exclusion of splenomegaly (Grover 1993). For children, spleen length is expressed as a standard deviation score relative to normal values for both age and sex (spleen length z‐score) (Megremis 2004).
Platelet count‐to‐spleen length ratio is a derivative mathematical model shown to increase the accuracy of both non‐invasive tests for the diagnosis of oesophageal varices. The cut‐off value used most often for adults is 909 (n/mm³)/mm. In children, platelet count‐to‐spleen length ratio is calculated using the spleen length z‐score.

Target conditions

The presence of any oesophageal varices (independent of size) was detected by oesophago‐gastro‐duodenoscopy. For secondary analyses, the target condition considered was the presence of oesophageal varices at high risk of bleeding. High‐risk varices were defined as medium or large varices or small varices with red marks, or in patients with decompensated cirrhosis, as assessed by a B‐C Child‐Pugh score (Garcia‐Tsao 2007). Studies will require at least one of two target conditions to be identified: the presence of any oesophageal varices, or the presence of high‐risk varices.

Reference standards

Oesophago‐gastro‐duodenoscopy is the clinical reference standard test for the diagnosis of oesophageal varices in which the presence of varices in the oesophagus is directly observed through the endoscope. The size and appearance of oesophageal varices are graded at the time of endoscopy according to one of the systems described below, and the largest varix identified is used to classify the patient. Severity of cirrhosis, which is the other factor that defines bleeding risk, is assessed by Child‐Pugh score, with three classes ‐ A, B, and C ‐ indicating increasing severity (Pugh 1973). Patients whose largest varix is medium or large or who are included in class B‐C are considered for prophylactic therapy.

The Baveno Consensus system differentiates small from large oesophageal varices (de Franchis 1992), defining small oesophageal varices as varices that flatten with insufflation during endoscopy or that minimally protrude into the oesophageal lumen, and large oesophageal varices as varices that protrude into the oesophageal lumen and touch each other, or that fill at least 50% of the oesophageal lumen.
The Japanese Research Society for Portal Hypertension used three grades for variceal size (JSPH 1980). Grade 1 varices collapse with insufflation during endoscopy, grade 2 varices do not collapse with insufflation and do not occlude the lumen, and grade 3 varices occlude the lumen. For this review, we will consider grade 2 as equivalent to medium, and grade 3 as large.
The Japanese classification was revised by the Italian Liver Cirrhosis Project (ILCP) Group (Pagliaro 1988; Zoli 1996), which describes variceal size as the percentage of the radius of the oesophageal lumen that is occupied by the largest varix. A small or grade 1 varix is said to occupy less than 25%, a medium or grade 2 varix occupies 25% to 50%, and a large or grade 3 varix occupies greater than 50% of the radius of the lumen of the oesophagus.
The Cales criteria define varices as small if they flatten with insufflation during endoscopy, medium if they do not flatten with insufflation, and large if they do not flatten with insufflation during endoscopy and are confluent (Cales 1990).
We will include studies applying alternate classifications if adequately described and logically defined.

Red marks are usually noted as present or absent and may be described according to different classifications. Even small varices showing red marks are classified as ’at high risk of bleeding’.    The interval between index tests and oesophago‐gastro‐duodenoscopy has to be less than 3 months to avoid possible evolution of the target condition. When a study reported longer time intervals, we included the study but considered it to be at risk of bias. Clinically, patients with medium or large oesophageal varices or with red marks are at greatest risk of haemorrhage; therefore, we confined secondary analyses to two subgroups: patients with no varices and small varices compared with patients at high risk.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Hepato‐Biliary Group Controlled Trials Register (Gluud 2016), the Cochrane Hepato‐Biliary Group Diagnostic Test of Accuracy Studies Register (Gluud 2016), the Cochrane Library, MEDLINE (OvidSP), Embase (OvidSP), and Science Citation Index ‐ Expanded (Web of Science) (Royle 2003). We have presented in Appendix 1 search strategies along with time spans of the searches. .We applied no language or document‐type restrictions.

Searching other resources

We identified additional references by manually searching the references of articles retrieved from computerised databases and relevant review articles. We sought information on unpublished studies by contacting experts in the field. In addition, we handsearched abstract books from meetings of the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) held over the past 10 years.

Data collection and analysis

We followed available guidelines as provided in the Cochrane Handbook for Diagnostic Test of Accuracy Reviews (DTA Handbook 2010).

Selection of studies

We retrieved publications if they were potentially eligible for inclusion on the basis of abstract review, or if they were relevant review articles for a manual reference search. Two review authors independently reviewed publications for eligibility. To determine eligibility, we assessed each publication to determine whether participants met the inclusion criteria detailed above. We included abstracts only if they provided sufficient data for analysis. We resolved disagreements by consensus.

Data extraction and management

Review authors, working in pairs (JCG and JY or AC and GC), completed a data extraction form for each included study. AC and GC completed extraction forms for studies retrieved during the last search (from 2009 to 2016). Each review author independently retrieved study data. In cases of discordance, we reached consensus through discussion.    We retrieved the following data.

General information: title, journal, year, publication status, and study design (prospective vs retrospective).
Sample size: number of participants meeting the criteria and total number of participants screened.
Baseline characteristics: baseline diagnosis, age, sex, race, and disease severity, and medications used concurrently. We considered severity of liver disease among the studied population by using the Child‐Pugh score (Pugh 1973) and the model for end‐stage liver disease (MELD) in adults (Kamath 2001), and by using the Child‐Pugh score and paediatric end‐stage liver disease (PELD) scores in children (McDiarmid 2002).
We reported index tests with all cut‐off values.
We used the following as clinical reference standard tests: variceal size, type of classification used, number of endoscopists, and handling of interobserver error on oesophago‐gastro‐duodenoscopy.
Numbers of true positive (TP), true negative (TN), false positive (FP), and false negative (FN) findings. We extracted these data for each presented cut‐off value and for the two target conditions.

We summarised data from each study in 2 × 2 tables (FP, FN, TP, TN) according to the two target conditions and entered the data into Review Manager 5 software.

Missing data

We contacted primary authors by email to ask for missing data that we needed to build the 2 × 2 tables. When we received no reply, we sent a second email two weeks later. When we still received no reply, we excluded the study.

Assessment of methodological quality

Two review authors independently assessed the risk of bias of included studies using QUADAS‐2 (revised tool for quality assessment of diagnostic accuracy studies) domains (Whiting 2011). In cases of discordance, we reached a consensus through discussion. We adopted the domains in Appendix 2 to address aspects of study quality involving the participant spectrum, index tests, target conditions, reference standards, and flow and timing. We did not plan to consider blinding of the index test to results of the reference standard for cases in which platelet count is obtained by an automated counter. We classified a study as having high risk of bias if we judged study to have high risk of bias or unclear risk of bias in at least one of the domains of QUADAS‐2.

Statistical analysis and data synthesis

We carried out statistical analyses according to recommendations provided in the Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (DTA Handbook 2010).

We built 2 × 2 tables (TP, TN, FP, FN) for each primary study for the three index tests for the two target conditions (any varices and high‐risk varices). We considered studies with adult participants and studies with paediatric participants separately, as we retrieved only studies that included only adult or paediatric participants.

For all combinations of index test/target condition/participants, we followed the following strategy of analysis. First, we performed a graphical descriptive analysis of the included studies: We reported forest plots (sensitivity and specificity separately, with their 95% confidence intervals (CIs)), and we provided a graphical representation of studies in the receiver operating characteristic (ROC) space (sensitivity against 1 ‐ specificity). Second, we performed a meta‐analysis. When primary studies reported accuracy estimates of an index test using different cut‐off points, we used the hierarchical summary ROC model (HSROC) to pool data (sensitivities and specificities) and to plot a summary ROC (SROC) curve (Rutter 2001). When considering studies with a common cut‐off value, we used the bivariate model and provided estimates of summary sensitivity and specificity. We used pooled estimates obtained from the fitted models to calculate summary estimates of positive and negative likelihood ratios (LR+ and LR‐, respectively).

For primary studies that reported accuracy results for more than one cut‐off point, we reported sensitivities and specificities for all cut‐off points, but we used a single cut‐off point for each study in HSROC (or bivariate) analysis.

We made pair‐wise comparisons between tests by adding a covariate for the index test to the HSROC (for comparisons of SROC curves) or bivariate (for comparisons of sensitivity and specificity at fixed cut‐off value) model. We assessed the significance of differences in test accuracy by using the log‐likelihood ratio test for comparison of models with and without the index test covariate term. We performed both indirect and direct comparisons, if sufficient data were available.

We considered P values less than 0.05 as two‐sided and statistically significant.

We performed all statistical analyses using SAS statistical software, release 9.4 (SAS Institute Inc., Cary, NC, USA) and macro METADAS (DTA Handbook 2010).

Investigations of heterogeneity

We investigated effects of the following predefined sources of heterogeneity.

Chronic liver disease compared with portal vein thrombosis.
Prevalence of oesophageal varices in the study group (≥ 50% versus < 50% for any varices; > 25% versus ≤ 25% for high‐risk varices).
Severity of liver disease Child A (> 50% versus ≤ 50%).
Different aetiologies (HCV‐associated cirrhosis versus all aetiologies),

by adding covariates to the bivariate or to the HSROC. We assessed the statistical significance of the covariate effect by using the log‐likelihood ratio test for comparison of models with and without the covariate term.

To limit the number of statistical analyses, we investigated sources of heterogeneity by considering only studies with the cut‐off value defined in the "Index test" section.

Sensitivity analyses

We attempted to assess effects of risk of bias of included studies on diagnostic accuracy by performing a sensitivity analysisfrom which we excluded studies with the following characteristics.

Studies classified at high risk of bias. We classified a study as having high risk of bias if we judged study to have high risk of bias or unclear risk of bias in at least one of the domains of QUADAS‐2 (Appendix 2). In addition, we identified the two following signalling questions as most relevant, and we decided to assess them in separate sensitivity analyses.
1. "Was a case‐control design avoided?"
2. "If a threshold was used, was it prespecified?"
Studies published only in abstract/letter form.

To limit the number of statistical analyses, we performed sensitivity analyses by considering only studies with the cut‐off value defined in the "Index test" section.

Results

Results of the search

We ran the search on 14 June 2016. We identified 3832 references by searching the following databases: the Cochrane Hepato‐Biliary Group Controlled Trials Register (n = 17), the Cochrane Hepato‐Biliary Group Diagnostic Test Accuracy Register (n = 8), the Cochrane Library (n = 73), MEDLINE (OvidSP) (n = 943), Embase (OvidSP) (n = 2188), and Science Citation Index ‐ Expanded (Web of Science) (n = 603). After exclusion of 1172 duplicates, 2660 references remained for possible eligibility. We retrieved five additional references through handsearching. After reading the title and the abstract of these 2665 references, we excluded 2566 of them, as they did not meet the inclusion criteria. We retrieved full texts of the remaining 99 records, and after reading the full texts, we excluded 34 studies for various reasons (see Characteristics of excluded studies). Finally, we included in our review 65 references reporting data on 71 studies (Figure 1).

We reported in the Characteristics of included studies tables the main characteristics of the 71 included studies. Investigators reported five studies (Primignani 2002; Lei 2007; Aqodad 2011; El Ray 2015; Wang CC 2015) only in abstract form and three (Zimbwa 2004; Sen 2008a; Sen 2008b) as letters. Four studies (Colecchia 2011; Gana 2011; Alcantara 2012; Adami 2013) included only paediatric participants, and the other 67 studies included only adult participants. All included studies were cross‐sectional studies, prospective or retrospective, conducted at tertiary referral centres. Sixteen studies (Madhotra 2002; Baig 2008; Parrino 2008; Sen 2008a; Sen 2008b; Sarangapani 2010; Schwarzenberger 2010; Cherian 2011; Colecchia 2011; Colecchia 2012; Esmat 2012; Mahassadi 2012a; Mahassadi 2012b; Adami 2013; Chiodi 2014; Grgurevic 2014) assessed the accuracy of more than one index test on the same participants. The number of participants enrolled in each of the 71 included studies ranged from 31 to 1016 (median = 111). Eight studies included only participants in Child‐Pugh class A, three studies did not include any participant in Child‐Pugh class A, and 26 studies did not report Child‐Pugh classification.

Methodological quality of included studies

We have reported in detail results of the quality assessment of included studies in the Characteristics of included studies tables, and we have summarised this information in Figure 2 and Figure 3.

Methodological quality of the 71 included studies.

Quality assessment summary: review authors' judgements about each risk of bias item for each included study.

Not all of the included studies considered all three index tests. Cells are empty when an index test was not considered in a study.

Patient selection

All 71 studies were cross‐sectional: 29 studies were prospective, 21 were retrospective, and, in 21 studies, it was not clear whether a prospective or retrospective design was adopted. Thirty‐four studies reported that they enrolled consecutive participants; six studies reported non‐consecutive enrolment of participants (Sebastiani 2010; Wang HM 2012; Grgurevic 2014; Wang CC 2015; Abd‐Elsalam 2016b; Sheta 2016); for the remaining 31 studies, this information was unclear. The authors of three studies did not avoid inappropriate exclusions (Giannini 2005; Sanyal 2006; Karatzas 2016): One study included only people with previous negative screening for oesophageal varices who regularly attended an outpatient clinic and excluded the others (Giannini 2005); one study excluded patients with contraindications for computerised tomography, which was one of the index tests considered in that study (Karatzas 2016); one study included only participants from an interventional randomised clinical trial according to the exclusion criteria of this trial (Sanyal 2006). In eight other studies, information about exclusions was unclear. In summary, we classified nine studies as having high risk of bias, 30 studies unclear risk of bias, and 32 low risk of bias for the patient selection domain.

We had high concern regarding patient selection in seven studies, as they included mainly participants with advanced and decompensated disease (Zaman 2001; Burton 2007d; Agha 2009; Barikbin 2010; Abu 2011; Agha 2011; Grgurevic 2014); we had unclear concern about three studies that did not report a definition for severity of liver disease (Sarangapani 2010; Aqodad 2011; El Ray 2015).

Index tests

Platelet count: We considered 11 studies to have low risk of bias, and 26 to have high risk of bias.

Spleen length: We considered three studies to have low risk of bias, and 12 to have high risk of bias as the threshold value was not predefined and/or blind interpretation of results was not ensured (Primignani 2002; Jeon 2006; Baig 2008; Parrino 2008; Sen 2008a; Sen 2008b; Sarangapani 2010; Cherian 2011; Esmat 2012; Mahassadi 2012a; Grgurevic 2014; Wang CC 2015). One study provided a predefined cut‐off value but blinding presented unclear risk of bias (Madhotra 2002).

Platelet count‐to‐spleen length ratio: We considered seven studies to have low risk of bias, 22 high risk of bias, and 14 unclear risk of bias as the threshold value was not predefined and/or blind interpretation of results was not clearly ensured.

We had no applicability concerns.

Reference standards

All studies used an acceptable reference standard: gastrointestinal endoscopy with varices graded according to a recognised common scoring system. We had some concerns regarding blinded (without knowledge of results of the index tests) interpretation of the reference standard. Investigators in 23 studies reported that reference standard results were interpreted without knowledge of the results, and 48 studies provided unclear information on this. On the basis of these results, we classified 48 studies as having unclear risk of bias and 23 as having low risk of bias for the reference standard domain. We had no concerns regarding applicability.

Flow and timing

All participants underwent the same reference standard in all studies. The time interval between the index test and the reference standard execution was appropriate (i.e. < 3 months) in 34 studies, was inappropriate in one study (Ding 2016; time interval < 6 months), and was not reported in the remaining 36 studies.

Eleven studies excluded some participants from the analysis. Reasons reported by study authors included incomplete information, participants lost to follow‐up, and participants who did not undergo the reference standard or the index test. On the basis of these results, we classified 12 studies as having high risk of bias, 32 unclear risk of bias, and 27 low risk of bias for the flow and timing domain.

Overall assessment

Only one study was at low risk of bias in all four QUADAS‐2 domains (Giannini 2006). We classified 52 studies as having high risk of bias in at least one domain. We judged the remaining 18 studies as having unclear risk of bias.

Funding

Sebastiani 2010 reported under "Financial support" that the first study author "... is funded by an unrestricted grant from Roche‐Italia".    Sanyal 2006 reported under "Disclosures" that "This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities, and by General Clinical Research Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). Additional funding to conduct this study was supplied by Hoffmann‐La Roche, Inc, through a Cooperative Research and Development Agreement with the National Institutes of Health".

Eighteen studies reported that they received no funding. The remaining 51 studies provided no information on funding.

Findings

Adult participants ‐ any varices

Platelet count for any varices

Any cut‐off value

Twenty‐five studies with 5096 participants provided data assessing platelet count for the presence of any varices. The median prevalence of the target disease was 57% (range 26% to 88%). Cut‐off values ranged from 82,000 to 150,000/mm³. Sensitivity of platelet count for the diagnosis of oesophageal varices of any size ranged from 0.37 to 0.92, and specificity ranged from 0.39 to 0.98 (Figure 4).

Forest plot. Adult participants ‐ platelet count ‐ any varices.

We then carried out three meta‐analyses that included only studies that reported a cut‐off value of around 100,000/mm³, around 120,000/mm³, and around 150,000/mm³.

Cut‐off value around 100,000/mm³

Eleven studies with 3506 participants provided data using a cut‐off value of around 100,000/mm³ (range 90,000 to 110,000/mm³). Sensitivity of the 11 studies varied from 0.37 to 0.80, and specificity from 0.60 to 0.91 (Figure 5). By using the bivariate model, we obtained the following estimates: sensitivity 0.57 (95% CI 0.50 to 0.64), specificity 0.75 (95% CI 0.67 to 0.82), LR+ 2.3 (95% CI 1.7 to 3.1), and LR‐ 0.57 (95% CI 0.49 to 0.67) (Figure 6).

Forest plots. Adult participants ‐ platetelet count ‐ various cut‐off values ‐ any varices.

Studies in the ROC space. Adult participants ‐ platelet count ‐ various cut‐off values ‐ any varices.

Cut‐off value around 120,000/mm³

Seven studies with 815 participants provided data using a cut‐off value of around 120,000/mm³ (range 117,000 to 132,000/mm³). Sensitivity of the seven studies varied from 0.67 to 0.84, and specificity from 0.39 to 0.83 (Figure 5). By using the bivariate model, we obtained the following estimates: sensitivity 0.77 (95% CI 0.72 to 0.81), specificity 0.69 (95% CI 0.57 to 0.78), LR+ 2.4 (95% CI 1.7 to 3.5), and LR‐ 0.34 (95% CI 0.26 to 0.44) (Figure 6).

Cut‐off value around 150,000/mm³

Ten studies with 2054 participants provided data using a cut‐off value of around 150,000/mm³ (range 140,000 to 150,000/mm³). Sensitivity of the 10 studies varied from 0.56 to 0.92, and specificity from 0.52 to 0.98 (Figure 5). By using the bivariate model, we obtained the following estimates: sensitivity 0.71 (95% CI 0.63 to 0.77), specificity 0.80 (95% CI 0.69 to 0.88), LR+ 3.6 (95% CI 2.4 to 5.4), and LR‐ 0.37 (95% CI 0.30 to 0.45) (Figure 6).

Heterogeneity analysis

We investigated heterogeneity while considering only studies with a cut‐off value of around 150,000/mm³ ‐ the predefined cut‐off value. We found no effect of prevalence of varices (≤ 50% vs > 50%) or Child A on accuracy. We found an effect of aetiology (P = 0.036). Sensitivity and specificity were 0.76 (95% CI 0.60 to 0.86) and 0.63 (0.59 to 0.67) for the four studies that included only participants with HCV. Sensitivity and specificity were 0.71 (95% CI 0.66 to 0.76) and 0.88 (95% CI 0.83 to 0.91) for the four studies that included participants with mixed aetiology.

Sensitivity analysis

When considering Zein 2004b, Levy 2007b, Colecchia 2012, and Abd‐Elsalam 2016b, with a prespecified cut‐off value among all studies of around 150,000/mm³, we obtained sensitivity of 0.74 (95% CI 0.57 to 0.86) and specificity of 0.78 (95% CI 0.57 to 0.90). We could not perform the remaining sensitivity analyses, as all studies were cross‐sectional, all were at high/unclear risk of bias, and all were published as full text.

Spleen length for any varices

Any cut‐off value

Thirteen studies with 1489 participants provided data on assessment of spleen length for the presence of any varices. The median prevalence of the target disease was 62% (range 17% to 82%). Sensitivity of the 13 studies varied from 0.40 to 0.96, and specificity from 0.48 to 0.98. Cut‐off values ranged from 107 to 150 mm (Figure 7). We included in this analysis one study reporting data on two cut‐offs (110 mm and 150 mm) by using only the cut‐off of 150 mm (Colecchia 2012).

Forest plot. Adult participants ‐ spleen length ‐ any varices.

Cut‐off value around 110 mm

Five studies with 594 participants reported data using a cut‐off value of around 110 mm (range 110 to 112.5 mm). Sensitivity of the five studies varied from 0.75 to 0.96, and specificity from 0.43 to 0.68 (Figure 8). By using the bivariate model, we obtained the following estimates: sensitivity 0.85 (95% CI 0.75 to 0.91), specificity 0.54 (95% CI 0.46 to 0.62), LR+ 1.8 (95% CI 1.6 to 2.1), and LR‐ 0.28 (95% CI 0.17 to 0.44) (Figure 9).

Forest plots. Adult participants ‐ spleen length ‐ any varices: various cut‐off values.

Studies in the ROC space. Adult participants ‐ spleen length ‐ any varices: various cut‐off values.

Cut‐off value around 150 mm

FIve studies with 598 participants reported data using a cut‐off value of around 150 mm (range 140 to 150 mm). Sensitivity of the five studies varied from 0.40 to 0.81, and specificity from 0.64 to 0.96 (Figure 8). By using the bivariate model, we obtained the following estimates: sensitivity 0.57 (95% CI 0.41 to 0.71), specificity 0.82 (95% CI 0.72 to 0.89), LR+ 3.2 (95% CI 2.3 to 4.4), and LR‐ 0.53 (95% CI 0.39 to 0.72) (Figure 9).

Heterogeneity analysis

We could not assess effects of sources of heterogeneity among studies with a cut‐off value around 110 mm, as the models failed to converge owing to the small number of studies.

Sensitivity analysis

In considering studies with a cut‐off value of around 110 mm, when we excluded the two studies reported only in abstract form, we obtained sensitivity of 0.84 (95% CI 0.71 to 0.92) and specificity of 0.58 (95% CI 0.43 to 0.71) (Primignani 2002; Wang CC 2015). We could not perform the remaining sensitivity analyses because all studies were cross‐sectional and were at high/unclear risk of bias, and all but one of the studies used a prespecified cut‐off value.

Platelet count‐to‐spleen length ratio for any varices

Any cut‐off value

Thirty‐eight studies with 5235 participants provided data on assessment of platelet count to spleen length for the presence of varices of any size. The median prevalence of varices was 65% (range 28% to 85%). Sensitivity of the 38 studies varied from 0.40 to 1.00, and specificity from 0.36 to 1.00. Cut‐off values ranged from 420 to 1847 (n/mm³)/mm (Figure 10).

Forest plot. Adult participants ‐ platelet count‐to‐spleen length ratio ‐ any varices.

We then carried out a meta‐analysis including only studies that reported a cut‐off value of 909 (n/mm³)/mm.

Cut‐off value of 909 (n/mm³)/mm

Seventeen studies with 2637 participants provided data using a cut‐off value of 909 (n/mm³)/mm. Sensitivity of the 17 studies varied from 0.40 to 1.00, and specificity from 0.42 to 1.00. By using the bivariate model, we obtained the following estimates: sensitivity 0.93 (95% CI 0.83 to 0.97), specificity 0.84 (95% CI 0.75 to 0.91), LR+ 5.9 (95% CI 3.5 to 9.9), and LR‐ 0.09 (95% CI 0.03 to 0.22) (Figure 11).

Heterogeneity analysis

We investigated effects of sources of heterogeneity among studies using a cut‐off value of 909 (n/mm³)/mm. We found no effect of prevalence of varices, of prevalence of Child A participants, or of aetiology.

Sensitivity analysis

We could not perform the remaining sensitivity analyses, as all studies were cross‐sectional, all but one were at high/unclear risk of bias (Giannini 2006), all but one were published as full text (Zimbwa 2004), and all but one used a prespecified cut‐off value (Giannini 2003a).

Comparative analysis of tests for any varices

Platelet count compared with spleen length

We compared the accuracy of platelet count (25 studies) and spleen length (13 studies) for the presence of any varices (Figure 12) among all included studies (indirect comparisons) using varying cut‐off values. The HSROC model analysis showed a statistically significant result (P = 0.001), suggesting higher overall accuracy of the platelet count test.

When we compared the 10 studies that reported a cut‐off value of 150,000/mm³ for platelet count with the five studies that reported a cut‐off value of around 110 mm for spleen length (indirect comparison; Figure 13), we observed higher accuracy of platelet count (P = 0.021; Figure 14; Table 6).

Forest plot. Indirect comparison. Adult participants ‐ platelet count (cut‐off around 150,000) compared with spleen length (cut‐off around 110 mm) ‐ any varices.

Indirect comparison. Studies in the ROC space. Adult participants ‐ platelet count (cut‐off around 150,000) compared with spleen length (cut‐off around 110 mm) ‐ any varices.

1. Any varices ‐ comparisons between tests.

Any varices ‐ indirect comparisons
Index test	No. of studies	Cut‐off value	Sensitivity (95% CI)	Specificity (95% CI)	P value*
Platelet count	10	Around 150,000/mm³	0.71 (0.63 to 0.77)	0.80 (0.69 to 0.88)	0.252
Platelet count‐to‐spleen length ratio	17	909 (n/mm³)/mm	0.93 (0.83 to 0.97)	0.84 (0.75 to 0.91)	0.252

Platelet count	9	Around 150,000/mm³	0.71 (0.63 to 0.77)	0.80 (0.69 to 0.88)	0.021
Spleen length	5	Around 110 mm	0.85 (0.75 to 0.91)	0.54 (0.46 to 0.62)	0.021

Platelet count‐to‐spleen length ratio	17	909 (n/mm³)/mm	0.93 (0.83 to 0.97)	0.84 (0.75 to 0.91)	<0.001
Spleen length	5	Around 110 mm	0.85 (0.75 to 0.91)	0.54 (0.46 to 0.62)	<0.001


Review question	What is the diagnostic accuracy of platelet count for the diagnosis of oesophageal varices in adults with liver disease or portal vein thrombosis?
Population	Adults with diagnosis of chronic liver disease or portal vein thrombosis. Age ≥ 18 years
Settings	Outpatients and inpatients in secondary/tertiary care setting
Study design	Prospective and retrospective cross‐sectional studies. No case‐control studies were found
Index tests	Platelet count
Reference standards	Upper endoscopy

Target condition	Summary accuracy (95% CI)	No. of participants (studies)	Prevalence, Median (range )	Implications in a hypothetical cohort of 1000 people	Post‐test probability	Quality and comments

Any varices Cut‐off value: around 150,000 /mm³ (range 140,000 to 150,000/mm³)	Sensitivity 0.71 (0.63 to 0.77) Specificity 0.80 (0.69 to 0.88) LR+ 3.6  (2.4 to 5.4) LR‐ 0.37  (0.30 to 0.45)	2054 participants (10)	38%  (25% to 79%)	With a prevalence of 38%, 380 out of 1000 people will have varices of any size. Of these 380 people, 110 (29% of 380) people with varices will receive misdiagnosis and will not received appropriate prophylaxis or follow‐up The remaining 620 people will have no varices. 124 people (20% of 620) will receive false diagnosis of varices and will undergo an unnecessary endoscopy	Assuming a pretest probability of 38% Post‐test probabilities: If test positive: 69% If test negative: 18%	Most studies are at high risk of bias No predefinition of cut‐off value of the index test for most studies Median prevalence of any varices is lower than that reported by most guidelines (around 50%) .

High risk varices Cut‐off value: around 150,000 /mm³ (range 140,000 to 160,000/mm³)	Sensitivity 0.80 (0.73 to 0.85) Specificity 0.68 (0.57 to 0.77) LR+ 2.5  (1.8 to 3.3) LR‐ 0.30  (0.23 to 0.39)	1671 participants (7)	20%  (6% to 48%)	With a prevalence of 20%, 200 out of 1000 people will have varices at high risk of bleeding. Of these 200 people, 40 (20% of 200) people with high‐risk varices will receive misdiagnosis and will not receive effective prophylaxis The remaining 800 people will not have high‐risk varices. 256 people (32% of 800) will receive false diagnosis of high‐risk varices and will undergo an unnecessary endoscopy	Assuming a pretest probability of 20% Post‐test probabilities: If test positive: 38% If test negative: 7%	Most or all studies at high risk of bias No predefinition of cut‐off value of the index test for most studies


Review question	What is the diagnostic accuracy of spleen length for the diagnosis of oesophageal varices in adult people with liver disease or portal vein thrombosis?
Population	Adults with diagnosis of chronic liver disease or portal vein thrombosis. Age ≥ 18 years
Settings	Outpatients and inpatients in secondary/tertiary care setting
Study design	Prospective and retrospective cross‐sectional studies. No case‐control studies were found
Index tests	Spleen length
Reference standards	Upper endoscopy

Target condition	Summary accuracy (95% CI)	No. of participants (studies)	Prevalence, Median (range )	Implications in a hypothetical cohort of 1000 people	Post‐test probability	Quality and comments

Any varices Cut‐off value: around 110 mm (range 110 to 112.5 mm)	Sensitivity 0.85 (0.75 to 0.91) Specificity 0.54 (0.46 to 0.62) LR+ 1.8 (1.6 to 1.21) LR‐ 0.28 (0.17 to 0.44)	594 participants (5)	53%  (17% to 71%)	With a prevalence of 53%, 530 out of 1000 people will have varices of any size. Of these 530 people, 80 (15% of 530) people with varices will receive misdiagnosis and will not receive appropriate prophylaxis or follow‐up The remaining 470 people will have no varices. 216 people (46% of 470) will receive false diagnosis of varices and will undergo an unnecessary endoscopy	Assuming a pretest probability of 53% Post‐test probabilities: If test positive: 67% If test negative: 24%	Most or all studies at high risk of bias


High‐risk varices Cut‐off value: no common cut‐off value. Range 120 to 160 mm	Sensitivity ranged from 0.50 to 0.88 and specificity from 0.55 to 0.84	883 participants (6)	42%  (13% to 70%)	Inconsistency of results (no common cut‐off value) prevents any conclusions .		Most or all studies at high risk of bias

		Pooled results
	Cut‐off	Sensitivity (95% CI)	Specificity (95% CI)	LR+ (95% CI)	LR‐ (95% CI)
Any varices

Platelet count	Around 100,000	0.57 (0.50 to 0.64)	0.75 (0.67 to 0.82)	2.3 (1.7 to 3.1)	0.57 (0.49 to 0.67)
	Around 120,000	0.77 (0.72 to 0.81)	0.69 (0.57 to 0.78)	2.4 (1.7 to 3.5)	0.34 (0.26 to 0.44)
	Around 150,000	0.71 (0.63 to 0.77)	0.80 (0.69 to 0.88)	3.6 (2.4 to 5.4)	0.37 (0.30 to 0.45)

Spleen length	Around 110 mm	0.85 (0.75 to 0.91)	0.54 (0.46 to 0.62)	1.8 (1.6 to 2.1)	0.28 (0.17 to 0.44)
Spleen length	Around 150 mm	0.57 (0.41 to 0.71)	0.82 (0.72 to 0.89)	3.2 (2.3 to 4.4)	0.53 (0.39 to 0.72)
Platelet count‐to‐spleen length ratio	909 (n/mm³)/mm	0.93 (0.83 to 0.97)	0.84 (0.75 to 0.91)	5.9 (3.5 to 9.9)	0.09 (0.03 to 0.22)

High‐risk varices
Platelet count	Around 90,000	0.59 (0.54 to 0.64)	0.72 (0.66 to 0.78)	2.1 (1.8 to 2.6)	0.57 (0.52 to 0.63)
Platelet count	Around 150,000	0.80 (0.73 to 0.85)	0.68 (0.57 to 0.77)	2.5 (1.8 to 3.3)	0.30 (0.23 to 0.39)
Spleen length	‐	‐	‐	‐	‐
Platelet count‐to‐spleen length ratio	Around 909 (n/mm³)/mm	0.85 (0.72 to 0.93)	0.66 (0.52 to 0.77)	2.5 (1.8 to 3.4)	0.22 (0.12 to 0.42)

Database	Time span	Search strategy
Cochrane Hepato‐Biliary Group Controlled Trials Register	June 2016	((((platelet* or thrombocyt) near (count or distribution or volume)) or PLT or PDW or MPV) OR (((splenic or spleen) near3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal)) AND (esophag near3 (varic* or varix*))
Cochrane Hepato‐Biliary Diagnostic Test of Accuracy Studies Register	June 2016	((((platelet* or thrombocyt) near (count or distribution or volume)) or PLT or PDW or MPV) OR (((splenic or spleen) near3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal)) AND (esophag near3 (varic* or varix*))
The Cochrane Library	2016, Issue 6	#1 MeSH descriptor: [Platelet Count] explode all trees #2 ((platelet* or thrombocyt) near (count or distribution or volume)) or PLT or PDW or MPV #3 #1 or #2 #4 MeSH descriptor: [Splenomegaly] explode all trees #5 ((splenic or spleen) near/3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal #6 #4 or #5 #7 MeSH descriptor: [Esophageal and Gastric Varices] explode all trees #8 esophag near/3 (varic* or varix*) #9 #7 or #8 #10 (#3 or #6) and #9
MEDLINE (OvidSP)	1946 to June 2016.	1. exp Platelet Count/ 2. (((platelet* or thrombocyt) adj (count or distribution or volume)) or PLT or PDW or MPV).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 3. 1 or 2 4. exp Splenomegaly/ 5. (((splenic or spleen) adj3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 6. 4 or 5 7. (Esophageal and Gastric Varices).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 8. ((esophag* or oesophag) adj3 (varic or varix*)).mp. [mp=title, abstract, original title, name of substance word, subject heading word, keyword heading word, protocol supplementary concept word, rare disease supplementary concept word, unique identifier] 9. 7 or 8 10. (3 or 6) and 9
Embase (OvidSP)	1974 to June 2016	1. exp thrombocyte count/ 2. (((platelet* or thrombocyt) adj (count or distribution or volume)) or PLT or PDW or MPV).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 3. 1 or 2 4. exp splenomegaly/ 5. (((splenic or spleen) adj3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 6. 4 or 5 7. exp esophagus varices/ 8. ((esophag* or oesophag) adj3 (varic or varix*)).mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword] 9. 7 or 8 10. (3 or 6) and 9
Science Citation Index ‐ Expanded	1900 to June 2016	#5 #4 AND #3 #4 TS=(esophag NEAR/3 (varic* or varix)) #3 #2 OR #1 #2 TS=(((splenic or spleen) NEAR/3 (enlarg or hypertroph or length or palpable or size or diamet* or index or examin)) or splenomegal) #1 TS=(((platelet* or thrombocyt*) NEAR (count or distribution or volume)) or PLT or PDW or MPV)

Domain	1. Participant selection	2. Index test	3. Reference standard	4. Flow and timing
Signalling questions and criteria	Q.1: "Was a consecutive or random sample of participants enrolled?" Yes ‐ If the study reports on a consecutive or a random selection of participants. No ‐ if the study reports on another form of selection of participants. Unclear ‐ if the study does not report on how the participants were enrolled. Q.2: "Was a case‐control design avoided?" Yes ‐ if the case‐control design was avoided. No ‐ if the study was a case‐control. Unclear ‐ if the study design was not clear. Q.3: "Did the study avoid inappropriate exclusions?" Yes ‐ if the study definitions of exclusion criteria are appropriate (i.e. previous bleeding or treatment for oesophageal varices) and all exclusions are reported. No ‐ if exclusion criteria are inappropriate and exclusions are not reported. Unclear ‐ if the study does not report causes of exclusions.	Q.1: "Were the index test results interpreted without knowledge of the results of the reference standard?" Yes ‐ if the study reports that results of the index test were interpreted without the knowledge of results of the reference standard. No ‐ if the study reports that results of the index test were interpreted with results of the reference standard. Unclear ‐ if the study does not report information about blinding of results of the index test and reference standard. Q.2: "If a threshold was used, was it prespecified?" Yes ‐ if the threshold used was reported in the methods section. No ‐ if the study reports that the threshold was chosen during the data analysis stage (e.g. maximum of Youden index). Unclear ‐ if the study does not report information about threshold selection.	Q.1: "Is the reference standard likely to correctly classify the target condition?" Yes ‐ if the reference standard correctly classifies oesophageal varices (according to common grading scores or systems detailed in "Reference Standard" section). No ‐ if there is some doubt whether the reference standard classifies oesophageal varices. Unclear ‐ if the study does not report on the reference standard used. Q.2: "Were the reference standard results interpreted without knowledge of results of the index test?" Yes ‐ if the study reports that results of the reference standard were interpreted without knowledge of results of the index test. No ‐ if the study reports that results of the reference standard were interpreted with results of the test index. Unclear ‐ if the study does not report information about blinding of results of the reference standard and the index test.	Q.1: "Was there an appropriate interval between the index test and the reference standard?" Yes ‐ if the interval between the index test and the reference standard was less than 3 months. No ‐ if the interval was longer than 3 months. Unclear ‐ if the study does not report the interval between the index test and the reference standard. Q.2: "Did all participants receive the same reference standard?" Yes ‐ if the study has only one reference standard for all participants (OGD with appropriate classification of oesophageal varices). No ‐ if the study has more than one reference standard. Unclear‐ if the study is not clear about the reference standard used. Q.3 "Were all participants included in the analysis?"   Answer: Yes ‐ if all enrolled participants were included in the analysis (even in the case of uninterpretable index test result). No ‐ if any participant was excluded from the analysis for any reason. Unclear ‐ if it is not clear about exclusions of participants from the analysis.
Risk of bias	Could the selection of participants have introduced bias? Low risk: "Yes" for all signalling questions. High risk: "No" or "Unclear" for at least one signalling question.	Could the conduct or interpretation of the index test have introduced bias? Low risk: "Yes" for the signalling question. High risk: "No" or "Unclear" for the signalling question.	Could the reference standard, its conduct, or its interpretation have introduced bias? Low risk: "Yes" for all signalling questions. High risk: "No" or "Unclear" for at least one signalling question.	Could the participant flow have introduced bias? Low risk: "Yes" for all signalling questions. High risk: "No" or "Unclear" for at least one signalling question.
Concerns about applicability	Are there concerns that the included participants and setting do not match the review question? Low concern: Participants included in the review represent participants for whom the test is used in clinical practice. High concern: Participants included in the review differ from participants for whom the test is used in clinical practice.	Are there concerns that the index test, its conduct, or interpretation differ from the review question? High concern: The index test, its conduct, or interpretation of the index test differs from the way it is used in clinical practice. Low concern: The index test, its conduct, or interpretation of the index test does not differ from the way it is used in clinical practice.	Are there concerns that the target condition as defined by the reference standard does not match the question?	‐

Test	No. of studies	No. of participants
1 Adults ‐ platelet count ‐ any varices	25	5096
2 Adults ‐ platelet count ‐ any varices ‐ cut‐off around 100,000	11	3506
3 Adults ‐ platelet count ‐ any varices ‐ cut‐off around 120,000	7	815
4 Adults ‐ platelet count ‐ any varices ‐ cut‐off around 150,000	10	2054
5 Adults ‐ platelet/spleen ratio ‐ any varices	38	5235
6 Adults ‐ platelet/spleen ratio ‐ any varices ‐ cut‐off 909	17	2637
7 Adults ‐ spleen diameter ‐ any varices	13	1489
8 Adults ‐ spleen diameter ‐ any varices ‐ cut‐off around 110 mm	5	594
9 Adults ‐ spleen diameter ‐ any varices ‐ cut‐off around 150 mm	5	598
10 Adults ‐ platelet count ‐ high‐risk varices	21	4266
11 Adults ‐ platelet count ‐ high‐risk varices ‐ cut‐off around 90,000	11	3084
12 Adults ‐ platelet count ‐ high‐risk varices ‐ cut‐off around 150,000	7	1671
13 Adults ‐ platelet/spleen ratio ‐ high‐risk varices	10	930
14 Adults ‐ platelet/spleen ratio ‐ high‐risk varices ‐ cut‐off around 909	7	642
15 Adults ‐ spleen diameter ‐ high‐risk varices	6	883
16 Paediatrics ‐ platelet count ‐ any varices	4	277
17 Paediatrics ‐ platelet/spleen ratio z‐score ‐ any varices	2	197

Study characteristics
Patient sampling	Prospective cross‐sectional
Patient characteristics and setting	110 adult patients with cirrhosis due to hepatitis C virus. Child A 49.1%. Setting: tertiary referral centre in Egypt
Index tests	Platelet count
Target condition and reference standard(s)	Presence of any and high‐risk oesophageal varices. Upper endoscopy
Flow and timing
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		High	Low
DOMAIN 2: Index Test Platelet count
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
		Unclear	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Unclear

Study characteristics
Patient sampling	Retrospective cross‐sectional
Patient characteristics and setting	103 paediatric patients (98 with chronic liver disease, 5 with extrahepatic portal vein obstruction). 55% Child A. Setting: tertiary referral centre in Brazil
Index tests	Platelet count, platelet count‐to‐spleen diameter ratio
Target condition and reference standard(s)	Any oesophageal varices. Upper endoscopy
Flow and timing
Comparative
Notes	Paediatric
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Unclear	Low
DOMAIN 2: Index Test Platelet count
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	No
		High	Low
DOMAIN 2: Index Test Platelet count to spleen length ratio
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	No
		High	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
		Unclear	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Low

Study characteristics
Patient sampling	Prospective cross‐sectional.
Patient characteristics and setting	316 consecutive adult patients with hepatitis C‐related liver cirrhosis. Child A: 25.8%. Setting: tertiary referral centre in Pakistan
Index tests	Platelet count‐to‐spleen diameter ratio
Target condition and reference standard(s)	Any oesophageal varices. Upper endoscopy
Flow and timing	5 patients did not complete the clinical workup
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	High
DOMAIN 2: Index Test Platelet count to spleen length ratio
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	No
		High

Study characteristics
Patient sampling	Cross‐sectional
Patient characteristics and setting	101 adult patients. Accuracy data reported only for 36 Child A patients. Child A: 100%. Setting: tertiary referral centre in Italy
Index tests	Platelet count
Target condition and reference standard(s)	High‐risk oesophageal varices. Upper endoscopy
Flow and timing
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Unclear
		Unclear	Low
DOMAIN 2: Index Test Platelet count
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
		Unclear	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Low

Study characteristics
Patient sampling	Prospective cross‐sectional study
Patient characteristics and setting	113 consecutive adult patients. Child A: 68%. Setting: tertiary referral centre in Italy
Index tests	Platelet count, platelet count‐to‐spleen diameter ratio, spleen diameter
Target condition and reference standard(s)	Presence of any oesophageal varices. Upper endoscopy
Flow and timing	13 patients excluded from the analysis
Comparative
Notes	Individual patient data available
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test Platelet count
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 2: Index Test Platelet count to spleen length ratio
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 2: Index Test Spleen length
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	No
		High

Study characteristics
Patient sampling	Retrospective cross‐sectional study
Patient characteristics and setting	160 adult patients. Child A: 57.6%. Setting: tertiary referral centre in Brazil
Index tests	Platelet count‐to‐spleen diameter ratio
Target condition and reference standard(s)	Presence of any oesophageal varices. Upper endoscopy
Flow and timing
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Unclear	Low
DOMAIN 2: Index Test Platelet count to spleen length ratio
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	Yes
		Unclear	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
		Unclear	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Yes
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Low

Study characteristics
Patient sampling	Cross‐sectional study
Patient characteristics and setting	118 adult patients. Child A: not reported. Setting: tertiary referral centre in Australia
Index tests	Spleen size
Target condition and reference standard(s)	Presence of any oesophageal varices. Upper endoscopy
Flow and timing	Only 86/118 patients underwent endoscopy
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test Spleen length
Were the index test results interpreted without knowledge of the results of the reference standard?	Yes
If a threshold was used, was it pre‐specified?	Yes
		Low	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Yes
Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes
		Low	Low
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	No
		High

Study	Reason for exclusion
Albreedy 2015	No data for 2 × 2 table
Amarapurkar 1994	In only a minority of patients, spleen length was assessed by ultrasound
Barrera 2009	No data for 2 × 2 table
Chalasani 1999	Study provides data only for combination of splenomegaly and platelet count as predictors of oesophageal varices. Individual 2 × 2 tables for platelet count or presence/absence of splenomegaly are not extractable from manuscript
Cho 2015	No data for 2 × 2 table (Table S3 provides unreliable data)
El Guindi 2008	No data for 2 × 2 table
El‐Sherif 2008	No data for 2 × 2 table. Published data not consistent. Study authors contacted by email. They did not respond
Fagundes 2008	Not acceptable reference standard
Gana 2010	No data on index tests of interest
Giannini 2007	Same data as Agha 2009 (n = 311 patients)
Hong 2009	Different index test (spleen width)
Koncoro 2014	No definition of the reference standard used
Lee 2009	No data for 2 × 2 table
Malik 2015	No data for 2 × 2 table
Nashaat 2010	No data for 2 × 2 table. Published data not consistent
Nazish 2011	No data for 2 × 2 table
Ng 1999	Study identified patients with oesophagogastric varices
Park 2015	No data for 2 × 2 table
Qamar 2008	No data for 2 × 2 table
Rockey 2016	Only patients wih acute upper gastrointestinal bleeding were included.
Sebastiani 2008	Preliminary data (Sebastiani 2010)
Sethar 2006	No data for 2 × 2 table
Shah 2011	No data for 2 × 2 table
Sharma 2007	Platelet data for large oesophageal varices were not extractable from the text. Study proposes predictor function model derived from multi‐variate analysis as better model to predict large oesophageal varices
Takuma 2016	No data for 2 × 2 table
Tao 2008	No data for 2 × 2 table. Published data not consistent
Thayumanavan 2012	No data for 2 × 2 table
Thomopoulos 2003	No data for 2 × 2 table
Treeprasertsuk 2010	No data for 2 × 2 table
Valente	No data for 2 × 2 table
Yu 2008	Different definition of the target condition (data reported only for severe vs moderate small and no varices)
Zaman 1999	Overlap with Zaman 2001
Zhang 2013	Reference standard different from endoscopy
Zhang 2016	No data for 2 × 2 table. Published data not consistent (see Table 3: sensitivity and specificity not consistent with positive and negative predictive values)

PERMALINK

Platelet count, spleen length, and platelet count‐to‐spleen length ratio for the diagnosis of oesophageal varices in people with chronic liver disease or portal vein thrombosis

Agostino Colli

Juan Cristóbal Gana

Jason Yap

Thomasin Adams‐Webber

Natalie Rashkovan

Simon C Ling

Giovanni Casazza

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Oesophageal varices in portal hypertension

Target condition being diagnosed

Oesophageal varices

Index test(s)

Platelet count, spleen length, and platelet count‐to‐spleen length ratio

Clinical pathway

Prior test(s)

Role of index test(s)

Alternative test(s)

Rationale

Objectives

Primary objectives

Secondary objectives

Methods

Criteria for considering studies for this review

Types of studies

Participants

Index tests

Target conditions

Reference standards

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Missing data

Assessment of methodological quality

Statistical analysis and data synthesis

Investigations of heterogeneity

Sensitivity analyses

Results

Results of the search

1.

Methodological quality of included studies

2.

3.

Patient selection

Index tests

Reference standards

Flow and timing

Overall assessment

Funding

Findings

Adult participants ‐ any varices

Platelet count for any varices

Any cut‐off value

4.

Cut‐off value around 100,000/mm3

5.

6.

Cut‐off value around 120,000/mm3

Cut‐off value around 150,000/mm3

Heterogeneity analysis

Sensitivity analysis

Spleen length for any varices

Any cut‐off value

7.

Cut‐off value around 110 mm

8.

Cut‐off value around 100,000/mm³

Cut‐off value around 120,000/mm³

Cut‐off value around 150,000/mm³

Cut‐off value of 909 (n/mm³)/mm

Cut‐off value of around 90,000/mm³

Cut‐off value of around 150,000/mm³

Cut‐off value of around 909 (n/mm³)/mm