Sensitivity and Specificity of Screening for Pulmonary Arteriovenous Malformations.

Marie E. Faughnan

A thesis submitted in conformi@ with the requirements for the degree of Muter's of Science, Gnduate Department of Health Admhistration, University of Toronto

@ Copyright by Marie E. Faugban (2000)

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ABSTRACT

Seiiaitivity and Spceificity of Serccaiag for Pulmonary Arteriavenous MaJformations.

Marie E. Faughnan, Masters of Science (Cllaical Epidemiology) 2000, Graduato

Department of Health Administration, University of Toronto.

Objective: To detennine sensitivity and speciticity of contrast echocardiography (CE) for

diagnosiiig pulmonary arteriovenous maiformations (AVMs) in Hereditary Hemorrhagic

Telangiectasia (HHT).

Methds: 143/164 (87%) consecutive patients seen between 98-02-0 1 and 99- 10-3 1 at the

Toronto HHT Clinic underwent CE, oxygen shunt test (OST) and chest radiography (CXR).

Patients with positive screening underwent pulmonary angiography (gold standard).

Results: Sensitivity and specificity of CE were 93% and 40%, when verification bias ignored.

CE was more sensitive than OST (p=0.0006) and CXR (p=0.000 l), but less specific than CXR

(p=0.0008). Using logistic regression to impute data for unverified patients, sensitivity and

specificity were both 79%. Using novel scenario analysis to address verification bias, the

possible range of sensitivity was 3494% and specificity was 29-84%.

Coiiclusion: CE is more sensitive than conventional screening tests for pulmonary AVMs in

HHT, when verification bias ignored. However, verification bias effects on estimates of

sensitivity and specificity may be large.

1 would like to tbank Charles, my husband, for bis infmite patience and unwavering support,

1 am aiso grateful to my supervisor, Dr. Donaid A. Redelmeier, aiid thesis cornmittee memben, Dr. Robert 8. Hyland and Dr. Ahmed Bayoumi. Dr. Redelmeier's insight and critique w e n invaiuable. Dr. Hyland9s enduring enthusiasm and support made a i s projeet possible. Dr. Bayoumi's encouragement beiped me surmount many obstacles.

Finally, 1 would like to tbank Dr. LP. Szalai for being so generous with bis time and advice.

TABLE OF CONTENTS

. .........................**........................................................... 1 1 Rationale 1 1.2 Study Question ................................................................................. 1

.......................... 2.1 Hereditary Hemonhagic Telangiectasia* ..... .............. 3 2.2 Epidemiology of pulmonary arteriovenous malformations ................. 6 2.3 Manifestations and complications of pulrnonary arteriovenous

............................................................................... malformations 8 2.4 Treatment of puimonary arteriovenous malformations .................... L I 2.5 Screening tests for pulmonary artenovenous malformations ............. 16

........ 2.6 Gold standard test for pulrnonary arteriovenous malformations 25 2.7 Rationale for screening for pulmonary artenovenous

............................................................... makonnations ............ ... 27 ...................................................... 2.8 The problem of verifkation bias 27

....................................................... 3.1 Patient population and database 29 3.2 Screening protocol ........... .. .......................................................... 31

................. ................ 3.2.1 Overview of specific screening tests ... 31 ................................................... 3 2.2 Contrast echocardiography 32

3.2.3 Shmt snidy .............. ... ..................................................... 33 3.2.4 Chest radiography ........ .......... ........................................ 34 . . 3.3 The gold standard cntenon ................ ... ........................................ 35

3.4 Analysis ........... .... .......................................................................... 35 3.4.1 Reliability analysis ........................................................... 3 5 . . 3.4.2 Statisticd d y s i s ................................................................. 36 3.4.3 Sample Sue calcdation ........ .. .......................................... 37 3.4.4 Scenario d y s i s ........... ... ..................~...................g........ 37 3.4.5 Cornparhg scnening tests ................................................... 38 3.4.6 Imputation analysis .........................o.................... ... ..... 38

............................................................................................................... 4 . Results 40

......... ............**...*. 4.1 Baseline characteristics of the study population .. -40 ..... 4.2 Observed prevaleace of pulmonary arteriovenous malformations -41

........... 4.3 Clinicd and angiographie disease severity in positive patients 43 ......... 4.4 Reliability of contrast echocardiogtaphy and chest radiography 44

4.5 Estimates of sensitivity and specificity of screening tests in four scenarios ........... .. ............................................................ -45

4.6 Cornparison between tests of sensitivity and specificity ..................... 47 4.7 Sensitivity and specificity of different combinations of

................................................ screening tests .................... ... -43 4.8 Comparison of screening tests in the study cohort and

the historical cohort .................. ............... ...................................... 49 4.9 bbLogistical" estimate o f sensitivity and specificity of

......................................................................... echocardiography -49 .................................. 4.1 0 Special cases of con- echocardiography -50

5 . Discussion ....................................................................e......e....e...........~...e..e..... 51

. . .............................................................................. 5.1 Principal f d n g s 51 .......................................................... 5.2 Influence of verification bias S2

.................... 5.3 "Thoughtless" estimates of sensitivity and specificity A 4 ...................................... 5.4 Addressing verification bias usùig scenarios 54

............. .......... 5.5 Co rrecting for verification bias using imputation ... 55 . 5.6 High rate of false positivity with contrast echocardiography ...... 3 5

5.7 Implications of the superior sensitivity of contrast echocardiography ..... ... . .... .. ... ..... .. 3 7

................................... 5.8 Referral bias and specmim bias .................... ... 58 .................................................. 5.9 Other major limitations of the study 59

5.10 Arguments for generahbility of the results ................................... 61 5.1 1 Impact of contrast echocardiography screening on

....................... .. ....**..... management of disease .... ...... 61 5.12 Feasibility of the three scmning tests ........................................ 62 5.13 Future research ......... ...... .................... .t., .... 64 5.14 Summary of principal findings ................. .. .................................. 65

LIST OF TABLES

Table 1: Baseline characteristics of the historical and shidy cohorts

Table 2: Spectrum of HHT discise in study and historical cohorts

Table 3: Logistic Rmessioii Mode1 for the probabüity of diamosing pulmonary AVMs baseà on the 3 scmning tests

Table 4: Prdicted fnqueiicies of diagnorb of pulmonary AVMs, based on logistic

LIST OF FIGURES

Figure 1: Seasitivity and Specificity of Contrist Ecbocardiography

Figure 2: Sensitivity and Speciacity of Shunt Study

Figure 3: Sensitivity and SpeciTicity of Chest Radiogrrphy

Figure 4: Cornpirison Between Contrast Echocardiography and Shunt Study Using McNernar's Test

Figure 5: Cornparison Between Contmst Echocardiography and Chest hdiography Using McNemar's Test

Figure 6: Sensitivity, specificity, iikeiihood ratios and predictive values for combinations of the screeaing tests, using the Uthoughtless" scenario

Figure 7: Sensitivity rad Specüicity for shunt study in the historical cohort

Figure 8: Sensitivity and specilicity for chest radiography in the historical eohort

Figure 9: 6bLogistical~' estimates of sensitivity and specitïcity

vii

CHAPTER 1

ïNTRODUCT1ON

The purpose of fhis chapfer is to:

I . Provide the rationale forthe shrdy;

2. Introduce the stuày question

1.1 Ratiooale

Pulmonary arteriovenous malformations can lead to serious complications, such as

stroke, brain abscess, spontaneous haemothorax or massive haemoptysis. Many patients

experience no waming symptoms pnor to developing a senous complication. At least

60% of patients with pulmonary arteriovenous malformations have Hereditary

Hemorrhagic Telangiectasia, and 20% of patients with Hereditary Hemorrhagic

Telangiectasia have puimonary arteriovenous malformations. Because a safe and

effective treatment exists for pulmonary arteriovenous malformations, screening for

pulmonary arteriovenous malfonnations has been recommended in patients with

Hereditary Hemorrhagic Telangiectasia. However, snidies evaluating diagnostic

screening tests in Hereditary Hemorrhagic Telangiectasia patients are few and small.

1.2 Study Question

We hypothesize that contrast echocardiography is the most sensitive available screening

test for pulmonary arteriovenous malformations in Hereditary Hemorrhagic

Telangiectasia patients. To test this hypothesis, we analyzed data fiom consecutive

patients fiom one hospital who were pm~pectively assessed for the presence of

puimonary arteriovenous malformations. All patients underwent the foiîowing tests:

chest radiography, oxygen shunt test and contrast echocardiography (as well as history

and physical examination). AD patients with positive screening tests underwent

diagnostic pulmonary angiography, the reference standard.

Contrast echocardiography rnay be the most sensitive non-invasive study available. It is

genedy more acceptable to patients than oxygen shunt testing, involves no exposure to

radiation and is usually relatively painless. For dl of these reasons, our study question

focuses on contrast echocardiography. The study question is: What are the sensitivity

and specificity of contrast echocardiography for diagnosing pulmonary artenovenous

malformations in patients with suspected Hereditary Hemorrhagic Telangiectasia?

CEAPTER 2

BACKGROUND

The objectives of rhis chapter are to:

1. Summarize the disease Hereditary Heniorrhagic Telangiectdu;

2. Review the epidemiology ofpultnorrury arteriovenous rnalformationî;

3. Describe manifslations und compIic'utions ufpulmonary arteriovenous

malformations;

4. Outline the treatment of pulmonary arteriovenous malfonnutions;

5. List the mailable screening tests for pulmonary arteriovenous malformations;

6. Preseni the gold standard test for pulmonary arteriovenous malformaiions;

7. Summarize the rutionule for screening for pulmonary arteriovenous malfrmations;

8. Address the pro6 lem of verification bias.

2.1. Hereditary Hemorrhagic Telaagiectrsia.

Heredi tary Hemorrhagic Telangiectasia (HHT) is a rare autosomal dominant disorder

chanicterized by vascdar dysplasia. HHT was described in 1896 by Henri Rendu

(1). Though HHT was initially thought to be a very rare disease (2), a recent French

study estimates the population ptevaience to be approximately 1 in 8000 (3). HHT bas

been identified in most races and areas of the world (4,5,6,7). The four diagnostic

criteria for diagnosing HHT are: recment spontaneous epistaxis, typical mucocutaneous

telangiectasias, viscerai arteriovenous malformations and positive family history (3,8).

Two types of vascular dysplasia are seen in HHT: telangiectasia and arteriovenous

malformations (AVMs). Telangiectasias are small dilated vessels, specifically post-

capillary vendes (9,lO). Telangiectasias are found on the skin, typically over the hands

and face, and on the mucosa of the mouth, nose and gastrointestinai tract.

Telangiectasias on the skia, the rnost common visible sign of HHT, are generaliy present

by age 40 (3). Epistaxis, secondary to telangiectasias of the nasal mucosa, is the most

fieqwnt symptom of HHT (3,11,12,13). Gastrointestinal telangiectasias lead to chronic

upper gastrointestinal bleeding in 1 5020% (3,5,12). Arteriovenous malformations

(AVMs) are larger abnormal blood vessels that occur in HHT due to a direct artery to

vein connection with no intervening capillary network (14). The physiologic term for

this abnomality is shunt. AVMs occur in the brain, liver and lungs of patients with

HHT (1 5) and more rarely in the bowels (1 6) and other organs. AVMs cm cause serious

complications through haemorrhage or phenornena associated with shunt.

The lungs are the most fiequent site for AVMs, occurring in 5 to 35% of patients with

HHT (3,12,17,18,19). Cerebral AVMs are present in 3 to 10% of patients with HHT

(3,12,20,2 1 ,22) and cm lead to debilitating and life-threatening complications such as

hemorrhagic stroke and seizures (22). Although cerebral AVMs occur, neurologicd

complications in HHT patients are more fkequently secondary to pulmonary AVMs (22).

The prevaience of liver AVMs has k e n estimated to be 3% (3), though in most series of

HHT patients the authors negiect to report rhis complication. Recently a family with a

prevaience of liver AVMs of 22.5% has been d e m i i d (23), as detected by dtrasound

doppler screening. There are no reports ofhaemorrhage secondary to liver AVMs.

Rather, liver AVMs have the potential to cause hi&-output heart failure (24), mesenteric

ischemia (25), pseudo-cinhosis (26) or refractory bleeding from gastrointestinal mucosal

telangiectasias (27). Colonic and s m d bowel(28) AVMs have also been described.

Spinal (29) and rend AVMs (30) have only rarely been described in HHT.

There is no available treatment for MT, but therapy has been developed for some of its

manifestations. Tmnscatheter embolotherapy is an effective intervention for pulrnonary

AVMs, as we will outline in section 2.4. Cerebral AVMs are effectively treated with

transcatheter embolotherapy, surgicai resection, stereotactic radiosurgery or a

combination approach (3 1). There is, however, no perfect cure for the recurrent epistaxis

that plagues these patients. Despite the availability of various types of laser therapy (32)

and surgery (33), the major@ of patients suffer fiom lifelong spontaneous episodes of

epistaxis. The same is tnie for the treatment of gastmintestinal bleeding, though some of

these patients respond to combined estrogen and progesterone therapy (34). Perhaps

gene therapy will be a solution for these patients in the firme.

HHT is inherited in an autosomal dominant fashion with near complete penetrance and

age-related expression (3). The genetics of HHT have been eiucidated in the past decade.

To date, two gene loci associated with this disorder have k e n identified, though othen

may exist. The f h t gene locus was mapped to chromosome 9, specifically 9q33-34, and

it encodes endoglin, a CO-receptor for transforming p w t h factor 8 (TGF-D) (35,36,37).

The second gene locus, the activin receptor-like kinase (ALK-1) gene is located on

chromosome 1 2 (3 8,39,4O). ALK-1 is another member of the TGF-B superfamil y.

Though the fuaction of both endoglin and ALK- 1 remah a mystery, their association

with the TGF-O superfamly is not surprishg since TGF-D modulates vascular growth.

Most families studied to date have a mutation in one of the two genes, though a few

families remain in whom a mutation has not been identified. There is some evidence to

suggest that families with a mutation in the endoglin gene are especially predisposed to

pulmonary AVMs: The prevaience of pulmonary AVMs has been reported to be 29-4 1 %

in affected members of families linked to the endoglin gene compared to 3- 14% in

afTected members of families not linked to the endoglin gene (1 7,41). The most

important recent advance in HHT has been the development of a mouse mode1 for M T ,

the endoglin knock-out mouse (42). The homoygotic mice al1 die during embcyonic

vasculogenesis. The hetemygotic mice display the entire phenotype seen in humans.

2.2 Epidemiology of pulmonary arterioveaous malformations

HHT is the underlying cause of 47-97% of al1 pulmonary AVMs (43,44,45,46). Other

causes of pulrnonary AVMs are polysplenia syndrome, hepatopulmonary syndrome,

congenitd idiopathic pulmonary AVMs and very rarely acquired pulmonary AVMs.

Polysplenia is a rare congenital disorder characterized by multiple anatomic

abnonnalities including two spleens, bilateral bilobed lungs, liver isomerism, right-sided

stomach, cardiac anomalies and biliary atresia (47). Rare cases of pulrnonary AVMs in

patients with polysplenia syndrome have ken described (48.49). Though intrapuimonary

shunt is not infiequent in patients with advanced chhosis, discrete pulmonary AVMs are

rare (50). Congenitai idiopathic puhonary AVMs are nue (5 1) and may in fat be

secondary to unrecognized HHT. Acquired pulmonary AVMs have been described in

association with tuberculosis (52). pulmonary SC histosomiasis (5 3,54), trauma (5 5).

neoplasm (56) and mitral stenosis (57). Acquired pulmonary AVMs have also been

described post-operatively in congenital heart disease patients who have undergone direct

cavopulmonary anastomoses, specificaiiy the Glenn and modified Fontan procedures

(58,59). There are rare reports of pulmonary AVMs in patients with elevated pulmonary

artery pressures (6O,6 1,62).

Pulmonary AVMs are reported to occur in 15-33% of patients with HHT

(3,12,17,18,19,63). This estimate cornes fiom small to moderate size case senes, O ften

with signiticant selection bias. These case senes al1 include a large number of patients

tiom a small number of families, and therefore better reflect the pattern of disease within

a family rather than withui a population. There have been few studies to date, with

relatively small numbers of patients, where HHT patients have been systematically

screened for puhonary AVMs (63,64). These screenhg studies will be discussed in

section 2.4.

Pulmonary AVMs are found in the lower lobes in 50-8 1 % of cases (65,66). Though an

early surgical series reported unilaterality in 67% of patients (66), pulmonary AVMs

were likely under-diagnosed in these patients. In more recent and larger senes

(44,46,65), 61-75% of patients have multiple pulmonary AVMs and 42.76% of these

have biiated disease (44,65). The eariy surgical series was informative in that the

authors demonstrated that puimonary AVMs involved the pleura in 81% (66).

Approximately 5% of patients with pulmonary AVMs have diffuse mal1 AVMs (67).

The architecture of pulmonary AVMs has been well described in a recent review (68).

The AVM consists of a feeding artery leading to a thin-walled dilated aneurysm,

emptying into a drriining vein. Puhonary AVMs are classified based on segmental

pulmonary artery anatomy. They are divided into simple and complex types, depending

on the number of segments h m which feeding arteries originate (69). Pulmonary AVMs

are of the simple type in 79%-92% (46,69,70). The feeding artery of pulmonary AVMs

can range in size from 1 to 16 mm (71).

2 3 Manifestations and complications of pulmonary artcriovenous malformations

Pdmonary AVMs can lead to life threatening and debilitating complications. The most

important complications are stroke, brain abscess, spontaneous haemothorax and massive

haemoptysis. These complications occur in patients of dl ages. Fortunately, these

complications can be largely prevented with transcatheter embolotherapy of the

pulmonary AVMs. However, many patients have no warning symptoms prior to

developing a senous complication, and therefore therapy comes too late. For these

reasons, screening for pulmonary AVMs has ken recommended in patients with HHT.

Pulmonary AVMs were first described on autopsy in 1897 (72), although it wasn't until

the late 1930s that an association between HIET and puimonary AVMs was suspected

(73) and that the first ante-mortem diagnosis was described (74). The fim description of

cerebrai abscess as a complication of pulmooery AVMs was in 1932 (75). In the fïrst

large case series (21), reporting 76 patients with 276 pulmonary AVMs, hvestigatoa

reported a prevalence of stroke of 18% (a total of 37% had stroke on CT scan), transient

ischemic attacks (TM) of 37%, brain abscess of 9%, spontaneous haemothorax of 9%

and massive haemoptysis of 13%. In a recent series of 93 patients with pulmonary

AVMs, 37% had a history of sûoke, transient ischemic attack, brain abscess or seizures

(46). Other work suggested that the majority of neurological events in patients with HHT

were secondary to pulmonary AVMs rather than cerebral artenovenous malformations

(22). These complications have ken reported in patients of both genders, of al1 ages,

with reports in newbonis (75) as well as in the elderly (46).

The absence of capillaries in pulmonary AVMs plays an important role in the

development of complications in these patients. Normally, pulmonary arterial blood

from the right side of the heart is oxygenated while in the thin-walled capillaries that are

jwtaposed with air-filled alveoli. Since pulmonary AVMs are direct artery to vein

connections, blood travelling through AVMs bypasses the capillaries, and travels to the

left side of the heart without k i n g oxygenated. This is cailed a right-to-left shunt and

leads to a low partiai pressure of oxygen in the systemic circulation. Normal capillaries

are aiso small enough (8 micron diameter) to trap srnall emboli in the blood, thereby

preventing them fiom reaching the lefi side of the heart and the systemic circulation.

The presumed pathophysiology for m k e in patients with puilnonary AVMs

hypothesizes that patients have asymptomatic peripherai deep venous thrombosis with

subsequent embolisation through pulmoaary AVMs to the brain (76). Another postulated

explanation is that tbrombus forms in pulmonary AVMs and then embolises to the brain

(77). The high blood flow through pulrnonary AVMs renden the second theory less

probable and explains why peripheral emboli in the nrst theory would preferentially flow

through pulmonary AVMs rather than normal pulmonary arteries. Other systemic

embolic events related to pulmonary AVMs likely occur but remain undiagnosed.

The pathophysiology for cerebral abscess is probably more complex. Circulating bacteria

in bacteremic patients are probably not filtered out by pulmonary capillaries, as the

capillary size is larger than the diarneter of bacteria. The principal theory, developed in

patients with cyanotic congenitai heart disease, is that patients with pulmonary AVMs

have areas of encephalomalacia related to micro-emboli, chronic hypoxia andor sludging

due to secondary polycythemia (78,79). These areas of encephalomalacia would be

easily seeded by bacteria fiom the blood, leading to the formation of an abscess.

Bacteraemia cm occur when a person has a serious infection such as pneumonia, but can

also occur during dental work and certain other procedures, in a healthy person.

The hemonhagic complications of pulmonary AVMs are explained by the fiagility of the

thin-wailed aneurysm interposed between the feeding artery and the draining vein. This

structure can rupture, leadllig to a haemothorax or haemoptysis depending on location

(21). There are several reports of deaths secondary to hemorrhagic complications fiom

pulmonary AVMs (80). Haemonbage fiom pulmonary AVMs seems to be especially

fiequent in women and ri& appears to be grratest during the second and third ûimesters

of pregnancy and eariy in the pst-partum period (8O,8 1,82). Hemorrhagic risk is

relatively low in children, presumably because it takes time for pulmonary AVMs to

grow to a size at risk of rupture.

Patients with pulmonary AVMs are ofteo asymptomatic prior to developing a senous

complication. Several case series of patients with pulmonary AVMs have shown that

dyspnea on exertion or exercise intolerance occurs in only 26-7 1 % (2 1 ,#,6,65,83).

One explanation may be that patients become accustomed to their level of dyspnea and

therefore limit their activities accordingiy. The other possibility is bat an increase in

cardiac output compensates for hypoxemia (84). In two recent series, careful history

taking revealed that 15% of patients with pulmonary AVMs were completely

asymptomatic (2 l,8S). The classical signs of pulmonary AVMs, such as cyanosis and

clubbing (86) are even less fkquent (18). Clearly, stroke can be the presenting symptom

of pulmonary AVMs (77). For this reason we cannot rely on the history and physical

examination to detect pulmonary AVMs prior to the development of a complication.

2.4 Treatment of pulmonary arteriovenous malçormations

Successfbl surgical resection of pulmonary AVMs was fVst described in 1942 (87) and

until the early 1980s, pulmonary AVMs were routinely treated by this method. This

first operation was a pneumonectomy. Over the next few years, lung-sparing resections

became the rule, generally involving segrnentectomy (88). However, patients with

bilateral multiple AVMs were not considered surgical candidates or underwent staged

bilaterai thoracotomies (89). A surgical mortality of 36% was reported in the earlier

surgical series (5 1,66). AU surgical approaches to pulmonary AVMs require

thoracotomy, general anaesthesia and several days of post-operative hospital stay.

The most recent surgical series (N=30) reported one death post-operatively, that patient

having developed haemothonur pst-pneumonectorny (90). in the same series, 3 patients

(1 0%) had a post-operative complication (prolonged mechanical ventilation,

haemonhage requving transfusion and prolonged air leak). There was no observed

surgical mortality in another recent surgical series of 8 patients (83), but the authors did

not report morbidity, pain and hospitai stay. Similady, most other recent surgical case

series show no mortaiity but neglect to describe morbidity or recurrence of symptoms or

pulmonary AVMs postsperatively (1 8,43,65,9l). Not only is thoracotomy for other

disorders associated with significant morbidity, but it also requires a substantial recovery

penod (92). Furthemore, since most patients with HHT have multiple pulmonary

AVMs, bilateraf thoracotomy with multiple nsections wodd often be necessary, which

potentially could lead to chronic shortness of breath or frank respiratory insufficiency.

In the late 19709, transcatheter embolotherapy was introduced as a new therapeutic

approach. Transcatheter embolotherapy is an endovascuiar approach to treating

pulmonary AVMs Uivolving selective occlusion of the feeding artenes of the AVMs with

embolic matetial(68). This was first described using coils (stauiless steel or platinum)

(93,94) and soon after using detachable silicone balloons (69,95). Blood flow, which had

been travelling through puimonary AVMs, is thetefore recürected to normal vascular

segments of the h g , where blood travels though capillaries. This improves shunt by

dlowing oxygenation of previously shunted blood. It also d o w s filtration of the blood.

Hence, therapy both improves oxygenation but dso prevents braui damage fiom stroke or

abscess.

Several authoa suggest that transcatheter embolotherapy is an effective treatment for

pulmonary AVMs (2 1,44,45,69). The technicai success rate per AVM, defined as

angiographie evidence of AVM occlusion imrnediately post embolisation, ranges Ciom

90- 100% (2 1,45). The clinical success rate, defined as sustained occlusion of pdmonary

AVMs one-yeat pst-embolisation, ranges from 85.94% (45,71). Success of

embolisation depends on the experience of the interventional radiologist as well as on the

anatomy. Embolisation failure is detected by persistence of shunt and evidence of

ongoing or recurrent perfusion of AVMs on imaging. Reperfusion of AVMs cm be due

to recanalisation of the feedhg artery or development of new, or previously

unrecognized, feeding arteries supplying the AVMs (68). Those AVMs that are not

successfully embolised on the first attempt can be successfûlly treated with repeat

transcatheter embolotherapy (68). Even the largest pulmonary AVMs are successfully

occluded through traascatheter embolotherapy, with sustained occlusion of 85% of

pulmonary AVMs after the first attempt (71) and persistent AVMs are successfully

tnated with a second or third procedure.

Foilow-up of patients who have undergone transcatheter embolotherapy for pulmonary

AVMs shows few neurological complications (2 1,44,45,7 1 ). In one series of patients

with large pulmonary AVMs(71), 2/45 (4%) of patients developed a stroke during the

average foliow-up pend of 4.7 years. One had recanalisation of a previously occluded

feeding artery and the other also had reperfùsion of a previously occluded AVM thmugh

an accessory feeding artery. In untreated patients, mortality fiom pulmonary AVMs

occurs in 0.29% of patients, and significant rnorbidity in 26933% of patients, in studies

with a mean follow-up penod of four to six years (1 8,46,9 1,96,97). in one surgical

series, the t h e patients with documented pulmonary AVMs who were followed without

any matment al1 developed neurological compiications (83). Clearly, treated patients

have a better prognosis than untreated patients.

Transcatheter embolotherapy of pulmonary AVMs is a low-risk procedure with a rapid

recovery period. The complication rate is low. In the Iarger series, reflecting results with

experienced radiologists, there were no &QUS sequelae. Short-term minor

complications include pleuritic chest pain in 9.30% of embolisation sessions (44,45,69)

or 1 1-3 1% of patients (2 1,44,45,46,7 1 ), deep venous thrombosis in 6% of patients (69),

transitory symptoms fiom air embolism in 506% of patients (2 1,44) and transitory

arrhythmias in 3% (45). In a recent series of 53 patients who underwent transcatheter

embolotherapy, one patient developed a stroke pst-procedure (44), but recovered M y

within five days. in the same series, two patients were temporarily disoriented and

confused pst-procedure.

Pleuritic chea pain is a fiequent adverse event fiom ernbolotherapy, as described above,

but generally miid and self-limiteci. Patients are generaiiy treated with non-steroidal anti-

inflammatory drugs with resolution of the pain in seven to ten days. In a smaD number of

patients, the pain is associated with fever and a puîmonary Uifarct rnay be visible on chest

radiograph. These patients have more intense and prolonged pain, sometimes requiring

narcotics for severai weeks*

The arrhythmias are generally transitory, related to myocardial imtability during passage

of the pulmonary artery catheter or related to transitory angina h m air ernbolisrn. Local

haematoma at the site of puncture is infiequent since the puncture performed is venous,

though erroneous artenal punchire occurs in Iess than 1% of patients (98). Haematoma

occurs in less than 1% of patients (98).

The potentially most serious complication that can occur is paradoxicd embolisation of

the coil or balloon during the procedure. This is reported to occur in 1.2% of AVMs or

4-6% of patients in an early series (69) and two small series (44,45). In a later Iarger

series with more patients, the rate was 0.7% per AVM or 3% of patients (2 1 ), suggesting

that this complication decreases with experience. In a series of patients with large

AVMS, the rate was 4% of patients (71). La al1 cases reported in the Iiterature, the coil or

balloon was retrieved using an endovascular transcatheter approach or lefi in place, with

no end-organ damage (21,44,45,69). In one patient, (45,99) retrieval of the coil from the

Ieft ventncle resulted in a hemopericardium, likely secondary to cardiac perforation.

Worsening pulmonary hypertension has also been reported in one case (99). Though

puimonary hypertension does not occur as a complication fiom pulmonary AVMs, it can

occur in HHT secondq to iiver AVMs or coexist as primary pulmonary hypertension.

Pulmonaty hypertension is considered a relative contraindication to transcatheter

embolotherapy, since embolisation of the AVMs may lead to a M e r increase in

pulmonary artery pressures.

Not only is transcatheter embolotherapy less invasive and associated with less risk, but

also it allows sparing of normal lmg tissue and treatment of bilateral Mons. There is no

incision and therefore no necessary recovery period in patients who develop no

complications. This procedure requires no general anaesthesia. Patients are admitted to

hospital for less than 24 hours and generally return to work two days after their

procedure. In a recent series comparing 25 patients who had undergone surgical

treatment and 48 patients who had undergone transcatheter embolotherapy, the surgical

group had a hospital stay of 5 to 7 days whereas the embolisation group had a hospital

stay of 1 to 2 days (46).

2.5 Screening tests for pulmona y arteriovenous maliomations

Watchful waiting of pulmonary AVMs cannot be advised since there is no evidence of a

correlation between growth of pulmonary AVMs and the occurrence of complications.

Furthemore, there is some evidence to suggest that stroke (clinicai or visible on MM)

occurs with pulmonary AVMs with a feeding artery as smaii as 3 mm (100). Since

senous complications can occur if pulmoaary AVMs remah undiagnosed a highly

sensitive screenhg test is desirable. There are three major types of tests that can be used

to screen for pulmonary AVMs. Fht , there are screening tests that yield images that can

be suggestive ofpulmonary AVMs. This has ken done using chest radiography,

computed tomography (CT) and magnetic resonance imaging o. Second, there are

those that quanti8 shunt, the underlying physiological abnomality in patients with

pulrnonary AVMs. These include oxygen shunt testing, radionuclide scanning and

invasive cardiopulmonary exercise testing. Third, there is one screening test that

qualitatively assesses shunt; namely contrast echocardiography.

haging has been used for many years to detect pulmonary AVMs. Some of the concems

about chest radiography as a screening test are that chest radiography is limited by

resolution and superimposition of structures. Moreover, blood vessels of pulmonary

AVMs are not necessady very enlarged, compared to the usual size vessels seen in a

particular area. For these reasons, distinguishiag pulmonary AVMs from nomal

vasculature can be difficult for the smaller AVMs. Finally, chest radiography

interpretation of subtle fmdings is highly dependant on the eye of the radiologist and their

experience in looking for a particular abnormaiity. Typical signs of AVMs that are

sometimes seen on chest radiography include oval, saccular or grapelike opacifications

(65,66).

In one senes of patients with docurnented pulmonary AVMs, chest radiography was

found to be abnormal in 95% (65). In two early screening studies, chest radiography

detected wsuspected pulmonary AVMs in 6%-17% of pa ients with HHT ( 19,lO 1).

Patients with negative screening chest radiogtaphy were not investigated m e r ,

however, so we cannot comment on the sensïtivity of chest radiography based on these

acticIes.

in a recent study of screening for pulmonary AVMs in HHT patients (N=98), chest

radiographs, as interpreted by experienced mdiologists, had a sensitivity of 83% and a

specificity of 92% (63). The sensitivity and specificity reported were uncorrected for

verification bias. In patients with abnormal chest radiography, diagnostic angiography

was perfomed. In patients with hypoxemia on arterial blood gas, an oxygen shunt test

was performed. If a shunt was confimed in this way, diagnostic angiography was

performed. In patients with negative screening tests, no M e r investigation was

performed and they were presumed to have no pulmonary AVMs. Therefore, the

authors have likely overestimated the sensitivity and underestirnated the specificity of

chest radiography. Furthemore, the authors did not describe the methods for

interpretation of the chest radiograph and so we m u t assume bat the radiologist was

unblinded and likely experienced in detecting pulmonary AVMs, leading to even M e r

overestimation of the sensitivity of imaghg. nie sensitivity would certainiy be much

lower for a general screening radiograph interpreted by an unsuspecting radiologist,

particularly because pulmonary AVMs occur predominantly in the lower lung zones

where they cm be difficult to detect due to superimposition of the heart and diaphragm

on the chea radiograph.

In the second recent screening study (64). the investigators reported a cohort of patients

(N=2S) with positive contrast echocardiography who were M e r screened with pulse

oximetry, oxygen shunt test and chest radiograph. Aii patients went on to a pulmonary

angiogram. The semitivity of chest radiograph was reported to be 73%, with a specificity

of 8O%, in this population of patients with a positive contnist echocardiography. These

estimates have not been corrected for verincation bis. Though d l reported patients went

on to pulmonary angiography we have no information about the patients who had

negative contrast echocardiography. The sensitivity of chest radiography may be either

overestimated or undereshated in this pre-screened group since the severity of

pulmonary AVMs in this pre-screened group is iikely not the same as it wodd be an

unscreened population.

Several groups have described the typical appearance of p ulmonary AVMs

conventionai chest CT (1 O2,lO3,lO4). Since CT imaging provides higher resolution,

there is less superimposition of structures than with chest radiography and we would

therefore expect it to be more sensitive. In the one study of CT screening for pulmonary

AVMs in HHT patients (los), the authors reviewed 20 patients who had been diagnosed

with pulmonary AVMs on pulmonary angiography. They retrospectively reviewed the

CT scans fiom these patients to detect al1 visible AVMs based on the typical

characteristics described in previous studies (102,103,104). Of the 65 AVMs detected by

angiography, 63 were detected on CT (97%). The authors reported detecting an

additional 42 pulmonary AVMs that were not seen on angiography. They interpreted this

to indicate that CT scan is more sensitive than pulmonary aagiography, the gold standard.

However, the diagnosis in these 42 suspected AVMs was not conoborated by any other

test. The images seen may in fact be mal1 AVMs or may not be AVMs at dl. Though

CT imaging provides higher resolution, structures other than AVMs can have similar

radiographie density, thus compromising specificity.

The same group went on, in another study, to describe the use of 3-dimensional helical

CT for the visualisation of the angioarchitecture of pulmonary AVMs (1 06). They

showed that helical CT is useful in determining whether an AVM is simple or cornplex

but they did not report sensitivity and specificity for the diagnosis of pulmonary AVMs.

Since CT, either conventional or helicd, is associated with significant radiation exposure

(approximately 2 rems), it is not an ideal test for screening asymptomatic patients. The

radiation exposure is similar to that for a pulmonary angiogram.

There are case reports of the use of MRI of the chest to detect pulmonary AVMs

(107,108) but this test has not ken studied extensively. MRI of pulmonary AVMs is

interesthg since rapidly flowing blood has little or no MRi signal. This characteristic of

MRI helps in the differentiation of vascular and non-vascular structures. However, there

are some significant limitations to the use of M N to screen for pulmonary AVMs. First,

for technical reasons, imaging time is very long for the chest. This is an issue since

availability of MRI is still problematic in most centres. Second, MRI of the chest is

difficult, since current MRI is not rapid enough to create an image between heartbeats.

This is an issue in chest MRI since the pulsating large vessels in the thorax are

particularly mobile and therefore it is difficuit to obtain adequate spatial resolution.

Quantitative shunt testing may appear to be a wful approach to screening for pulmonary

AVMs. However, the available methods have limitations. Oxygen shunt testing was f i

described in 1942 (109). This involves arterial oxygeoation measurement, d g artenai

blood gas anaiysis, when the patient is breathing rwm air and then again when the patient

is breathing 100% oxygen. This test has the advantage of minimiïing ventilation-

perfusion mismatch, which cm fdsely elevate the shunt estimate when assessed on room

air. Unfomuiately, there is no standardized procedure for administering 100% oxygen for

this tests and therefore each institution develops their own protocol.

Oxygen shunt testing requires administration of 100% oxygen, which can be dificult. A

system must be implemented where there are no leaks and no mixture of inspiratory and

expiratory gases, in order to administer 100% oxygen. A small right-to-left shunt (0.3-

1 .O%) exists even in normal subjects due to venous admixture of pulmonary artenal

blood from branchial, mediastinal and Thebesian veins (1 10). There are also some

concems that breathing 100% oxygen may actually alter the intrapuhonary shunt

fraction, but this is likely only true in patients with the diffuse type of pulmonary AVMs

(1 1 1 ). In one of the screening studies, the sensitivity of shunt was reported as 7 1 % and

the specificity as 87.5% (63), though once again these numben have not been conected

for verification bias.

Another quantitative method is radionuclide shunt assessment. This test involves

uitravenous injection of radioactive particles which will normaily travei thorough the

veins to the right side of the heart, then on to the pulrnonary circulation, where the

particles wiii be trapped in the pulmonary capillaries. Since particles less than 8 microns

in diameter are w d y trapped within the pulmonary capiliary bed, any passage into the

systemic cùculation indicates the presence of a right-to-Ieft shunt at either the pulmonary

or catdiac Ievel. Radionuclide estimation of shunt is perfomed by measuring systemic

levels of radioactivity after passage through the lungs. This is generally estimated by

meamring radioactivity over the kidneys.

Early investigators used radiolabeled albumin macroaggregates to quanti@ right-to-left

shunt, in patients with cyanotic congenital heart disease, but found poor correlation with

otber physiological tests (1 12). Subsequently, investigators described a method using

Technetiurn (99Tcm) albumin microspheres in patients with pulmonary AVMs (1 13). In

this study, the authoa reported shunt assessment in 7 patients and compared it to oxygen

shunt test results. They found a good correlation between the two methods, with a

comlation coefficient of 0.993. However, their protocol for oxygen shunt measurement

was not optimal, since they did not have separate inspiratory and expiratory valves. In

other words, they likely were not admuiistering 100% oxygen and therefore were likely

underestimating shunt with their "gold standard".

In a later study by the same group, they compared tnuiscutaneous arterial oxygen

saturation to macroaggregate and microsphere scanning, in 16 patients and 8 controls

(1 14). In the eight controls, the mean shunt was 2.0% (standard deviation 1.4) and did

not ciiffer significaatly between the two radionuclide methods. They showed that shunt

assessment by rnacroaggregate scaaning or albumin microsphere method was not

significantly different fiom the oxygen shunt measwment. Radionuclide estimation of

shunt has not been weii validated and shunt assessment is iikely af5ected by regional

blood flow.

Cardiopulmonary exercise testing, through hcremental exercise on a stationary cycle

ergorneter, is another appmach for meastuhg shunt. The first report of exercise testing in

patients with known pulrnonary AVMs (1 15) reported worsening hypoxemia with

exercise. A later report from the same group suggested, however, that in some patients

hypoxemia worsens and in othea it improves (1 16). A third study (1 17) showed stable

hypoxemia during exercise. These studies are clearly contradictory and unfomuiately

there are no other studies assessing exercise testing in this group. Furthemore, accwate

oxygen measurement during exercise requires intra-artetid monitoring during the

procedure. It is therefore more invasive than the previous methods

Contrast echocardiography has been used for many years in patients with congenital heart

disease to detect either left-to-right or right-to-lefi shunt (1 18). In patients with known or

suspected atriai septal defect, contrast echocardiography has been s h o w to be as

sensitive for detecting the resulting right-to-left shunt as invasive shunt assessrnent

performed during cardiac catheterization (1 19), the gold standard for intra-cardiac shunt.

Tbough there were no fdse positives for the detection of atnai septai defect, contrast

echocardiography fiequently detected small right-to-left shunts that were not detectable

using the gold standard. The authors interpreted this to mean that contrast

echocardiography was more sensitive than the gold standard for the detection of very

small shunts. No fdse negatives were observed in this study.

The authors aiso performed con- echocardiography on a control group, 10 patients

schedded to undergo cardiac catheterization for comnary artery disease. There were no

false positives in this group. m e r small study of patients with proven atriai septai

defect reported 100% positivity of contrast echocardiography (1 20). However, the same

authors mentioned that in theù experience they had encountered one patient with proven

atrial septai defect who had negative contrast echocardiography. Though there are no

shidies specifically assessing the sensitivity and specificity of contrast echocardiography

for the detection of intm-cardiac right-to-left shunt, there is a large experience with h i s

procedure. In one study lookllig at the safiety of contrast echocardiography, a total of

5 1,180 examinations were reported, with a side effect rate of 0 .O62% (1 2 1). The reported

side effects in 32 patients included transient arrhythrnias (bradycardia, premature atrial

complexes), TIA, light-headedness, nausea, coughing, shortness of breath, hallucinations

and abdominal pain. Al1 reported side effects were transitory with no long-tem

complications.

The rVst descriptions of the use of contrast echocardiography to detect intrapulmonary

shunt due to puimonary AVMs were in 1978 (122,123). More than ten years later, a

small study of patients with diagnosed puimonary AVMs demonstrated positive contrast

echocardiography in al1 14 patients (124). More recently, a screening study in 25 HHT

patients recommended screening for pulmonary AVMs with contrast echocardiography

(64). These authon could not establish the sensitivity of contrast echocardiography since

only patients with positive con= echocardiography were reported and underwent

diagnostic testing. Patients with negative contrast echocardiography were not reported in

the papa and not investigated finthet. Sensitivity of con- echocardiography is iikely

very high, if performed by an experienced operator, but we camot assume it to be 100%.

in fact, in another article in 1999 (46), only 26 of 29 (90%) patients with known

puimonary AVMs were found to have positive contrast echocardiography. Our group

published, in abstract fom (125), very eariy results from this study suggesting that

con- echocardiography may be very sensitive. There is no data in the literatue

regarding reliability of con- echocardiography interpretation or on the effect of

operator experience, for detection of intracardiac or intrapulmonary shunt.

2.6 Gold standard test for pulmonary arteriovenous malformations.

Diagnostic puhonary angiography is the gold standard for diagnosing pulmonary

AVMs. The advantage of pulmonary angiography over other forms of imaging for

puimonary AVMs is that in angiography, only the blood vessels will be filled by

radiographic contrast and therefore be visible. There is therefore no superimposition of

other structures or confusion with other structures. It is an invasive procedure reqiiuing

catheterization of the pulmonary arteries. In order to catheterize the pulmonary arteries, a

catheter is introduced into a fernord vein and then advanced through the inferior vena

cava, the right atrium and the right ventricle into the pulmonary arteries. Contrast is then

injected to visualise the pulmonary arteries and any AVMs, with sequential radiographic

image acquisition. The radiation exposure associated with diagnostic puimonary

angiography is approximateiy 1-5 rems. For these reasons, puhnonary angiography is not

considend an appropriate screening test for pdmonary AVMs.

The sensitivity of pulmonary angiography has not been assessed, but there are some case

reports of pulmonary AVMs that were missed at angîography. This is likely due to

incomplete angiography, with insuflicient views or too proximal an injection. Specificity

is likely very high since the angiographie appearance of pulmonary AVMs is quite

typical and unlürely to be confused with any other anatomic structure or any other

abnormality. No autopsy studies exist to vaiidate pulmonary angiography as the goid

standard. S m d pulmonq AVMs are difficult to diagnose on pathology unless special

preparation has been performed to prevent blood vessels from coiiapsing post-mortem

( 1 26,127). The architecture necessary to make the diagnosis of pulmonary AVMs on

pathology is lost if the vessels are no longer patent. This lack of sensitivity makes

autopsy a poor gold standard. In other words, pulmonary angiography is more sensitive

than pathology, particularly for srnall AVMs.

An early series of patients undergohg pulmonary angiography to d e out pulmonary

emboiism (N=367) reported mortality (0.2%) and significant rnorbidity (4%) with

diagnostic pulmonary angiography (128). The complications reported included cardiac

perforation, fever, arrhythmia, bronchospasm, angioedema and anaphylaxis. The one

death occurred secondary to cardiogenic shock in a patient with severe puimonary

hypertension complicated by recent acute pulmonary embolism. Technical advances

have led to improvements in these complication rates. In a recent large series (707

patients), there was no mortality, serious complications in 0.1% (bleeding in groin

requiruig surgery) and minor complications (transient angina and heart failure, minor

haematomas, urticaria) in 1.4% (1 29).

2.7 Rationale for screcning for pulmona y arteriovenous malformations.

Puimonary AVMs are frequent in HHT and can cause senous complications. Patients

often expenence M) warning symptoms prior to developing a serious complication.

Effective and safe therapy is available for pulmonary AVMs. For these reasons, early

detection and treatrnent of puimonary AVMs may improve prognosis. Since very small

AVMs can lead to senous compücations, a very sensitive screening test is desirable.

Since pdmonary angiography is invasive and is associated with considerable radiation

exposure, it is not the ideal screening test.

2.8 The problem of verifkation bias

Verification bias, also known as work-up bis, is a type of selection bias that occurs in

diagnostic snidies. This occurs when patients with positive (or negative) diagnostic test

resuits are preferentially referred to receive verification by the gold standard procedure

(130). Verification bias can substantially distort indices of accuracy, with the magnitude

of distortion affected by the protocol used to decide which patients go on to verification.

For example, verification bias is likely responsible for the wide range of sensitivity and

specificity reported for exercise testing for coronary artery disease (1 3 1). In a recent

review, 54% of diagnostic studies were found to be affected by verification bias (1 30).

OAen the issue is not even addressed by the authors, as was the case in al1 of the

aforementioned studies assessing screening tests for pulmonary AVMs.

Some apptoaches to correct for verifkation bias have been recommended in the

Iiterature. One approach is to use long-term follow-up to nile out development of the

disease or its compücations in patients who tested aegative and did not undergo the gold

standard (1 32). Statisticd approaches have also been described, whereby missing data is

inferred ushg different assumptions. One statistical approach used logistic regression to

mode1 the disease status based on diagnostic test results (133). Others have used similar

modellhg techniques but relied on the assumptioa that missing data is missing at random

( 1 34). Unfominately, these approaches have serio us limitations, since they invoive

imputation of data from a part of the distribution where little or no data exists.

CHAPTER 3

METHODS

The objectives of this chapter are to:

1. Describe the patient population and database;

2. Rrvir w îhr scrtening protocol und three specifc screening tests;

3. Expiain the gold standard criterion;

4. Outiine the methodr med io analyre the data.

3.1 Patient population and database

We selected to study ail patients seen at the Toronto HHT C h i c between February 1,

1998 and October 3 1, 1999 with no exclusion criteria. The Toronto HHT Clinic,

established in Febnuiry 1997, is a specialized HHT clhic at St. Michael's Hospital. St+

Michael's Hospital is a tertiary care University of Toronto teaching hospital. The

Toronto HHT Clinic is the only HHT Centre in Canada, though there are three HHT

Centres in the United States. The Toronto HHT Chic is a predorninantly outpatient

prograrn. The mission of the Clinic is to provide muitidisciplinary specialized clinical

care to patients with HHT. This includes screening and treatment for the more serious

manifestations of the disease, which include puimonary and cerebral AVMs.

Patients are r e f e d to the clinic by f d y physicians, geneticists, ENT physicians,

respirologists, neurosurgeons and gastroenterologists. Approximately 40% of the

patients leam of the clinic through the Toronto HHT Centre Website. Approximately

40% of patients are fiom the p a t e r Toronto area, 40% are fiom elsewhere in Ontario

and the fmal20% are fiom out ofprovince.

Patients were ail seen by an HHT physician/respirologist, &ad a thorough history and

physical examination, and underwent screening for pulmonary AVMs on the day of their

initial visit. Mer the initial visit, patient data were entered into the Toronto HHT Clinic

Database as the following variables: Patient ID, Name, Date of Birth, Gender, Height,

Weight, Smoking History, History of Asthma, History of Chronic Obstructive Pulmonary

Disease, HHT Diagnosis, Previous History of pulmonary AVMs, Previous Treatment for

Pulmonaiy AVMs, Previous Stmke, Previous Brain Abscess, Previous Haemoptysis,

Previous Spontaneous Haemothorax, Chest Radiograph, Contrast Echocardiogram as

well as output from the shunt study. Shunt study output hcluded arterial partial pressure

of oxygen while breathing room air (P.02 (RIA)), artenai partial pressure of carbon

dioxide while breathing room air (P,C02 (21 %)), arterial partical pressure of oxygen while

breathing 100% oxygen ( P a (100%)) and partial pressure of carbon dioxide while

breathing 100% oxygen (PaC02 (1 00%)). If patients underwent diagnostic testing, the

following variables were entered: Pulmonary AVM Diagnosis, Other Angiographie

Diagnosis, Nurnber of Pulmonary AVMs, Size of Pulmonary AVMs and Lobes Involved.

The HHT Chic Database is a relational database (Filemaker Pro version 5.0) on a PC.

The database is located in the HHT Office to which only two people have access and is

password protected. Data was recorded by the physician onto a standardîzed f o m and

then entered into the database by one of two data-entry employees. Demographic data as

weil as data on chest radiograph, contrast echocardiogram, shunt test and pulmonas,

angiography were reviewed and corrected in Febnüuy 2000. A 5% enor rate in data entry

was observed. Al1 errors were corrected prior to data analysis. The analysis of the data

recorded in the database was approved by the St. Michael's Hospital Ethics Review

Board.

3.2 Screening protocol

3.2.1 Ovewiew o f specific screening tests

During the first year (Febniary 1997 to Febmary 1998), patients seen at the clinic were

screened for pulmonary AVMs with chest radiography and a shunt study. We will refer

to this population as the "historicd" cohort. Beginning in February 1998, conmt

echocardiography was added to the screening protocol. We will refer to the population of

patients who were screened during this period as the "study" cohort. In al1 patients with

at least one positive screening test, diagnostic pulmonary angiography was

recomrnended. Patients with completely negative screening were assumed to have no

pulmoaary AVMs. The screening tests and pulmonary angiography are described below.

Patients who had been previously treated for pulmonary AVMs prior to their initiai visit

at the Toronto HHT C h i c undenvent the same screeniag in order to detect pulmonary

AVMs that remained patent despite therapy, AVMs that had not been treated or mal1

AVMs which had grown to a size requiring treatment. Patients with a suspicion of HHT

were screened, whether or not they had a definite diagnosis. This screening protocol was

performed as standard clinical care since screening for pulrnonary AVMs is

recommended and a sensitive protocol is desired.

3 2 3 Contrast echocardiography

Contrast echocardiography involves ultrasound visualisation of Uitracardiac air bubbles.

In normd patients, bubbles innoduced through a vein in the ami are visualized in the

right atrium and venûicle and then disappear, as they are captured in pulmonary

capillaries. In patients with pulmonary AVMs, the bubbles pass through the AVMs and

therefore return to the heart and can be visualised in the left atrium and ventricle.

Patients were positioned in the left lateral decubitus position and a standard

echocardiogram was performed by trained technicians. Views were obtained fkom the

parastemal, apical and subcostal regions. Particular attention was focussed on identifying

an intra-cardiac cause of shunting. In each patient a 19 gauge, 2.5 cm intravenous

catheter with a saline lock was placed in the forearm. A tbree-way stopcock was attached

and two lOml syringes were attached to the two other ports. One syringe was empty with

air excluded and the other was full of saline. The contrast (bubbles) was obtaiaed by

flushing the saline fiom one syiinge to another. A forceful hand injection of lOml of

agitated saline was performed while images were obtained simultaneously in the apical

four-chamber view (1 19). Contraindications to contrast injection included intra-cardiac

thrombus or atrial myxoma and were d e d out by a preliminary study.

A positive con- echocardiognun was defined as the appearance of bubbles in the left

atrium fo110wing injection of agitated saline. Appearance of bubbles in the left atrium

was pre-specified to be greater than three cardiac cycles &et fim appeanince in the nght

atrium. This was done to exclude intra-cardiac shunting due to patent fonunen ovale,

atrial septal defector ventricular septal defect. The echocardiognuns were reviewed by an

experienced cardiologist blinded to the clinicai history, oxygen shunt test, chest

raâiograph and puhonary angiogram results. The echocardiograms were rated as

positive, negative or indetedate.

3.2.3 Shunt study

An oxygen shunt study is performed to measure arterial oxygenation in a subject to

detemine whether shunt exists, and then to deteiniine whether this shunt can be corrected

with 100% oxygen. In patients with pulmonary AVMs, shunt should not be corrected by

100% oxygen administration. The oxygen shunt study was first described in 1942 (109)

as a method to mess shunt in a range of diseases. Though these generai principles for

oxygen shunt study have remained the same since the original description, the specifics

of how to administer 100% oxygen were not described in detail the historical paper or

since that time,

uiitiaily a room air artenal blood gas sample was obtained from the radial artery, by an

experienced respiratory therapist. The patient then breathed 100% oxygen for 20 minutes

after which another arterid blood gas was performed, by the same therapist. in order for

inspired air air0 be as close as possible to 100% oxygen, a non-rebreathing demand valve

set-up was irnplernented. This was repticated h m a system established at Yale

University (unpublished). The patient breathed h u g h a mouthpiece with a Ham

Rudolph valve that contained two 1-way valves to mhbke rebreathing of air. Pure

oxygen was suppiied to the Ham Rudolph valve through a demand valve (MTV-1000

ventilator demand valve). The patient wore a nose clip to minimize leak through the nose.

Artenal blood gas samples were collected in Sm1 Concord syringes containhg 33 USP

heparin. nie sample was then injected for analysis into a Nova Medical Ultra E blood

gas machine, to detemiine PaOz, P,C02 and pH. A positive shunt study, was defined as

an alveolar-artenal gradient X75rnmHg on 100% oxygen. This cut-off was based on

local results, using a receiver operating characteristics (ROC) cwe , interpreted to

optirnue sensitivity (1 25). S ince October 3 1, 1999, a different blood gas analysis

machine has been employed (since the clinic changed locations), and therefore the study

population only includes those patients seen prior to October 3 1, 1999.

32.4 Chest ndiogriphy

Since pulmonary AVMs are cornprised of enlarged vessels and an intervening aneurysm,

these structures shouid be detectable on chest radiograph. They should have the density

of vascular structures but be abnormaily enlarged. However, nomial vessels and some

other structures can have a similar density on chest radiography and therefore are

sometimes difficuit to distinguish fiom pulmonary AVMs. Chest radiography is a widely

available test that has been used for many years to detect pulmonary AVMs.

Patients underwent a standard chest radiograph including a postero-antenor view and a

lateral view. No special views or exposures were performed. Chest radiopphs were

interpreted by radioiogists at St Michael's Hospital, The radiotogists were not blinded to

the fact that these were screening tests for HHT patients nor were they blinded to the

resdts of the other screening tests. They were blinded to the results of pulmonary

angiography .

3.3 The gold standard criterion

Pulmonary angiography is the gold standard for diaguosing pulmonary AVMs since it

ailows fluoroscopic visualisation o€AVMs through injection of radiographic contrast uito

the pulmonary d e s . Only vessels that are filled with radiographic contrast are visible

on angiography and therefore superimposition of other structures is not a significant

limitation.

Patients underwent conventional pulmonary angiography (1 29) with a 7-French catheter

introduced into each pulmonary artery under fluoroscopic guidance through the comrnon

femoral vein with an under water seal. A total dose of 40 to 60 ml of iodinated contrast

material was injected for each angiographie nui, at a rate of 20 to 30 ml per injection.

Multiple injections and magnification views were employed as necessary. Al1

angiograms were performed and interpreted by the same radiologist. The angiograrn was

considered positive if any discrete AVMs were Msualised.

3.4 AnalysW

3.4.1 Reiiabiiity analysis

In order to d e t e d e inter-observer agreement, the first 78 echocardiograms were

independently reviewed by a second cardiologist. The second catdiologist was blhded to

the first cardiologist's hterprebtion as well as the redts of screening tests and

puimonary angiography. The echocardiograms were rated as positive, negative or

indeterminate. The inter-observer agreement was calculated ushg the weighted kappa

statisîic.

intersbserver agreement for chest radiography interpretation was determined by having

one of our radiologists interpret a subset of nIms (N=61) that had been initially

interpreted by the study radiologist. Both of these radiologists are very experienced in

detecting pulmonary AVMs on chest radiography. The radiologists scored each chest

radiograph as positive, negative or 44could not d e out pulmonary AVMs". The inter-

observer agreement was calculated using the weighted kappa statistic. The second

radiologist was blinded to the interpretation of the first, as well as the resuits of ail

screening tests and pulmonary angiography. We also had the study radiologist re-

interpret the sarne 61 films, with the same blinding as the second radiologist. We used

this data to calculate inter-observer agreement for the blinded situation as well as intra-

observer agreement.

Reliability testuig was not assessed for shunt study shce the result is numericai, requiring

no interpretation.

3.4.2 Statistical analyshi

Data was anaiyzed us!ng STATA soAware. Sensitivity and specificity for each screening

test are reported with 95% confidence intervals. Confidence intervals were generated

using the binomial equation, with the normal approximation to the binomial distribution.

Al1 pvalues were two-tded. No adjustments were made for multiple comparisons.

3.4.3 Sample size calculation

We guessed that the sensitivity of con- echocardiography for the detection of

pulmonary arteriovenous malfornations might be about 90% in tlus population. We

proposed to nile out a sensitivity of contrast echocardiography of l e s than 80%, since a

sensitivity this low would not be a significant improvement over the current screening

tests. Using the binomial equation for the 95% confidence intervals of sensitivity, we

calculated the required number of diseased patients to be about 35. With a presumed

prevalence of pulnionary AVMs of 30%, we required about 1 17 patients in the study

cohort. In this estimate we have not accounted for verification bias in the sample size

calculation, nor have we considered the importance of a precise estimate of specificity.

3.4.4 Scenario anaiysL

For each screening test, four different scenarios were employed to estimate sensitivity

and specificity, as described below. The 'Vioughtless" estirnate was a direct calculation

of sensitivity and specificity based only on the subjects in the study cohort who

undenvent gold-standard evaluation. For the "dismai" calculation, patients who did not

undergo puimonary angiography but had positive contrast echocardiography were

assumed to be fdse positives and patients who did not undergo pulmonary angiography

and had negative echocardiography were assumed to be false negatives. For the

"pessimistic" estimate, patients with positive echocardiography but no angiography were

distributed between fdse positives and trw positives with the same ratio as those patients

who did undergo angiography (with the same approach to allocate the patients with

negative echocardiography). Finally, for the "euphorie" estimate, patients with positive

echocardiography but no angiography were assumed to be true positives and patients with

negative echocardiography and no angiography were assumed to true negatives.

3A.S.Compa~g screening tests

P-values for comparing the accuracy of the three tests for the '~oughtless" scenario in

the study cohort were obtained using McNemar's test statistic, focusing on those patients

where dieerent tests yielded different results. Since our emphasis is on the sensitivity of

the screening tests, we went on to compare the sensitivity of the ihree screening tests for

the "thoughtless" scenario by using McNemar's test statistic for only those patients with

a positive angiogram. Similady, we also compared the specificity of the three tests using

McNemar's statistic for only those patients with a negative angiogram.

In the same way, sensitivity and specificity for shunt study and chest radiography in the

study C O ~ O ~ were compared to those in the histoncal cohort. Likelihood ratios, positive

and negative predictive values were caicdated for al1 three tests for the "thoughtless"

scenario.

3.4e6 Imputation rnalysh

Sensitivity and specificity were also estimated for the entire triple-screened population by

using logistic regression to predict the outcornes for the patients who did not undergo the

gold standard. Logistic cegression was peâormed by modeling the probability of a

positive angiogram with the three screening test scores as independent variables. Product

interaction terms were also tested as independent variables in the model. The Hosmer-

Lemeshow test was used to assess goodnesssf-fit. Once the model was detennined,

predicted frequencies were calculated for al1 combinations of screening test results. Then

the expected number of patients with a positive angiogram was calculated among patients

in whom the gold standard was not perfomed. From here a new 2x2 table was

constructed from which the sensitivity and specificity were calculated. This estimate was

called the "logistical" estimate.

The objectives of this chapter are to:

List the badine characteristics of the subjects;

Indicare the o bserved prevalence ofpulmonary wteriovenous mul/orrncrtions;

Describe the clinical and angiogiaphic disease severity in the positive patients;

Report reliabiliiy of contrast echocardiography and chest radiography interpretation;

Esritnate sensitivity and specijtcity of the screening tests in four scenarios;

Compare between the three screening tests in the study cohort;

Preseni the sensifivity and specifcity for combinations of the three screening tests;

Compare screening tests in the study cohort to the historical CO hort;

Provide the "logistical" e s t ime for sensitivity and specifcity of echocardiogruphy;

10. Review some ofthe special cases of contrast echocardiogruphy.

4.1 Baseüne char acte ris tic^ of the study population

A total of 288 patients were seen since establishment of the Toronto HHT Clinic in 1997.

During the histoncal intervai (Febniary 1, 1997 to February 1, 1998), when patients were

screened with only chest radiography and shunt test, a total of 82 patients were seen of

whom 74 were screened (seven patients were not screened because HHT was considered

very unlikely; 1 patient was too il1 to undergo screening). During the study interval

(Febniary 1, 1998 to October 3 1, 1999), another 164 patients were seen of whom 143

undenvent aii three screening tests (6 did not have HHT, 8 declined screening, 4 were

lost because contrast echocardiography was not available on the day of their visit, 2 were

too il1 to undergo screening and L had a contraindication for contrast echocardiography).

Patients seen after October 3 1, 1999 were not included, since a dif5erent blood gas

analysis machine was employed d e r Uiis date (the c h i c moved to another site) and

therefore cut-offs became uncertain.

Baseline characteristics of the historical cohort and the study cohort are compared in

Table 1. The two cohorts were not significantly different in terms of average age,

average height and average weight. The two cohorts did not differ significantly with

respect to gender, history of smoking, history of asthma or history of chronic obstructive

pulmonary disease. HHT was definitively diagnosed in the majority of patients in both

cohorts. The prevalence of other HHT manifestations was not significantly different

between the historical and study cohorts, except for a srnall ciifference in the prevaience

of rnucocutaneous telangiectasias (Table 2).

In the snidy cohort of 164 individuals, nine patients had been previously diagnosed and

treated for pulmonary AVMs. In total, four had undergone transcatheter embolotherapy,

two had undergone surgical resection and three had undergone combined therapy. In the

historical cohort of 82 patients, 15 patients had been previously diagnosed and treated for

pulmonary AVMs. Of these, nine had undergone transcatheter embolotherap y, three had

undergone surgical resection and three had undcrgone both.

4.2 Observed prevaknce of pulmonary artcriovenous malformations.

Of the 143 study cohort patients who underwent al1 three screening tests, at lest one

screening test was positive in 77 end diagnostic puimonary angiography was performed

in 65. Of the 66 patients with al1 negative screening tests, five underwent pulmonary

angiography (three of these patients had been felt to have a positive chest mdiograph on

verbal consultation with a radiologist, though the Fmai report was negative, the other two

had borderline shunt studies and it was decided to proceed to angiography). Of the 65

patients who underwent angiography, pulmonary AVMs were diagnosed in 40. This

included eleven patients with residual pulmonary AVMs despite previous treatment and

29 patients with newly diagnosed pulmonary AVMs. The prevalence of pulmonary

AVMs was therefore at least 40/143 (28%) in the study cohort. When we included four

other screened patients with previously successfblly treated pulmonary AVMs, this

estimate of the lower limit of prevalence was 44/143 (3 1 %).

Of the 74 screened patients in the historical cohort, diagnostic pulmonary angiography

was performed in 22. Pulmonary AVMs were diagnosed in 13 patients. This kcluded

eight patients with residual pulmonary AVMs despite previous treatment and five

patients with newly diagnoûed pulmonary AVMs. The prevalence of pulmonary AVMs

was therefore at least 13/74 (1 8%) in the historical cohort. Men we include three other

patients with previously successfblly treated puhonary AVMs this estimate of the lower

b i t of prevalence is 16/74 (22%).

The observed difference in prevalence between the two cohorts did not reach statistical

significance @=O. 15), although it mggests a trend toward higher rates of pulmonary

AVMs for those screened in more recent eras.

4 a 3 Clinical and angiopphic disease severity in positive patients.

Of the 44 patients with pulmonary AVMs in the study cohort, 17 (39%) had a serious

complication pnor to detection of pulmonary AVMs. The specific complications were

stroke in 6144 (14%), transient ischemic attack in those without stroke in 7/44 (16%),

brain abscess in 4/44 (9%), massive haemoptysis in 3/44 (7%) and spontaneous

haemothorax in 2/44 (5%).

Of the 16 patients with pulmonary AVMs in the historical cohort, 9 (56%) had had a

senous complication pnor to diagnosis of pulmonary AVMs. These complications were

stroke in 5/16 (3 1%), transient ischemic attack in those without stroke in 3/16 (19%) and

spontaneous haemothorax in 1/16 (6%). None of these patients had a history of brain

abscess. The observed diflerence in the rate of senous complications did not reach

statistical sîgnificance (p=0.21).

In the study cohort, 34 of the 40 patients (85%) underwent transcatheier embolotherapy

for dieu pulmonary AVMs. The remaining six patients had AVMs that were too small to

be treated at the time of diagnosis. Three of the six patients had ody a positive

echocardiogram, two haà both positive contrast echocardiography and shunt snidy and

one had only a positive shunt study. in the historical cohort, ai i 13 patients (100%)

diagnosed with pulmonary AVMs underwent transcatheter embolotherapy. The observed

difference in treatment rates was not statistically significant @=O. 14).

in the study cohort, 145 pulmonary AVMs were diagnosed in 38 patients, with a mean of

3.8 AVMs per patient. The AVMs of the other two patients were not included in the sum

since they both had innumerable small AVMs. Feeding artery diameter ranged from 1 to

12 mm, with a mean of 3.5 mm (standard deviation=1.7mm). AVMs were bilaterai in

20/40 (50%). In the historicai cohort, 44 pulmonary AVMs were diagnosed in 12

patients, with a mean of 3.7 AVMs per patient. The AVMs of one patient were not

included in the surn since he had innumerable small AVMs. Feeding artery diameter

ranged from 1 to 10 mm, with a mean of 3.7 mm (standard deviation= 1.2rnm). Mean

feeding artery size was not significantly different between the two cohorts. AVMs were

bilateral in 1 1112 (92%). The prevaience of bilaterai AVMs was significantly greater

@<0.0001) in the histoncal cohort than in the study cohort.

4.4 Reliabüity o f contmst echocardiography and radiography interpretation

The inter-observer agreement (weighted kappa) between the two cardiologists for

interpretation of the contrast echocardiography was 0.96 in the first 78 patients screened

with contrast echocardiography. They disagreed on two patients. in the first case, one

cardiologist read the echo as positive and the other cailed it indeterminate due to poor

views. In the second case, one read the echocardiogram as "miidly" positive and the

other as negative. For the anaiysis we coded these two disputed interpretations according

to the M remit.

One radiologist had interpreted the chest radiograph of 79 of the tripie-screened patients.

Of the 79 chest radiograpbs, 61 (77%) were available for interpretation by the second

radiologist. The inter-observer agreement (weighted kappa) between the two radiologists

was 0.46. In 39 cases, the two radiologists agreed. in 20 cases one called the fihn

indeterminate ("cm not nile out pulmonary AVMs'") and the other called the film

positive or negative. In two cases, one called the film negative and the other positive.

The second radiologist had more indeterminate readings (22/61) than the first (6/61), and

less positive (3 1 /6 1) than the fint (4716 1 ). If the indetedate readings were considered

to be positive, each radiologist had 53/61 positive readings. However, these were not dl

in the same patients as the kappa performed in this way was ody 0.34.

4.5 Estimates of sensitivity and specüïcity of screening tests in four scenarios.

Sensitivity of contrast echocardiography was estimated to be 93% when calculated in ail

patients who undenvent triple-screening and angiography. Specifïcity was estimated to

be 40% in the same group. These are c'thoughtiess" estimates (Figure 1) since sensitivity

and specificity were calculated without considering the distribution of the missing data.

M e n the missing data were generated using the c'dismai" scenario, the sensitivity was

estimated to be 34% and the specincity to be 29%. Using the 'bpessirnistic" scenario, the

sensitivity was estimated to be 70% and the specificity to be 78%. Finally, ushg the

"euphoric" scenario, the sensitivity was estimated to be 94% and the specificity to be

84%. Overall, the sensitivity estimates ranged fiom 34% to 94% and the specificity

estimates ranged from 29 to 84%, depending on the scenario.

Sensitivity of shunt study was estimated to be 55% when calculated in dl patients who

underwent triple-screening and angiography. Specificity was estimated to be 64% in the

same group. These are "thoughtless" estimates (Figure 2) since sensitivity and specificity

were calculated without considering the distribution of the missing data. When the

missing data were generated using the "dismal" scenario, the sensitivity was estimated to

be 20% and the specificity to be 48%. Using the "pessimistic" scenario, the sensitivity

was estimated to be 33% and the specificity to be 81%. Finally, using the "euphorie"

scenario, the sensitivity was estimated to be 63% and the specificity to be 91%. Overall,

the sensitivity estimates ranged fiom 20% to 63% and the specificity estimates ranged

from 48 to 9 1%, depending on the scenmio.

Sensitivity of chest radiography was estimated to be 50% when calculated in al1 patients

who tmderwent triple-screening and angiography. Specificity was estimated to be 92% in

the saine group. These are "thoughtless" estimates (Figure 3) since sensitivity and

specificity were calculated without considering the distribution of the missing data.

When the missing data were generated using the "dismal" scenario, the sensitivity was

estimated to be 17% and the specificity to be 82%. Using the "pessimistic" scenario, the

sensitivity was estimated to be 29% and the specificity to be 96%. Finally, using the

"euphonc" scenario, the sensitivity was estimated to k 53% and the specificity to be

98%. Overall, the sensitivity estimates ranged from 17 to 53% and the specincity

estimates ranged fiom 82 to 98%, depending on the scenario.

Using ''thoughtiess" estimates in patients with PAVMs, the sensitivity of contrast

echocardiography was 100% for patients with the largest PAVMs (minimum feeding

ariery diameter~Smm), 95% for patients with medium sue PAVMs (minimum feeding

artery diameter between 3 and 5mm inclusively) and 86% for small PAVMs (minimum

feeding artery diameter<3mm). In the same way, sensitivity of contnst

echocardiography for patients with PAVMs and a history of serious compiicaiion was

94%, compared to 9 1% in those with PAVMs but no complication.

4.6 Cornparison between tests of sensitivity and specificity

We have focused on the cornparison of sensitivity since this is the parameter of interest.

Complete McNemar's test results are illustrated in Figures 4 and 5 for sensitivity but aiso

for specificity and overall accuracy. In the "thoughtless" scenario, the overail accuracy

of contrast echocardiography was not significantly different from that of chest

radiography Q~0.49) or shunt study @=O. 10). in the same scenario, contrast

echocardiography was significantly more sensitive than chea radiography @=0.0001). It

was also significantly more sensitive than shunt study @-0.0006). There was no

significant difference between the sensitivity of chest radiography and shunt study

(g~0.64).

In the 9houghtless" scenario, the specüicity of contrast echocardiography was only 40%.

The specificity of chest tadiography (92%) was significantly greater than the specificity

of contmst echocardiography @=0.0008). There was no signifïcant Merence between

the specificity of conhast echocardiography and shunt study (p=0.13), in this scenario.

The positive likelihood ratio (LR+) for contrast echocardiography was 1.5 (1.1 -2.2) in the

"thoughtless" scenario. The LR+ for shunt study was 1.5 (0.8-2.8) and for chest

radiography was 6.3 (1.6-24.4). The negative likelihood ratio (LR-) for conmt

echocardiography was 0.2 (0.1-0.6). The LR- for shunt study was 0.7 (0.5-1.1) and for

chea radiography \vas 0.5 (0.4-0.8). With an estimated prevaience of jO%, the positive

predictive value for contrast echocardiography was 40% (28-52%), cornpared to 40%

(2647%) for shunt snidy and 71% (48-89%) for chest radiography. The positive

predictive value for contrast echocardiography was not significantly different from that

for shunt study @=0.99) but was significantly lower than that of chest radiography

@=0.02). nie negative predictive value was 93% (78-99%), compared to 78% (65987%)

for shunt study and 8 1 % (7 1089%) for chest radiography. The negative predictive value

for contrast echocardiography was not significantly different from that for shunt study

@=O.OS) or chest radiography @=O. 12).

4.7 Sensitivity and specüicity of dincrent combinations of screening tests.

With contrast echocardiography and chest radiography combined (Figure 6), the

sensitivity was 95% and the specificity was 36%, for the "thoughtless" scenario. This

sensitivity was not significantly greater than the sensitivity of contrast echocardiography

alone WO.3 2). The specificity was not significantiy ciifTiexnt (p=û. 1 6) fiom the

specincity of contnist echocardiography alone.

When contrast echocardiography was combined with shunt study (Figure 6), the

sensitivity was 98% and the specificity was 20%. This sensitivity was not significantiy

greater tban the sensitivity of contrast echocardiography alone @=O. 14). The specificity

was significantly worse e 0 . 0 2 ) for this combination than for contrast echocardiography

alone.

When al1 three tests were combined (Figure 6), the sensitivity was 98% and the

specificity was 16%. This sensitivity was not significantly greater than that for contrast

echocardiography done @=O* 16). This specificity was significantly worse than that for

contrast echocardiography alone (p=0 .O 1 ).

4.8 Cornparison of screening tests in the study cobort and the historical cohort

The sensitivity of shunt shidy was greater in the historical cohort (Figure 7) cornpared to

the study cohort (Figure 2), for the '?houghtless7' scenario @<0.0 1). Specificity of shunt

snidy was not significantly dwerent between the historical and study cohorts, for the

"thoughtless" scenario 0 . 1 ) . There was no significant dwerence in the sensitivity of

chest radiography between the snidy cohort (Figure 3) and the historicd cohort (Figure 8)

for the "thoughtless" scenario WO. 1). Specificity of chest radiography was not

significantly Werent between the historical and stuciy cohorts, for the "thoughtless"

scenario (p=0.08).

4.9 uLogisti~aF estimate of sensitivity and specifieity o f echocardiography

Using logistic regression, the probability of having a positive angiogram was modeled

based on the three screening tests. The p values for contrast echocardiography and chest

radiography were significant (cO.05) and the p-value for shunt study was 0.10 (Table 3).

With this model, 29% of the variance was explained. The Hosmer-Lemeshow goodness-

of-fit test revealed a reasonable fit, with a chi-squared of 0.75 with a p-value of 0.862.

Using the kappa statistic, there was only weak evidence for colinearity arnong the three

tests (kK0.3).

Using the model, predicted fiequencies of diagnosis of pulmonary AVMs for different

combinations of test resuits were calculated (Table 4). Based on these predicted

frequencies, the 2x2 table for conrrast echocardiography vs. angiography results was

modified (Figure 9). This allowed us to estimate sensitivity and specificity of contrast

echocardiography in the whole triple screened group. This is called the "logisticai"

estimate. The estimated sensitivity was 79% and specificity is 79%. For perspective. the

"logistical" estimates for shunt study were 48% and 85% and for chea radiography were

41% and 94%.

4.10 S p i a l cases of coatrast echocardiogirphy.

In two o f the 14 patients with fdse positive echocardiography, the obsewed bubbles were

later attributed to an intra-cardiac shunt (aeiai septai defect). The remaining 12 patients

with fdse positive contnist echocardiography were unexplained. In 2 of the patients who

were diagnosed with pulmonacy AVMs but had negarive contrast echocardiography, the

AVMs detected were very srnaii (1 and 2 mm) and therefore did mt require treatment at

the time of diagnosis. In the one remaining patient false negative case, the contrast

echocardiogram was interpreted as indeterminate. For the purposes of the analyses it was

considered to be negative.

CLIAPTER 5

DISCUSSION

The objectives of this chapter are to:

I. State the principalfiindigs;

2. ûutline how verifcation bias influences the results in the study;

3. Review the "thoughtless " estimates of semitiviry and specifciîy;

4. Review the resulrs of the scenario based approach;

5. Review the r e d s of the imputation analysis;

6. Provide theories for high rate offalse positivity of contrmt echocardiography;

7. Discuss the implications of the stiperior sensitivity of contrast echocardiography;

8. Address the issues of refera1 and spectrum bias;

9. Discuss the other major limitations of the study;

IO. Present arguments for the generalizabili~, ofthe resuits;

I I . Indicate the impact of echocardiography screening on management of diseuse;

I2. Compare the fiasibili~ of the three screening tests;

13. Tramiate findings to dinical pructice;

I 4 Propose future research directions;

1 S. Summarize the principal findings.

5.1 Principal findings.

Puimonary arteriovenous malformations (AVMs) cause serious complications if left

untreated in asymptomatic patients. For ihis reason, early detection of pulmoaary AVMs

in patients with Hereditary Hemordiagic Telangiectasia (HHT) may improve prognosis.

A highly sensitive screening test is desirable to detect even very small AVMs which c m

lead to stmke or cerebral abscess. We have calculated the sensitivity and specificity of

contrast echocardiography for detecting pulmonary AVMs in patients with suspected

HHT, and conclude that it is a fairly sensitive test and is superior to chest radiography

and oxygen shunt testing, though this temains somewhat uncertain due to verification

bias.

5.2 Influence of verifkation bias.

When we calculated the sensitivity of contrast echocardiography without any corrections,

the "thoughtless" estirnate, we obtained a very high sensitivity of 93%. This is likely an

overestimate due to verification bias because ody those patients with at least one positive

screening test were recommended to undergo the diagnostic gold standard, pulmonary

angiography, and only patients who undenvent ppulmnary angiography were included in

the 4'thoughtless" estimate. We would also expect verification bias in this study to lead to

an underestimation of specificity, since most of the patients without disease will not

undergo the gold standard with this type of study design.

Some direct evidence of vetification bias was observed in the cornparisons between the

study cohort and the histo~cai cohort The hding that the sensitivity for shunt study

tended to be higher among the historical cohort compared to the study cohon suggests

that verincation bias may have also idated the sensitivity for th is test. This was so

despite the fact that basehe characteristics of the two cohorts were not signincantly

different. The trend was not as clear for chest radiography. Once conaast

echocatdiography became part of the screening protocol, the observed prevalence of

pulmonary AVMs increased (though not statistically significant), and the estimates of

sensitivity for shunt study decreased by v h e of the cases detected by contrast

echocardiography .

Venfication bias is a problem in analysing many diagnostic tests. Articles often report

the sensitivity and specificity of tests in cohorts afEected by verification bias. In turn, the

over-estimated sensitivity can lead to over-enthusiasm toward implementation of

screening or diagnostic protocols. As discussed in the background section,

methodologists have introduced different approaches to correct for verification bias. One

approach is to obtah long-term follow-up for subjects who have not undergone the

diagnostic gold standard to check for sequelae of disease (1 32). However, long-tem

follow-up data are not available for our study. Another approach has been described by

Zhou' whereby the sensitivity and specificity are corrected using a maximum likelihood

approach. We have not used Zhou's maximum likelihood correction since his approach

requires that the missing data are missing at random (134). This is clearly not a valid

assumption in our study, where patients were selected for pulmonary angiography on the

basis of their screening test resuits. Another statistical approach involves prediction of

missing data h m logistic cegression modelling (133), as used in our approach. The

limitations and assumptions involved in these modelling approaches led us to use a

second approach to the problem involving a scenario based type of sensitivity analysis.

5.3 64Thoughtlessw estimates of sensitivity and specificity

When only patients who had undergone puimonary angiography were analysed (the

''thoughtless" scenario), the sensitivity of contrast echocardiography was quite high at

93%. The sensitivity of conûast echocardiography was shown to be significantly greater

than the sensitivity of chest radiography or shunt study. When combinations of tests

were analysed, no signifcant gain in sensitivity was demonstrated though significant ioss

in specificity occurred. Contrast echocardiography, therefore, appears to be at least as

good a screening test on its own than when it is combined with shunt study a d o r chest

radiograp hy .

5.4 Addressing verification bhs using scenarios

We perfonned a sensitivity analysis using different scenarios, mging from the worst-

case to the best-case distribution of the missing data. Doing so is a stringent evaluation

of the verification bias effect on each of the three tests. Indeed, we observed a wide

range of sensitivity and specifcity for each test when considering al1 scenarios. This

analysis provides w with an original and somewhat soberuig view of the uncertainty in

our '%houghtless" estimate. This broad range has not been appreciated in most diagnostic

studies with verification bias. This d y s i s is perhaps too stringent, since the both the

"euphorie" and "dismal" scenarios are quite unlikely. It is more Iikely that the sensitivity

is with the range between the "pessimistic" and "thoughtless" estimates.

in each scenario, contrast echocardiography was more sensitive than the other two

screening tests. This Werence was significant for the 6'thoughtless'* scenario, as

discussed above. We did not detennine p-values for the cornparisons between tests in the

other scenarios, for two reasons. First, we cannot assume that the distribution of Mssing

data will foiiow the same pattern for both tests. Second, since the data is partidly paired

in these tables, there is no easy way to calculate an appropriate p-value.

5.5 Correcting for verülcation bias using imputation.

Another approach used to correct for verification bias requires imputation. We have used

logistic regression to model the probability of having pulmonary AVMs using the three

screening tests as variables. The model explains a reasonable amount of the variance,

with a significant p-value for contrast echocardiography and chest radiograph but not for

shunt study. Logistic regression diagnostics showed a reasonable goodness-o'fit, using

the Hosmer-Lemeshow statistic. We have used the model to predict the fiequency of

pulmonary AVMs in those subjects who did not have a pulmonary angiogram, in order to

create a complete 2x2 table containhg the missing data. The calculated "logisticai"

estimate of the sensitivity of contrast echocardiography was intemediate between the

"thoughtless" and "pessimistic" scenarios and was about 79%.

One of the problems with imputation is that most of the patients for whom we generated

fkequencies are from a part of the distribution for which we have very linle data In other

words, the majority (78%) of the unverified subjects haci three negative screening tests,

whereas only five of the verified subjects had three negative tests. We have therefore

iittle evidence that these imputed values are accurate. Most of the data regarding

negative screening tests cornes fiom patients who had at least one other positive

screening test. These patients would presumably be more likely to have a positive

angiogram than would those with al1 thcee negative tests. In other words, our mode1

Likely overestimates the probability of pulmonary AVMs among imputed patients and

therefore undereshates the sensitivity. For this reason the "logistical" estimate of the

sensitivity of coatrast echocardiography is impressive given that it is likely an

underestimate. The "logistical" estimate strengîhens our impression that the sensitivity of

contrast echocardiography Iikely lies in the interval between the "pessimistic" and the

"thoughtless" estimates.

5.6 High rate of faise positivity with conhast echocardiography

Contrast echocardiography is sigaificantly less specific than chest radiography in al1 four

scenarios. Similarly, contnist echocardiography is significantly less specific than shunt

study in al1 but the "pessimistic" scenario. One potential explanation for the high false

positive rate with contrast echocardiography is intmcardiac shunt, due to aûial septal

defect or patent foramen ovale. However, most of our patients did not have an intra-

cardiac shunt based on con- echocardiography and pulmonary angiography. Instead,

we wonder whether these patients have microscopie pulmonary AVMs that are too mal1

to visualise on puimonary angiography. Two M e r observations support this idea.

First, di patients who underwent successful üanscatheter embolotherapy or surgery of d l

visible pulmonary AVMs retained positive con- echocardiography after treatment.

Even in patients who have undergone repeat angiography and who have been s h o w to

have no residual AVMs, the conaast echocardiogram remained positive. Second, several

patients with pulmonary AVMs were noted to have tiny AVMs that were only visualised

when a special smaller angiocatheter was inserted hto distal arteries. This distal

catheterization is never done during a standard diagnostic augiography and therefore

these tiny AVMs would go unnoticed with routine pulmonary angiography.

Amther possible explmation for the false positives is that during the saline agitation

process some very small bubbles couid be generated that are smail enough to naverse the

capillary bed. This hypothesis has not been addressed in the literature.

5.7 Implications of the superior sensitivity of contnst echocardiography

Some might argue that contrast echocardiography is an overly sensitive screening test. If

patients with tiny AVMs that are too small for treatment are diagnosed, several negative

repercussions might result. First, patients will have undergone unnecessary pulmonary

angiography, with its small but red risks (129). Second, patients will endure the

detrimentai psychologicai effects of the diagnosis, without king able to benefit fiom

therapy. Third, patients wiii likely undergo M e r subsequent investigations to 'bfollow"

the AVMs.

One benetit of diagnosing pulmonary AVMs that are too mal1 for treatment is that these

patients might therefore receive antibiotic prophylaxis for bacteremic procedures.

niough pulmonary AVMs place a patient at risk for brain abscess and therefore antibiotic

prophylaxis is recommendeà, we do aot have any evidence that such prophylaxis is

beneficid in patients with tiny AVMs. The second potential benefit is that patients with

tiny AVMs WU be foiIowed ard treated when the AVMs potentiaiiy grow to a larger

size, hopefully before any complications occur. The lack of evidence to support these

potential harms and benefits makes it hard to resolve the debate on whether the diagnosis

of tiny AVMs is useful.

5.8 Referrai bias and spectnim bias

Referral bias is a concem in this population, paaicuiarly since the clinic is nui by two

respirologists. The concem would be that patients with pulmonary AVMs are

preferentiaily referred to the clinic, though the clhic mission is to see and screen dl

patients with HHT, whether or not there is any suspicion of pdmonary AVMs. It is

reassuing that the prevaience of pulmonary AVMs in the study cohort is within the range

reported in the medium to large series in the literatwe. The fact that this prevalence in

the study cohort is at the upper limit of the range is not surprishg since patients have

been screened for pulrnonary AVMs in this study, with a diligent protocol. This is a

more likely explanation than referral bias for the high prevalence.

The ciinicai and pathologie spectrum of pulmonary AVM disease in the study cohort are

similar to those in the historical cohort and to those in the large series of HHT patients

reported in the literature. The rate of serious complications fiom pulmonary AVMs prior

to screening was 38% in the study cohort and 56% in the histoncal cohort. These rates

are not statistically significantiy different and are simiiar to those reported in the

literature. The trend towards a lower rate of serious complications in the study cohort is

not surprishg since the goal with more semitive screening is to detect more patients with

asymptomatic disease. The comparability of the serious complication rate to that in the

literature is evidence that we have tested contrast echocardiography in a population of

patients with appropriate clinical spectnun of disease. In tems of pathologic specLnim of

pulmonary AVM disease, we reported similar n u m h of AVMs per patient as other

series in the literature (21,45) and between our two cohorts. Mean AVM feeding artery

diameter was not significantly diffennt between the two cohorts, though can not easily be

compûred to any series in the literature, since other authors did not provide this rnean.

We do know that pulmonary AVMs diagnosed on pulmonary angiography in our study

mged in size (feeding artery diameter) fiom 1 to 12 mm. This is comparable to the size

range reported in the literature. Finaiiy, sensitivity of contrast echocardiography did not

change significantly with size of PAVMs or history of complications, though the trend

was toward greater sensitivity in the patients with more severe disease. For these

reasons, we conclude that specmim bias is not a significant problem in out study and

does not limit the generdizability of our results.

5.9 Other major limitations of the study

The most important limitation ofthis study is the venfication bias inherent to the design,

as we have discussed above. Another limitation is sample size. Though our sample size

(N=143) was greater than required (N=l17) based on the sample size calculation,

verification bias had not been taken into account. Despite this, we were able to

demonstrate that the sensitivity of contrast echocardiography was signifcantly greater

than that of chest radiography or shunt study. If sample size had been greater, we may

have seen a significant Unprovernent in sensitivity with combinations of tests as

cornparrd to con- echocardiography.

hterpretation of contrast echocardiography was blinded, though interpretatim of chest

radiography was not. This is may have led to an overestimation of the sensitivity of chest

radiography. This is would only strengthen ou. conclusion than contntst

echocardiography is more sensitive than chest radiography.

hterpretation of shunt study was not subjective and so blinding was unnecessary.

However, shunt study results are poorly reproducible (135) for several reasons. It is

technically dificuit to completely isolate expired and inspued air that is necessary in

order to adrninister exactly 100% oxygen. The apparatus that was constructed to best

approximate the delivery of 100% oxygen is prone to leaks, which can be dificult to

detect. The artenal blood gas obtained while the patient breathes 100% oxygen contains

a very high Pa02. This is unstable and within minutes the Pa02 can decrease by more

than 30 mm Hg. This instability is likely more severe if there is any air leA in the blood

gas syringe. Furthemore, high Pa02 standards do not exist, due to their instability, for

calibration of the blood gas machine for high Pa02 readings. The highest Pa02 standard

available is for 200 mm Hg, whereas Pa02 on 100Y0 oxygen should theoretically be oear

600 mm Hg. For al1 of these reasons, the shunt study tends to overestimate shunt and

therefore we have not used a theoretical cut-off value for the shunt study but rather have

used a reasonable cut-off based on an ROC curve, determined in a previous study.

We have not assessed the influence of patient and procedure characteristics on sensitivity,

specificity anci reliability of the three screening tests. Patient obesity or poor

echogenicity, for example, rnay have led to fdse negative contrast echocardiography

results. Procedural factors, such as insunicient agitation of saline, may also have led to

false negative results. The effect of these factors is dificult to estimate due to the

verification bias in the study. However, it is somewhat reassuring that few patients were

diagnosed on the basis of shunt test aione, the only test which would not be affected by

obesity. Patients with intracardiac shunt may have led to fdse positive

echocardiography, as discussed in section 5.6. There are no known procedure related

factors that would be likely to cause fdse positive results of contrast echocardiography.

For chest radiography, we suspect that obesity, increased breast tissue and presence of

other lung disease might have led to some of the false negatives. We did not assess

procedure characteristics, but the procedure is generally well standardized for chest

radiography. For the oxygen shunt test, we do not suspect patient factors to be important,

but procedural factors limiting ability to administer 100% oxygen and measure high

Pa02 levels probably contributed to the poor sensitivity, specificity and reproducibility of

the test.

We have not assessed patient disutility for contrast echocardiography but the literature

suggests that contrast echocardiography is a well-tolerated procedure. We have also not

addressed cost effectiveness of screening nor have we fomally assessed d e t y of

contrast echocardiography or other tests.

5.10 Arguments Cor genemlizabiiity of the nsults

We believe that the results of this study cm be reasonably generaiized to screening for

Canadian HHT patients. Of the 164 patients seen during the study period 143 (87%)

underwent triple screening, therefore the triple screened population is reasonably

representative of the study cohort. Also, a reasonably representative proportion of

patients (78%) with at least one positive screening test underwent diagnostic

angiography. in other words, apart from the issue of verification bias, the results can be

generalized to the population of patients seen at the HHT clinic for screening.

Cornparison to the histoncal cohort reveals no significant ciifferences in baseline

characteristics compared to the study cohort. Furthemore, rates of other HHT disease

manifestations are not significantly different between the two cohorts, except for a small

difference in the rate of mucocutaneous telangiectasia. The rates are also similar to those

reported in other large series of HHT patients. This suggests that these results can be

generalized to HHT patients seen in tertiary care HHT centres for screening. Though

there is a greater proportion of women than men in the study cohort and in the histoncd

cohort, we believe that this is probably due to the fact that women are more likely to seek

preventative medicine than men and therefore we do not feel that this compromises

generalizability of the redts. This gender distribution is aiso similar to that in most

other HHT series (3,21,63,64).

5.11 Impact of echocardiogrphy ~reening on management of disease

Patients who were diagnosed with puimonary AVMs after positive screening contrast

echocardiography went on to have treatment of the AVMs, in 93% of cases. The

screening test did therefore influence treattnent decisions for these patients. However,

the design of this study did not allow us to assess an improvement in outcornes.

5.12 Feasibility of the three scmning tests

Contrast echocardiography is a feasible screening test for pulmonary AVMs in patients

with HHT. We have demonstrated that contrast echocardiography is a reproducible

screening test for pulmonary AVMs in patients with HHT. The weighted kappa was

excellent reflecting near perfect intersbserver agreement. Though interpretation of

contrast echocardiography is probably somewhat operator-dependent, we suspect that the

Iearning curve is steep, since we have observed such a high kappa in the frst 78 patients.

Contrast echocardiography is also a relatively inexpensive test available in most

hospitals. The cost of performance and interpretation of contrast echocardiography is

approximately $280 in Canada

We believe that sensitivity is the single most important characteristic of a screening test

for pulmonary AVMs in HHT patients. This has k e n our focus, rather than positive

likelihood ratio or positive predictive value because our purpose was to d e t e d e

whether or not contrast echocardiography is a desirable screening test for a population of

patients with HHT. Though not our primary objective, we can estimate the usefùiness of

contrast echocardiography for a given patient. The negative predictive value of contrast

echocardiography, in the Wtoughtless" senario was reasonable at 93% and not

signincanily Metent h m diat of the other two tests. The positive Wrelihood ratio for

contrast echocardiography was poor at 1.5, however, the negative likelihood ratio of 0.2

is more useful. AU of the combinations of screening tests have poor positive and

negative iikelihood ratios.

The likelihood ratios and predictive values were not calculated for contrast

echocardiography in the other scenarios since verification bias woufd be expected to

affect sensitivity and specificity differently and therefore its effect on likelihood ratios

becomes compiex and the caiculated ratios are difficult to interpret.

Chest radiography appeared to be the least sensitive screening test of the three.

Moreover, even between our two radiologists experienced in detecting pulmonary AVMs,

inter-observer agreement was only moderate. This is consistent with kappas for chest

radiography (0.48-0.68) in other diseases (136,137,138) and may be related to biologic

variation in the senses of the examiner as well as entrapment by prior expectation. The

positive likelihood ratio of chest radiography (6.3), using the 'Vioughtless" scenario, has

interesting clinical relevance however.

Our nported sensitivity of chest radiography for the detection of pulmonary AVMs in a

screening protocol in a tertiary care centre for the treatment of HHT should not be

generalized to other clinical contexts, such as the use of '"routine" chest radiogiaphy

interpreted by an unsuspecthg tadiologist. The study radiologists were not only

experienced in diagnosing pulmooary AVMs but dso were aware of the diagnosis of

HHT. For this reason the sensitivity of chest radiography for detecting pulmonary AVMs

calculated in this study is greater than it would be ifwe were to measure the sensitivity of

chest radiograph as interpreted by a radiologist with little experience in detecting

pulmonary AVMs. The sensitivity would clearly be even lower for a "routine" chest

radiograph interpreted without the knowledge that the patient has HHT. We have not

attempted to address this clhical problem, but rather have focused on the sensitivity of

testing in a centre experienced in HHT.

We did not find the oxygen shunt study to be a very useful test. It was neither as

sensitive as con- echocardiography nor a specific as chest radiography. Its

combination with contrast echocardiography was not significantly better than contrast

echocardiography alone. This may have k e n partly due to poor reproducibility of the

test and the cut-off values selected for the shunt study in our institution. Overail, the

shunt study does not perform well as a screening test, since it is poorly reproducible,

underestimates Pa02 and overestimates shunt. Finally, the oxygen shunt test is

uncornfortable for the patient.

5.13 Implications for Clinical Practice

Since contnist echocardiograpby appears to be more sensitive than the other two

screening tests, a logicd approach would be to screen HHT patients with contrast

echocardiography alone. However, verifkation bias and small sample size may have

prevented us from obseMng incremental benefit with shunt test or chest radiography.

Furthemore, the %oughtless" negative predictive value is not as hi& as we

conventionaüy require (95%) for a scrrening test for a severe disease. I f we address the

problem by looking at the usefulness for a specific patient, including chest radiography in

the screening protocol becomes interesting. Shce its positive likelihood ratio is high,

patients could be screened with chest radiography first and then go dkectly to diagnostic

angiography if positive. If the chest radiography were negative, the patient would then

go on to contnist echocardiography.

5.14 Future research

Future research will help address the major limitation of this study, verification bias.

Long-terni follow-up of the study cohort will help to correct for verification bias.

Screened negative patients will be followed for development of symptoms, signs or

complications of pulmonary AVMs. They will also be screened again in Five years.

Follow-up will also help to confimi that these screened and treated patients develop no

M e r neurological complications.

There are several other directions which future research should take to improve our

understanding of conaast echocardiography as a screening test for pulmonary AVMs.

We should address the issue of the high false-positive rate of contrast echocardiography.

A protocol involving selective catheier angiography in these patients would help to

a m e r the question about whether or not dl of these patients have tiny pulmonary AVMs

undetected on standard diagnostic angiography. Another helpful study would involve a

group of non-HHT patients that would be studied to detemine whether positive contrast

echocardiography occurs in the nonnai population without aay intxacardiac shunt It

wouid also be very usefiil to deveIop an adequate scoring system for contrast

echocardiography. If the false positives had, for example, al1 the lowest scores, we could

establish a cut-off value to guide decisions about the necessity of pulmonary

angiography. Assessing patient utilities for screening tests as well as for outcornes of

screening and treatment is one way in which we plan to m e r characterize the role of

contmt echocardiography as a screening test for pulmonary AVMs.

Finaily, ongoing studies in the HHT mouse will hopeiùily shed light on the development

of pulrnonary and other AVMs. We suspect that microscopie pulrnonary AVMs form

during embryogenesis and then grow during life. The growth rate likely depends on

many environmentai factors, though these remain to be elucidated.

5.15 Summary of principal dadings

In surnmary, contmst echocardiography is a sensitive screening test for puhonary AVMs

in patients with HHT. When venfication bias is not considered, the sensitivity of conûast

echocardiography is estimated to be 93%. However, there is considerable verification

bias in this analysis. With two different approaches to correcting for verification bias, we

estimate that the sensitivity is between 34 and 94%, and is most likely between 70% and

93%. The specificity is also close to 80%. We have demonstrated that it is more

sensitive than chest radiograph and oxygen shunt study. A highiy sensitive test is desired

in order to avoid missing and patients with pulmonary AVMs, so that preventative

therapy can be instituted in a timely manner.

Table 1. Baseüne charicteristics of the hltorical and study cohorts.

Characteristic

' age (years) mean age (95% CI)

I 1 - -

1 COPD 1 0.026 1 0.007 1 0.23

height (cm) mean height (95% CI) smoker (%) female (%) asthma

Historical cohort N=82 40.1 37.1-43.2

' 167.5 I 1

1 1 1 HHT definite 1 0.74 1 0.68

Study cohort N=164 41.4 38.7-44.2

165.2-1 69.8 0.44 0.69 0.22

. --

0.34

p-value

0.55

COPD=chronic obstructive pulmonary disease

167.9 166.2-1 69.7 0.4 1 0.64 0.18

0.77

0.6 1 0.49 0.46

Table 2. Spechim of Hlïï diseaae in atudy and historical cohorts.

1 Manifestation 1 Historical(%) 1 Shidy (%) 1

1 ~ i v e r AVMs 1 4 1 4 1 I I

*p<0.05 HHT=Hereditary Hemorrhagic Teeiangiectasia AVMs=arteriovenous malformations

- - -

3 9

64* 67

. -

Cerebrai AVMs Gastrointestinal bleeding Telangiectasia Epistaxis

8 1 6 78 60

Tabk 3. Logistic Regression Mode1 for the probabüity of diagnosing pulmonary AVMs baseà on the 3 scncning tests. This calculation was perfonned using the 65 subjects who were triple-screened and had a pulmoaary angiogram.

R2=0.29

echo=conüast echocardiography ; xraFhest radiography ; shun~shunt study

Variable echo *raY shunt test

Coefficient (95% CI) 2.22 (0.57,3 36) 2.37 (0.67,4.07)

Odds Ratio (95% CI) 9.17 (1.77,47.35)

10.65 (1.95,58.32)

I P

0,008 0,006

1 .O6 (-0.22,2.34) 1 2.88 (0.80,10.33) 0.1 04

Table 4. Predicted fnquencies of diagnosis of pulmonary AVMs, based on logistic regmaion model.

Test

ody echo positive only xray positive ody shunt positive on& echo i d nntv wsitive only echo and shunt positive oniy xray and shunt positive aîi three positive --

al1 three negative

Frequency Observed Frequency

0.47 0.00 0.17 0.89

1 0.20

*number of patients who did not undergo pulmonary angiography, for whom the redicted fiequency is therefore used in the logistic 2XZ table. 6 number of patients who undenvent pulmonary angiography, fmrn whom the observeci frequency is calculated.

echo=contnist echocardiography; xraychest radiography; shunt=shunt study

Figure 1. Sensitivity and Specificity of Contrast ~chocardiognphy*~. Sensitivity and specificity are reported with 95% confidence intervals.

Pessimis tic

Euphorie

6 1 Sensitivity=94% (87- 1 0 1 %)

79 82 Specüicity=84% (77992%)

*data apply to triple-screened study cohort (W143) in total, 65 patients underwent angiography and 78 did not undergo angiography.

berall, 61 patients had a positive contrast echocardiogram of which 52 underwent mgiography A overail, 82 patients had a negative contcast echocardiogram, of which 13 underwent angiwaphy 'confidence intervals sometimes include vaiues> 100% due to normal approximation of the binomial distribution angio==u.imonary angiography echo=contrast echocardiography

Figure 2. Sensitmty and Specüicity of Shunt studyf '. Sensitivity and specificity are reported with 95% confidence intervals.

Thoughtless

Pessimistic

Eupboric

*data apply to triple-screened study cohort (N443). in total, 65 patients underwent angiography and 78 did not undergo angiography.

# overall, 39 patients had a positive shunt study, of which 3 1 underwent angiography. ' overall, 104 patients had a negative shunt study, of which 34 underwent angiography. angio==uim~nary angiography shuneshunt study

Figure 3. Sensitivity and Specificity of Chest RadiographyfS. Sensitivity and specifkity are reported with 95% confidence intervals.

Pessimistic

25.0 Sensitivity=290/0 (1 9039%) 1 1 8.0 Specüicity=96% (92- 1 O 1 %)'

77.6 65.4 1 43 .O

Euphorie

25 Sensitivity=53% (3948%) 1 18 Specülcity=98% (95- 10 1 %)'

*data apply to triple-screened study cohort (N=143). in total, 65 patients underwent angiography and 78 did not undergo angiography. ' overall, 25 patients had a positive =y, of which 22 underwent mgiography. overall, 1 18 patients had a negative xray, of which 43 underwent angiography.

Sconfidence intervals sometimes include values>lOO% due to the normal approximation of the binomial distriiution aogio==ulmonary angiography xray==hesî radiograph

Figure 4. Cornparison Between Contmst Echocardiography and Shunt Study Using McNemar's Test.

In all patients in the "thoughtless" scenario:

In only those patients with a positive a n g i o m :

In only those patients with a negative angiogram:

# shunt or echo was correct @shunt was positive 'echo was positive echo=contnist echocardiography; shunt~shunt snidy

Figure 5. Cornparison Between Contrast Echocardiography and Chat Radiography Using McNemar9s Test.

In aîi patients in the 'Viou~tless" scenario:

In only those patients with a positive angiogram:

In O& those patients with a nepiative angiogt.am:

'xray was correct # echo was correct @xtay was positive 'echo was positive xray=chest radiography; echo=contnist echocadiography.

Figure 6. Sensitivity, specificity, ükeühood ratios and predictive values for combinations of the scmnùig tests, using the uthoughtless" scenario.

Combination #l: Positive Test: echo or shunt positive; Negative Test: echo and shunt negative tl Sensiîivity=98% (93- 102%)'

39 20 59 Specüicity=20% (436%) 6 LR+1.22(1.00-1.49) LR-=0.13(0.02-1.01)

PPV=66% (54978%) NPV=83% (54- 1 1 3 %)' 40 25 65

Combination #2: Positive Test: echo or xray positive; Negative Test: echo and xray negative 41 Sensitivity=95% (88- 102%)'

38 16 54 Specif1city=36% (1 7055%) i i LR+-l.48(l.lO-2.Ol) LR- =0.14(0.03-0.59)

PPV=70%(58-83%) NPV=82% (59- 105%)' 40 25 65

Combination #3: Positive Test: shunt or xray positive; Negative Test: shunt and xray negative

SensitiMty=75% (6248%) 4 1 Speciacity-56% (37-75%) 24 LR+-1.70(1.06-2.75) LR-=0.45(0.24-0.85)

PPV=73% (6047%) NPV=58% (39.78%) 40 25 65

Corn bination #4: Positive Test: echo, xray or shunt positive; Negative Test: echo, xray and shunt negative

Sensitivity=98% (93- 1 02%)' + jg 21 60 Specificity=16% (2.30%) - 1 4 5 LR+Sl.i6(0.97-i.39) LR-=0.16(0.02-1.32)

PPV45%(53-77%) NPV=85%(45-11~%)~ 40 25 65

Sconfidence intervais sometimes include valuee 100% due to the normal approximation of the binomial distribution angio==uimonary angiography; echo=contnist echocardiography; myehest radiogaphy; shuntdmt study; LR+cpositive iikeLihood ratio; LR-aegative likelihood ratio; PPV=positive predictive valw; NPV=negative predictive value.

Figure 7. Semitivity and Specificity for shunt study in the historieal cohort*q Sensitivity and specificity are reported with 95% confidence intervals.

*data apply to the screened histoncal cohort (N=74). in total, 22 patients underwent angiography and 52 did not undergo angiography.

l# overail, 22 patients had a positive shunt study, of which 13 uaderwent angiography. LoveraIl, 52 patients had a negative shunt study, of wbich 9 underwent angiography. 'confidence intervals sometimes include value9 100% due to the nomial approximation of the binomial distribution angio==uimonary angiography shuntshunt study

Figure 8. Sensitivity and specificity for chest radiography in the bistorical c ~ h o r t * ~ . Sensitivity and specincity are reported with 95% confidence intervals.

*data apply to the screened historical cohort (N=74). in total, 22 patients underwent angiography and 52 did not undergo angiography.

# oved, 13 patients had a positive shunt study, of which 9 undervuent angiography. ' o v e d , 61 patients had a negative shunt study, of which 13 underwent angiography. 'confidence intervals sornetimes include value~lûû% due to the nomal approximation of the binomial distribution anpio==uimonary angiography

Figure 9. 'LogUticaP estimates of sensitivity and specifieity. The "logistical" estimates of sensitivity and specificity of the k e e screening tests in the triple-screened group were generated using predicted frequencies fkom logistic regression*.

Conmst echocardiography

6 1 .O Sensitivity-79% (68990%) 82.0 Spdfki@=79% (70987%)

Shunt study

39.0 Sensitivity=48% (4 1 -55%) 104.0 Specifieity=BS% (72099%)

*confidence intervals were calcuiated using the binomial equation and do not include uncertainty fiom the prediction process. *confidence intervals sometimes include values>lOO% due to the normal approximation of the binomial distribution angio==uimoonary angiography ; echosontrast echocardiography; xray-chest tadiography; shuntshunt study

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