Common use of Study Population Clause in Contracts

Study Population. It is a cross-sectional study involving patients referred for the Pulmonary Circulation Unit of Hospital das Clínicas of the Federal University of Minas Gerais (HC/UFMG), a local PH reference center, in Belo Horizonte, Minas Gerais, in the period from September, 2004 to April, 2015. It includes all 18-year-old or older patients, who were evaluated in an ambulatory basis, and had a clinical and laboratory suspicion of pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), a high or intermediate probability by TTE of pulmonary hypertension and who underwent RHC to confirm diagnosis. A maximum 6-month interval was established between the TTE and the RHC. Patients with diagnosis of PH due to left heart disease (group 2), associated with pulmonary diseases and/or hypoxemia (group 3) and with unclear and/or multifactorial mechanisms (group 5) were not eligible for this study, since RHC is not usually indicated for the diagnosis of patients with pre-defined criteria for these PH groups [1, 3]. Echocardiography and right heart catheterization This study was approved by UFMG’s Research Ethics Committee (ETIC nr. 1.057.219/2015), and all participants who agreed to participate signed the Term of Informed Consent. TTE and RHC examinations were requested according to the protocol and performed in health care units authorized by SUS’s municipal public system. The evaluation by TTE took into consideration echocardiographic variables suggestive of PH, the peak of TRV, the RAP and the sPAP, estimated by the modified form of Bernoulli’s equation: sPAP = 4TRV² + RAP. The RAP was estimated during the inspiratory maneuver as follows: for diameter of the inferior vena cava (IVC) smaller than 2.1cm associated with its collapse > 50%, estimated RAP = 3mmHg (0-5mmHg); for diameter of the IVC larger than 2.1cm with its collapse < 50%, RAP = 15mmHg (10-20mmHg). An intermediate value of 8mmHg (5-10mmHg) was used when these criteria were not met [4, 10]. Other echocardiographic parameters suggestive of PH were the presence in at least two of the following three categories: the ventricles (right ventricle/left ventricle basal diameter ratio > 1 and/or flattening of the interventricular septum); the pulmonary artery (acceleration time in the pulmonary artery < 105ms and/or increased pulmonary regurgitation velocity > 2.2m/sec and/or increased diameter of pulmonary artery > 25mm); and the IVC and right atrium (diameter of the IVC larger than 2.1cm associated with its collapse < 50% and/or area of the right atrium > 18 cm²) [1, 3–4, 10]. The probability of being diagnosed with PH was considered high in patients presenting TRV > 3.4m/s or TRV between 2.9 and 3.4 m/s with other echocardiographic signs. This probability was considered intermediate when the TRV was between 2.9 and 3.4 m/s with no other signs, or TRV ≤ 2.8m/s with other additional signs [1]. These data were obtained from SUS’s database, medical records and examination results. Statistical analysis Diagnosis of PH was confirmed when RHC done in the HC-UFMG found a mPAP equal to or higher than 25mmHg at rest, based on the international guidelines at the time of this study [3]. Briefly, RAP (mmHg), sPAP (mmHg) and mPAP (mmHg) and PAWP (pulmonary arterial wedge pressure, mmHg) were recorded at the end of a normal expiration. Cardiac output (CO, L/min− 1) was calculated based on the indirect Fick method, which estimates the oxygen uptake (VO2, ml/min) and the cardiac index (CI, L·min− 1·m− 2) should be calculated as the ratio of CO to body surface area. The PVR was calculated as PVR = (mPAP- PAWP)/CO. All measurements were obtained with reference to the zero level at the mid-thoracic line [11]. Data distribution has been established according to the Shapiro-Wilk test. This way, data have been presented as frequency and percentage, mean (standard deviation) or median (interquartile range). The agreement of values between the RHC and the TTE has been analyzed by the Bland-Altman plot and the coeficients of variation (CV) and repetition (CR) [12–14]. The estimated bias (average of differences in the measurements of sPAP and RAP between the TTE and the RHC) and its standard deviation (SD) and the 95% agreement limits have been calculated for preparation of the Bland-Altman plot [12, 13]. This method evaluates the measurement error, calculated by dividing the standard deviation of the average differences by the square root of two [14]. The CV is a dispersion measurement that describes the amount of data variability related to the mean, and it has been calculated by the formula: CV = SD of the average difference of the measurements made by TTE and by RHC / mean of the averages of these measurements multiplied by 100 [13]. The CR shows the expected variation of the results for 95% of the repeated measurements, calculated as follows: CR = SD of the average difference of the measurements made by TTE and by RHC multiplied by 1.96 [12]. The ROC curve was used to determine sPAP and TRV cut-off values for the diagnosis of PH. Differences of 5mmHg for RAP and 10mmHg for sPAP between the TTE and the RHC were considered as clinically acceptable [5]. The sample power has been calculated by the paired t-test to allow evaluation of the agreement of the sPAP measurements between the TTE and the RHC, by using the Minitab Release 14 statistical package. The sample from 90 patients obtained an 80% statistical power in the estimate of the actual difference in the sPAP measurements between the TTE and the RHC, assuming a clinically acceptable difference of 10mmHg, with a significance level of 0.05. A p level lower than 0.05 was considered significant for all the analyses. This analysis has been made in the Statistical Package for the Social Sciences, SPSS18. Results Ninety-five patients were consecutively admitted in the HC/UFMG reference center and met the inclusion criteria in the study period. One patient was excluded because it was not possible to retrieve the sPAP and RAP measurements from the TTE preceding the RHC. Five patients had no confirmed diagnosis of PH by RHC. The mean age was 47.6 ± 14.5years old (range from 18 to 79 years old), most of them (69.4%) women and in functional class III (42.1%). Fifty-six patients (62.9%) were diagnosed with PAH and 33 (37.1%) with CTEPH. No patient was being submitted to specific therapy for PH at the time of the examinations (Table 1). Table 1 Demographic, Clinical, Doppler Echocardiography and Hemodynamic Characteristics of the Study Population (n = 95) Age, mean ± SD, y 47.6 ± 14.5 Women, n (%) 66 (69.4%) FC NYHA, n (%) I 8 (8.4%) II 37 (38.9%) III 40 (42.1%) IV 10 (10.5%) PH prevalence No PH, n(%) 5 (5.2%) PH, n (%) 90 (94.8%) Interval between noninvasive and invasive measurement, median (IQR), days 104 (62–153) PAH, n (%) 56 (62.9%) Schistosomiasis 19 (33.9%) Idiopathic 14 (25%) Congenital heart disease 9 (16.1%) Connective tissue disease 8 (14.8%) Portopulmonary hypertension 4 (7.1%) HIV 2 (3.6%) CTEPH – n (%) 33 (37.1%) Data are given as mean ± SD or median (IQR: interquartile range). CI: cardiac index; CTEPH: chronic thromboembolic pulmonary hypertension; FC: functional class (New York HeartAssociation); HIV: human immunodeficiency virus; mPAP: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity. Age, mean ± SD, y 47.6 ± 14.5 Transthoracic echocardiogram sPAP, mean ± SD, mmHg 79.9 ± 24.7 RAP, mean ± SD, mmHg 12.9 ± 4.7 TRV, mean ± SD, m/s 3.78 ± 0.71 TAPSE, median (IQR), mm 16 (15–18) Pericardial effusion, n(%) 11 (12%) Right heart catheterization sPAP, mean ± SD, mmHg 87.6 ± 27.2 mPAP, mean ± SD, mmHg 70.2 ± 14.4 RAP, mean ± SD, mmHg 9.6 ± 5.6 PAWP, median (IQR), mmHg 10.0 (9.2–12.4) CI, median (IQR), L.min− 1.m− 2 2.46 (1.71–3.36) PVR, median (IQR), Wood units 6.6 (5.1–8.2) Data are given as mean ± SD or median (IQR: interquartile range). CI: cardiac index; CTEPH: chronic thromboembolic pulmonary hypertension; FC: functional class (New York HeartAssociation); HIV: human immunodeficiency virus; mPAP: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity. The data from the TTE and from the RHC are described on Table 1. In the TTE, the mean sPAP was 79.9 ± 24.7mmHg and the RAP was 12.9 ± 4.7mmHg, whereas sPAP and RAP was 87.6 ± 27.2mmHg and 9.6 ± 5.6mmHg, respectively, in the RHC. A statistically significant bias was verified between both examinations regarding the sPAP measurement (8.0 ± 21.9mmHg), as shown in Fig. 1. Regarding the agreement parameters (Table 2), the measurement error was of 15.5mmHg, the CV was of 26% and the CR was of 42.9mmHg. Table 2 sPAP and RAP Measurements on Transthoracic Echocardiogram and Right Cardiac Catheterization and their Reproducibility Variables sPAP RAP Average of measurements in TTE, mmHg 79.9 ± 24.7 12.9 ± 4.7 Average of measurements in RHC, mmHg 87.6 ± 27.2 9.6 ± 5.6 Average of differences, mmHg 8.0 ± 21.9 -3.3 ± 6.4 95% agreement limits (mmHg) -34.9 to 50.9 -15.9 to 9.3 Measurement error (mmHg) 15.5 4.6 Coeficients of variation (%) 26 57 Coeficients of repetition (mmHg) 42.9 12.7 Data are given as mean ± SD. sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; RHC: right heart catheterization; TTE: transthoracic echocardiogram. Figure 2 and Table 2 show the agreement parameters between the RAP measurements in the TTE and in the RHC, with a significant bias of -3.3 ± 6.4mmHg (95% IC:-15.9 to 9.3). The ROC curve presented a high discriminatory power, with area under the curve of 0.936 (95%IC: 0.84- 1.0) for sPAP and of 0.919 (95%IC: 0.84-1.0) for TRV, measured by the TTE, and cut-off point of 48mmHg (sensitivity = 0.907, specificity = 1.0, negative predictive value (NPV) = 0.286 and positive predictive value (PPV) = 1.0) and 3.075m/s (sensitivity = 0.907, specificity = 1.0, NPV = 0.333 and PPV = 1.0), respectively, for diagnosis of PH (Fig. 3). By using the definition of measurement accuracy for sPAP (variation up to 10mmHg) and RAP (variation up to 5mmHg) in the TTE compared to the RHC, only 55.1% of the estimates of RAP and 33.4% of the estimates of sPAP were accurate (Fig. 4). TTE underestimated the sPAP values by 41.5% versus 25.1% (-30.4 ± 10.2 versus 15.2 ± 8.9mmHg; p = 0.04) and overestimated the RAP values by 33.7% versus 11.2% (11.3 ± 4.8 versus − 8.4 ± 3.7mmHg; p = 0.03) in cases with difference above the clinically acceptable one. An illustration of echocardiographic evaluation of estimated sPAP and RAP in a patient with schistosomiasis associated pulmonary arterial hypertension and the difference of these measurements in the RHC are provided in Fig. 5.

Study Population. It is a cross-sectional study involving patients referred for the Pulmonary Circulation Unit of Hospital das Clínicas of the Federal University of Minas Gerais (HC/UFMG), a local PH reference center, in Belo Horizonte, Minas Gerais, in the period from September, 2004 to April, 2015. It includes all 18-year-old or older patients, who were evaluated in an ambulatory basis, and had a clinical and laboratory suspicion of pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), a high or intermediate probability by TTE of pulmonary hypertension and who underwent RHC to confirm diagnosis. A maximum 6-month interval was established between the TTE and the RHC. Patients with diagnosis of PH due to left heart disease (group 2), associated with pulmonary diseases and/or hypoxemia (group 3) and with unclear and/or multifactorial mechanisms (group 5) were not eligible for this study, since RHC is not usually indicated for the diagnosis of patients with pre-defined criteria for these PH groups [1, 3]. Echocardiography and right heart catheterization This study was approved by UFMG’s Research Ethics Committee (ETIC nr. 1.057.219/2015), and all participants who agreed to participate signed the Term of Informed Consent. TTE and RHC examinations were requested according to the protocol and performed in health care units authorized by SUS’s municipal public system. The evaluation by TTE took into consideration echocardiographic variables suggestive of PH, the peak of TRV, the RAP and the sPAP, estimated by the modified form of Bernoulli’s equation: sPAP = 4TRV² + RAP. The RAP was estimated during the inspiratory maneuver as follows: for diameter of the inferior vena cava (IVC) smaller than 2.1cm associated with its collapse > 50%, estimated RAP = 3mmHg (0-5mmHg); for diameter of the IVC larger than 2.1cm with its collapse < 50%, RAP = 15mmHg (10-20mmHg). An intermediate value of 8mmHg (5-10mmHg) was used when these criteria were not met [4, 10]. Other echocardiographic parameters suggestive of PH were the presence in at least two of the following three categories: the ventricles (right ventricle/left ventricle basal diameter ratio > 1 and/or flattening of the interventricular septum); the pulmonary artery (acceleration time in the pulmonary artery < 105ms and/or increased pulmonary regurgitation velocity > 2.2m/sec and/or increased diameter of pulmonary artery > 25mm); and the IVC and right atrium (diameter of the IVC larger than 2.1cm associated with its collapse < 50% and/or area of the right atrium > 18 cm²) [1, 3–4, 10]. The probability of being diagnosed with PH was considered high in patients presenting TRV > 3.4m/s or TRV between 2.9 and 3.4 m/s with other echocardiographic signs. This probability was considered intermediate when the TRV was between 2.9 and 3.4 m/s with no other signs, or TRV ≤ 2.8m/s with other additional signs [1]. These data were obtained from SUS’s database, medical records and examination results. Statistical analysis Diagnosis of PH was confirmed when RHC done in the HC-UFMG found a mPAP equal to or higher than 25mmHg at rest, based on the international guidelines at the time of this study [3]. Briefly, RAP (mmHg), sPAP (mmHg) and mPAP (mmHg) and PAWP (pulmonary arterial wedge pressure, mmHg) were recorded at the end of a normal expiration. Cardiac output (CO, L/min− 1) was calculated based on the indirect Fick method, which estimates the oxygen uptake (VO2, ml/min) and the cardiac index (CI, L·min− 1·m− 2) should be calculated as the ratio of CO to body surface area. The PVR was calculated as PVR = (mPAP- PAWP)/CO. All measurements were obtained with reference to the zero level at the mid-thoracic line [11]. Data distribution has been established according to the Shapiro-Wilk test. This way, data have been presented as frequency and percentage, mean (standard deviation) or median (interquartile range). The agreement of values between the RHC and the TTE has been analyzed by the BlandXxxxx-Altman Xxxxxx plot and the coeficients coefficients of variation (CV) and repetition (CR) [12–14]. The estimated bias (average of differences in the measurements of sPAP and RAP between the TTE and the RHC) and its standard deviation (SD) and the 95% agreement limits have been calculated for preparation of the Bland-Altman plot [12, 13]. This method evaluates the measurement error, calculated by dividing the standard deviation of the average differences by the square root of two [14]. The CV is a dispersion measurement that describes the amount of data variability related to the mean, and it has been calculated by the formula: CV = SD of the average difference of the measurements made by TTE and by RHC / mean of the averages of these measurements multiplied by 100 [13]. The CR shows the expected variation of the results for 95% of the repeated measurements, calculated as follows: CR = SD of the average difference of the measurements made by TTE and by RHC multiplied by 1.96 [12]. The ROC curve was used to determine sPAP and TRV cut-off values for the diagnosis of PH. Differences of 5mmHg for RAP and 10mmHg for sPAP between the TTE and the RHC were considered as clinically acceptable [5]. The sample power has been calculated by the paired t-test to allow evaluation of the agreement of the sPAP measurements between the TTE and the RHC, by using the Minitab Release 14 statistical package. The sample from 90 patients obtained an 80% statistical power in the estimate of the actual difference in the sPAP measurements between the TTE and the RHC, assuming a clinically acceptable difference of 10mmHg, with a significance level of 0.05. A p level lower than 0.05 was considered significant for all the analyses. This analysis has been made in the Statistical Package for the Social Sciences, SPSS18. Results Ninety-five patients were consecutively admitted in the HC/UFMG reference center and met the inclusion criteria in the study period. One patient was excluded because it was not possible to retrieve the sPAP and RAP measurements from the TTE preceding the RHC. Five patients had no confirmed diagnosis of PH by RHC. The mean age was 47.6 ± 14.5years old (range from 18 to 79 years old), most of them (69.4%) women and in functional class III (42.1%). Fifty-six patients (62.9%) were diagnosed with PAH and 33 (37.1%) with CTEPH. No patient was being submitted to specific therapy for PH at the time of the examinations (Table 1). Table 1 Demographic, Clinical, Doppler Echocardiography and Hemodynamic Characteristics of the Study Population (n = 95) Age, mean ± SD, y 47.6 ± 14.5 Women, n (%) 66 (69.4%) FC NYHA, n (%) I 8 (8.4%) II 37 (38.9%) III 40 (42.1%) IV 10 (10.5%) PH prevalence No PH, n(%) 5 (5.2%) PH, n (%) 90 (94.8%) Interval between noninvasive and invasive measurement, median (IQR), days 104 (62–153) PAH, n (%) 56 (62.9%) Schistosomiasis 19 (33.9%) Idiopathic 14 (25%) Congenital heart disease 9 (16.1%) Connective tissue disease 8 (14.8%) Portopulmonary hypertension 4 (7.1%) HIV 2 (3.6%) CTEPH – n (%) 33 (37.1%) Data are given as mean ± SD or median (IQR: interquartile range). CI: cardiac index; CTEPH: chronic thromboembolic pulmonary hypertension; FC: functional class (New York HeartAssociation); HIV: human immunodeficiency virus; mPAP: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity. Age, mean ± SD, y 47.6 ± 14.5 Transthoracic echocardiogram sPAP, mean ± SD, mmHg 79.9 ± 24.7 RAP, mean ± SD, mmHg 12.9 ± 4.7 TRV, mean ± SD, m/s 3.78 ± 0.71 TAPSE, median (IQR), mm 16 (15–18) Pericardial effusion, n(%) 11 (12%) Right heart catheterization sPAP, mean ± SD, mmHg 87.6 ± 27.2 mPAP, mean ± SD, mmHg 70.2 ± 14.4 RAP, mean ± SD, mmHg 9.6 ± 5.6 PAWP, median (IQR), mmHg 10.0 (9.2–12.4) CI, median (IQR), L.min− 1.m− 2 2.46 (1.71–3.36) PVR, median (IQR), Wood units 6.6 (5.1–8.2) Data are given as mean ± SD or median (IQR: interquartile range). CI: cardiac index; CTEPH: chronic thromboembolic pulmonary hypertension; FC: functional class (New York HeartAssociation); HIV: human immunodeficiency virus; mPAP: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension; PAWP: pulmonary arterial wedge pressure; PH: pulmonary hypertension; PVR: pulmonary vascular resistance; sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; TAPSE: tricuspid annular plane systolic excursion; TRV: tricuspid regurgitation velocity. The data from the TTE and from the RHC are described on Table 1. In the TTE, the mean sPAP was 79.9 ± 24.7mmHg and the RAP was 12.9 ± 4.7mmHg, whereas sPAP and RAP was 87.6 ± 27.2mmHg and 9.6 ± 5.6mmHg, respectively, in the RHC. A statistically significant bias was verified between both examinations regarding the sPAP measurement (8.0 ± 21.9mmHg), as shown in Fig. 1. Regarding the agreement parameters (Table 2), the measurement error was of 15.5mmHg, the CV was of 26% and the CR was of 42.9mmHg. Table 2 sPAP and RAP Measurements on Transthoracic Echocardiogram and Right Cardiac Catheterization and their Reproducibility Variables sPAP RAP Average of measurements in TTE, mmHg 79.9 ± 24.7 12.9 ± 4.7 Average of measurements in RHC, mmHg 87.6 ± 27.2 9.6 ± 5.6 Average of differences, mmHg 8.0 ± 21.9 -3.3 ± 6.4 95% agreement limits (mmHg) -34.9 to 50.9 -15.9 to 9.3 Measurement error (mmHg) 15.5 4.6 Coeficients Coefficients of variation (%) 26 57 Coeficients Coefficients of repetition (mmHg) 42.9 12.7 Data are given as mean ± SD. sPAP: systolic pulmonary arterial pressure; RAP: right atrial pressure; RHC: right heart catheterization; TTE: transthoracic echocardiogram. Figure 2 and Table 2 show the agreement parameters between the RAP measurements in the TTE and in the RHC, with a significant bias of -3.3 ± 6.4mmHg (95% IC:-15.9 to 9.3). The ROC curve presented a high discriminatory power, with area under the curve of 0.936 (95%IC: 0.84- 1.0) for sPAP and of 0.919 (95%IC: 0.84-1.0) for TRV, measured by the TTE, and cut-off point of 48mmHg (sensitivity = 0.907, specificity = 1.0, negative predictive value (NPV) = 0.286 and positive predictive value (PPV) = 1.0) and 3.075m/s (sensitivity = 0.907, specificity = 1.0, NPV = 0.333 and PPV = 1.0), respectively, for diagnosis of PH (Fig. 3). By using the definition of measurement accuracy for sPAP (variation up to 10mmHg) and RAP (variation up to 5mmHg) in the TTE compared to the RHC, only 55.1% of the estimates of RAP and 33.4% of the estimates of sPAP were accurate (Fig. 4). TTE underestimated the sPAP values by 41.5% versus 25.1% (-30.4 ± 10.2 versus 15.2 ± 8.9mmHg; p = 0.04) and overestimated the RAP values by 33.7% versus 11.2% (11.3 ± 4.8 versus − 8.4 ± 3.7mmHg; p = 0.03) in cases with difference above the clinically acceptable one. An illustration of echocardiographic evaluation of estimated sPAP and RAP in a patient with schistosomiasis associated pulmonary arterial hypertension and the difference of these measurements in the RHC are provided in Fig. 5.