Doppler trans‐thoracic echocardiography for detection of pulmonary hypertension in adults
Appendices
Appendix 1. World Health Organization (WHO) functional classification for pulmonary hypertension
| Class | WHO functional classification for pulmonary hypertension |
| I | Patients with pulmonary hypertension but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue or dyspnoea, chest pain, or heart syncope. |
| II | Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in undue fatigue or dyspnoea, chest pain, or heart syncope. |
| III | Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less‐than‐ordinary physical activity causes undue fatigue or dyspnoea, chest pain, or heart syncope. |
| IV | Patients with pulmonary hypertension resulting in inability to carry on any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea or fatigue, or both may be present even at rest. Discomfort is increased by physical activity. |
Appendix 2. MEDLINE (Ovid) search strategy
1. exp Hypertension, Pulmonary/
2. Pulmonary Heart Disease/
3. (pulmonary adj3 hypertens$).tw.
4. pulmonary vascular disease.tw.
5. or/1‐4
6. exp Echocardiography/
7. (echocardiogra$ or echo‐cardiogra$).tw.
8. doppler.tw.
9. or/6‐8
10. 5 and 9
11. Animals/ not (Animals/ and Humans/)
12. 10 not 11
Appendix 3. Data extraction sheet
| Study ID | ______________________________________ |
| Report ID | ______________________________________ |
| First author | ______________________________________ |
Study eligibility
| Type of study Is the study a diagnostic test accuracy study? | Yes | Unclear | No |
| Next question | Next question | Exclude | |
| Is the study a diagnostic case‐control study (two‐gate design)? | Yes | Unclear | No |
| Exclude | Next question | Next question | |
| Participants Were the participants suspected as having pulmonary hypertension? | Yes | Unclear | No |
| Next question | Next question | Exclude | |
| Were the participants already diagnosed with pulmonary hypertension? | Yes | Unclear | No |
| Exclude | Next question | Next question | |
| Index tests Did the study evaluate pulmonary arterial pressure by Doppler echocardiography against the reference standard? | Yes | Unclear | No |
| Next question | Next question | Exclude | |
| Target conditions Was the aim of the diagnostic test to confirm pulmonary hypertension? | Yes | Unclear | No |
| Next question | Next question | Exclude | |
| Reference standard Was right‐heart catheterization performed as a reference standard of pulmonary hypertension? | Yes | Unclear | No |
| Next question | Next question | Exclude | |
| Was the reference standard threshold different to 25 mmHg? | Yes | Unclear | No |
| Exclude | Next question | Next question | |
| Were the index test and reference standard performed within one week? | Yes | Unclear | No |
| Final decision | Include | Unclear | Exclude |
If the study is to be excluded, record the reason and details to add to 'Table of excluded studies.'
Appendix 4. Table of excluded studies
| Study ID | _________________________________________________________________ |
| Report ID | _________________________________________________________________ |
| Review author name | _________________________________________________________________ |
| Reason for exclusion (e.g. right‐heart catheterization was not reference standard) | _________________________________________________________________ |
Appendix 5. General information
| Study ID | __________________________________________________________________________ |
| Report ID | __________________________________________________________________________ |
| Review author name | __________________________________________________________________________ |
| Authors | __________________________________________________________________________ |
| Contact address | __________________________________________________________________________ |
| Country of the study | __________________________________________________________________________ |
| Language of publication | __________________________________________________________________________ |
| Participants | |
| Age (mean, median, range) | ______________________________________________________ |
| Sex (male numbers/%) | ______________________________________________________ |
| BMI | ______________________________________________________ |
| Study characteristics | |
| Design (prospective or retrospective) | ______________________________________________________ |
| Single or multicenter? | ______________________________________________________ |
| Inclusion criteria of participants | ______________________________________________________ |
| Classification of PH defined by WHO | ______________________________________________________ |
| Total number of participants | ______________________________________________________ |
| Total number of intubated patients | ______________________________________________________ |
| Index test (method to estimate right atrial pressure) | ______________________________________________________ |
| Index test (cut‐off to declare PH) | ______________________________________________________ |
| Index test (estimated mean systolic pulmonary arterial pressure) | ______________________________________________________ |
| Reference standard (threshold to define PH) | ______________________________________________________ |
| Reference standard (mean systolic pulmonary arterial pressure) | ______________________________________________________ |
| Time gap between index and reference standard | ______________________________________________________ |
| Study outcome (number of people) | |
| PH exists and correct detection by echocardiography (i.e. true positive of the test) | ______________________________________________________ |
| PH does not exist but interpreted as pulmonary hypertension (i.e. false positive of the test) | ______________________________________________________ |
| PH exists but failed to detect by echocardiography (i.e. false negative of the test) | ______________________________________________________ |
| PH does not exist and correctly detected by echocardiography (i.e. true negative of the test) | ______________________________________________________ |
| Total number of participants whose results of index test were uninterpretable | |
| Total number of participants whose results of reference standard were uninterpretable | |
| How uninterpretable results were handled within the analyses | |
| Additional information | |
| Conflict of interest | ______________________________________________________ |
BMI: body mass index: PH: pulmonary hypertension; WHO: World Health Organization
Appendix 6. Study quality assessment form (QUADAS‐2)
| Domain 1: Patient selection | |
| A. Risk of bias | |
| Describe methods of patient selection: | |
| ···· Was a consecutive or random sample of patients enrolled? | Yes/No/Unclear |
| ···· Did the study avoid inappropriate exclusions? | Yes/No/Unclear |
| Could the selection of patients have introduced bias? | RISK: LOW/HIGH/UNCLEAR |
| B. Concerns regarding applicability | |
| Describe included patients (prior testing, presentation, intended use of index test and setting): | |
| Is there concern that the included patients do not match the review question? | CONCERN: LOW/HIGH/UNCLEAR |
| Domain 2: Index test (echocardiography) | |
| A. Risk of bias | |
| Describe the index test and how it was conducted and interpreted: | |
| ···· Were the index test results interpreted without knowledge of the results of the reference standard? | Yes/No/Unclear |
| ···· If a threshold was used, was it prespecified? | Yes/No/Unclear |
| Could the conduct or interpretation of the index test have introduced bias? | RISK: LOW/HIGH/UNCLEAR |
| B. Concerns regarding applicability | |
| Is there concern that the index test, its conduct, or interpretation differ from the review question? | CONCERN: LOW/HIGH/UNCLEAR |
| Domain 3: Reference standard (right‐heart catheterization) | |
| A. Risk of bias | |
| Describe the reference standard and how it was conducted and interpreted: | |
| ···· Were the reference standard results interpreted without knowledge of the results of the index test? | Yes/No/Unclear |
| ···· Were the criteria of reference standard for target condition prespecified? | Yes/No/Unclear |
| Could the reference standard, its conduct, or its interpretation have introduced bias? | RISK: LOW/HIGH/UNCLEAR |
| B. Concerns regarding applicability | |
| Is there concern that the target condition as defined by the reference standard does not match the review question? | CONCERN: LOW/HIGH/UNCLEAR |
| Domain 4: Flow and timing | |
| A. Risk of bias | |
| Describe any patients who did not receive the index test(s) and/or reference standard or who were excluded from the 2x2 table (refer to flow diagram): Describe the time interval and any interventions between index test(s) and reference standard: | |
| ···· Was the interval between the index test and reference standard less than one day? | Yes/No/Unclear |
| ···· Did all patients receive the same reference standard? | Yes/No/Unclear |
| ···· Were all patients included in the analysis? | Yes/No/Unclear |
| Could the patient flow have introduced bias? | RISK: LOW/HIGH/UNCLEAR |
Appendix 7. Study quality assessment details
Domain 1: Patient selection
Risk of bias: Could the selection of patients have introduced bias?
Signaling question 1: Was a consecutive or random sample of patients enrolled?
Signaling question 2: Did the study avoid inappropriate exclusions?
Studies that make inappropriate exclusions, for example excluding 'difficult to diagnose' patients, whose image of echocardiography is difficult to detect due to obesity or overinflated lungs, may result in overoptimistic estimates of diagnostic accuracy. We will classify the studies as 'yes' if all patients were included in the study regardless of clinical suspicion following index test, 'no' if they conduct any inappropriate exclusions, for example excluding patients with low clinical suspicion based on index test, and 'unclear' if this information is not clear.
Applicability: Are there concerns that the included patients and the setting do not match the review question?
If studies include only a clinically relevant population that would have undergone index test in real practice and includes representative form of target condition, we will assess as 'low' concern. If the study population differed from the population defined in the review question in terms of demographic features (e.g. studies include mainly younger patients or specific group of WHO classification), we will assess as 'high' concern. If this information is unclear (e.g. WHO classification was not reported), we will assess as 'unclear'.
Domain 2: Index test
Risk of bias: Could the conduct or interpretation of the index test have introduced bias?
Signaling question 1: Were the index test results interpreted without knowledge of the results of the reference standard?
Signaling question 2: If a threshold was used, was it prespecified?
We will classify the study as 'yes' if echocardiography results were interpreted without knowledge of the reference standard, 'no' if the echocardiography tests were interpreted with knowledge of the reference standard results, and 'unclear' if this information is not clear. We will classify the study as 'yes' if a threshold was prespecified, 'no' if authors selected a cut‐off value based on the analysis of data collected, and 'unclear' if insufficient information is provided.
Applicability: Are there concerns that the index test, its conduct, or its interpretation differ from the review question?
We will include studies where systolic pulmonary artery pressure calculated from the maximum tricuspid regurgitation jet velocity by using the modified Bernoulli equation and adding right atrial pressure (RAP) evaluation of pulmonary artery pressure by echocardiography is an index test regardless of threshold, and we will include index tests using various RAP estimation methods. However, the most common method is using the diameter and collapse of the inferior vena cava during spontaneous respiration. We will therefore judge studies where RAP was estimated by using the diameter and collapse of the inferior vena cava during spontaneous respiration as 'low' concern, those where RAP was estimated by using any other method as 'high' concern, and 'unclear' concern if this information is not clear.
Domain 3: Reference standard
Risk of bias: Could the reference standard, its conduct, or its interpretation have introduced bias?
Signaling question 1: Were the reference standard results interpreted without knowledge of the results of the index test?
Signaling question 2: Were the criteria of reference standard for target condition prespecified?
We will classify the study as 'yes' if right‐heart catheterization results were interpreted without knowledge of the index test, 'no' if right‐heart catheterization was interpreted with knowledge of the index test results, and 'unclear' if this information is not clear. We will classify the study as 'yes' if the criteria of reference standard for target condition were prespecified, 'no' if the criteria of reference standard for target condition were not prespecified, and 'unclear' if this information is not clear.
Applicability: Are there concerns that the target condition as defined by the reference standard does not match the question?
The target condition is pulmonary hypertension defined as mean pulmonary artery pressure assessed by right‐heart catheterization of 25 mmHg or higher (Hoeper 2013). Use of right‐heart catheterization for reference standard and the threshold of 25 mmHg are inclusion criteria for this review, so we anticipate that all studies will be classified as 'low' concern.
Domain 4: Flow and timing
Risk of bias: Could the patient flow have introduced bias?
Signaling question 1: Was the interval between the index test and reference standard less than one day?
Signaling question 2: Did all patients receive the same reference standard?
Signaling question 3: Were all patients included in the analysis?
Both echocardiography and right‐heart catheterization are subject to disagreement when performed at different times (e.g. days or weeks apart), which is a major limitation of the studies that compare their accuracy in the diagnosis of pulmonary hypertension (Lewis 2016). We will classify the study as 'yes' if there is a delay of less than a day, 'no' if there is a delay of more than or equal to a day, and 'unclear' if the information is not clear. We will classify the study as 'yes' if all patients had the same reference standard, 'no' if some included patients did not undergo the same reference standard, and 'unclear' if this information is not clear. Uninterpretable results may be present (e.g. unclear echocardiography or failure to insert right‐heart catheterization). Additionally, withdrawals from the study may be present. We anticipate that uninterpretable results would occur associated with the severity of pulmonary hypertension (e.g. difficulty to detect Doppler echocardiography among severe chronic obstructive pulmonary disease patients due to overinflated lung) and not at random. If uninterpretable results are withdrawn from analysis, diagnostic accuracy will be overestimated. We will classify the study as 'yes' if uninterpretable results were reported and the study had no withdrawals or the withdrawals were unlikely to affect the results; 'no' if uninterpretable results were not reported or there were withdrawals that were likely to affect the results, or both; and 'unclear' if this information is not clear.
Clinical pathway of diagnostic evaluation for pulmonary hypertension among adults, adolescents, and children.
PH: pulmonary hypertension; PAH: pulmonary arterial hypertension (Rubin 2016)
