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. 2020 May 7;15(5):e0232575. doi: 10.1371/journal.pone.0232575

Prevalence of pectus excavatum in an adult population-based cohort estimated from radiographic indices of chest wall shape

Mikaela Biavati 1, Julia Kozlitina 1, Adam C Alder 2, Robert Foglia 2, Roderick W McColl 3, Ronald M Peshock 3, Robert E Kelly Jr 4, Christine Kim Garcia 1,5,*
Editor: J J Cray Jr6
PMCID: PMC7205298  PMID: 32379835

Abstract

Background

Pectus excavatum is the most common chest wall skeletal deformity. Although commonly evaluated in adolescence, its prevalence in adults is unknown.

Methods and findings

Radiographic indices of chest wall shape were analyzed for participants of the first (n = 2687) and second (n = 1780) phases of the population-based Dallas Heart Study and compared to clinical cases of pectus (n = 297). Thoracic computed tomography imaging studies were examined to calculate the Haller index, a measure of thoracic axial shape, and the Correction index, which quantitates the posterior displacement of the sternum relative to the ribs. At the level of the superior xiphoid, 0.5%, 5% and 0.4% of adult Dallas Heart Study subjects have evidence of pectus excavatum using thresholds of Haller index >3.25, Correction index >10%, or both, respectively. Radiographic measures of pectus are more common in females than males and there is a greater prevalence of pectus in women than men. In the general population, the Haller and Correction indices are associated with height and weight, independent of age, gender, and ethnicity. Repeat imaging of a subset of subjects (n = 992) demonstrated decreases in the mean Haller and Correction indices over seven years, suggesting change to a more circular axial thorax, with less sternal depression, over time.

Conclusions

To our knowledge, this is the first study estimating the prevalence of pectus in an unselected adult population. Despite the higher reported prevalence of pectus cases in adolescent boys, this study demonstrates a higher prevalence of radiographic indices of pectus in adult females.

Introduction

Pectus excavatum, or “funnel chest,” results from the posterior displacement of the sternum and adjoining ribs into the thoracic cavity. It is the most common anterior chest wall deformity, which has been estimated to have an occurrence of 1 in 40 to 1 in 400 individuals across different cohorts[1–5]. Males are referred for evaluation 3–5 times more often than females[6]. Pectus carinatum, or “pigeon chest,” is the second most common chest wall deformity and is characterized by the anterior protrusion of the sternum and the adjoining ribs. Although pectus can be present at birth, most patients experience a marked worsening in the severity of their sternal deformity in adolescence during their pubertal growth spurt[7]. When severe, pectus excavatum leads to dyspnea, pulmonary restriction, compression of the heart and great vessels and psychological distress. Cardiopulmonary limitations are generally considered to be related to the severity of the pectus deformity[8]. Severe cases of pectus excavatum can be corrected surgically, with either the open or Ravitch procedure or the minimally invasive Nuss procedure[9, 10]. Pectus carinatum can be corrected by surgery or the application of a compressive chest brace[11].

Radiographic measures can quantify thoracic skeletal abnormalities and influence decisions regarding the need for surgical repair. One standard metric is the Haller index, which is the quotient of the internal transverse thoracic distance and the internal anteroposterior dimension at the level of the deepest point of the sternal deformity[12]. A Haller index greater than 3.25 is considered an indication for surgical evaluation. Another quantitative measure is the Correction index, which is a measure of the posterior depression of the sternum relative to the adjacent ribs[13]. A Correction index of greater than 10% is considered to be indicative of substantial pectus excavatum[13].

Although the prevalence of pectus in birth and pediatric cohorts has been studied[1, 14, 15], its prevalence in adult population-based cohorts is unknown. The purpose of this study was to quantify radiographic measures of thoracic shape in the Dallas Heart Study (DHS), a large adult, multiethnic, population-based cohort, to estimate the prevalence of pectus excavatum in adults. To decrease bias, we calculated measures of thoracic shape at three skeletal landmarks (T6, T8, and Superior Xiphoid). Thoracic imaging of pectus cases were used for comparison.

Methods

Study populations

This study was approved by the University of Texas Southwestern Medical Center and the Eastern Virginia Medical Center Institutional Review Boards. Written informed consent was obtained from all subjects. All studies were performed in accordance with relevant guidelines and regulations. The DHS is a longitudinal, multiethnic, population-based probability sample of Dallas County residents. Details of the study design have been described previously[16]. The study was initiated in 2000 and transformed from a cross-sectional study to a longitudinal study in 2007. Some participants from the first study phase (DHS1) underwent repeat evaluation. Participation of unrelated spouses and friends of the original cohort augmented the follow-up DHS2 cohort (NCT00344903). A subset of the original DHS1 cohort (n = 2687) had cardiac electron beam computed tomographic scans (Imatron EBCT Scanner) available for analysis. A subset of DHS2 participants (n = 788 unrelated and n = 922 prior DHS1 participants) had cardiac multi-detector computerized tomographic scans (Toshiba Aquilon 64-slice MDCT) available for analysis.

The cases referred for evaluation of pectus were obtained by Children’s Hospital of The King’s Daughters/Eastern Virginia Medical School from 2009–2017 and by Children’s Medical Center of Dallas/University of Texas Southwestern Medical Center from 2014–2017. Cases included those diagnosed with a chest wall defect by a pediatric surgeon. Only those cases with an available thoracic computed tomography (CT) scan were included in this study, representing 58% cases from Children’s Hospital of the King’s Daughters/Eastern Virginia Medical School and 17% cases from Children’s Medical Center of Dallas/University of Texas Southwestern Medical Center. The cases included those with pectus excavatum, carinatum or a complex mix of both (mixed deformity). Patients were treated with a variety of surgical or non-surgical (brace, vacuum bell, or other) approaches.

Quantitation of sternal deformity

Scans were excluded if there was evidence of chest trauma or prior thoracic surgical procedure or if skeletal landmarks were not visible. Axial (transverse) images of the thorax were inspected. The indices were calculated at the levels of the mid-vertebral T6 and T8 as well as the superior xiphoid. An additional measurement was calculated at the point of maximal sternal depression or maximal sternal protrusion.

The Haller index[12] was calculated as the quotient of the greatest transverse dimension of the chest (A) and the minimal anterior-posterior dimension from the vertebral body or its horizontal tangent to the posterior sternum (B), that is, Haller index = A/B (Fig 1B). In cases of asymmetric pectus excavatum the anterior-posterior dimension was measured from the vertebral body (or its horizontal tangent) to the most posterior depression of the costal cartilage adjacent to the sternum. The Correction index[13] measurements include the anterior-posterior distance between the vertebral body and the sternum or the most posterior depression of the adjacent costal cartilage (B) as well as the maximal distance from the horizontal tangent of the vertebral body to the inner margin of anterior chest cavity (C). It was calculated as Correction index = [(C–B)/C] as shown in Fig 1C. For pectus carinatum cases, we drew a line posterior to the sternum connecting the right and left hemithoraces that followed the curvature of the thorax; line segment (C) was measured between the intersection of this line with the anterior chest and the horizontal tangent of the vertebral body. All distance measurements were made using the ImageJ ruler tool.

Fig 1. Calculation of the haller index and correction index from axial images of chest computed tomography scans of pectus cases.

Fig 1

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Anatomic schematic of the lateral view of the thorax (A) demonstrating the position of the T6 and T8 vertebral bodies relative to the body of the sternum and the superior xiphoid process. Measurements of chest wall dimensions (red lines) used to calculate the Haller Index (B) and Correction Index (C) from a patient with pectus excavatum (left) and a patient with pectus carinatum (right). Measurements in B and C are shown at the level of the superior xiphoid. Haller (D) and Correction (E) Index measurements of patients with pectus excavatum (PE, n = 274, blue circles), pectus carinatum (PC, n = 19, red triangles) and those with a mixed pectus excavatum and carinatum defect (Mixed, n = 4, orange diamonds) at the level of T6, T8, Superior Xiphoid, as well as the point of maximal (max.) sternal depression (n = 278) or protrusion (n = 23). Patients with a mixed defect are included in both the maximal sternal depression and protrusion data sets. Box and whisker plots (black) are superimposed.

Statistical methods

Data are summarized as number and percentage or median and interquartile range (IQR). Measures of sternal deformity were compared between demographic groups using Wilcoxon rank-sum test. The prevalence of pectus was compared between groups using Fisher’s exact test. The relationship of Haller and Correction indices with age (years), height (cm), weight (kg), and BMI (kg/m2) was first examined using simple (unadjusted) linear regression. Multivariable-adjusted linear regression models were used to examine the association of chest wall shape with demographic and anthropometric characteristics. Repeated measures of Haller and Correction indices in the DHS participants were compared using Wilcoxon signed-rank test. We applied an inverse normal transformation to Haller and Correction indices prior to fitting linear models to achieve approximate normality of the residuals.

Results

Assessment of chest wall abnormalities of 297 pectus cases

The Haller and Correction indices were calculated from axial images of thoracic CT scans of patients referred for surgical evaluation of pectus (n = 297). The cases were mostly men (78%), Non-Hispanic White (91%) and adolescent, with a median age of 15 years (S1 Table). We calculated indices for cases (pectus excavatum, n = 274; pectus carinatum, n = 19; mixed deformity, n = 4) at the level of T6, T8, and the superior xiphoid as well as the point of maximal sternal depression or protrusion (Fig 1). The Haller index measurements at T6, T8 and the superior xiphoid do not differ much from that measured at the point of maximal depression (Fig 1D). In contrast, the Correction index at the site of maximal deformity correlates best with that measured at the level of the superior xiphoid (Fig 1E), consistent with the observation that the deepest part of the pectus depression usually affects the caudal portion of the sternum. The female pectus cases had a greater degree of severity of excavatum than the male cases, as determined by Haller and Correction indices at four different axial levels (T6, T8, Superior Xiphoid and the point of maximal depression) (Fig 2, S2 Table). A Correction index of >10% was found at the point of maximal depression in 96% of the PE cases, whereas, a Haller index of >3.25 was found in fewer (78%) cases (Fig 3A).

Fig 2. Comparison of haller and correction index measurements for men and women from the Dallas Heart Study (DHS) and pectus cohorts.

Fig 2

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Haller (A) and Correction (B) indices of the DHS1 cohort (n = 2687) and pectus cases (n = 297) at T6, T8 and superior xiphoid axial levels. Individuals from DHS1 (gray circles) and subjects with pectus excavatum (PE, n = 274, blue circles) pectus carinatum (PC, n = 19, red triangles) or a mixed pectus excavatum and carinatum defect (Mixed, n = 4, orange diamonds) are individually plotted with superimposed box and whisker plots (black). *, ** and *** indicative of P-value <0.05, <0.001 and <0.0001, respectively.

Fig 3. Correlation of the correction index with the haller index for pectus and Dallas Heart Study (DHS) cohorts.

Fig 3

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The Correction and Haller index at the level of the superior xiphoid is plotted for each of the pectus excavatum (PE, n = 274, blue circles), pectus carinatum (PC, n = 19, red triangles) and mixed pectus excavatum and carinatum (Mixed, n = 4, orange diamonds) patients (A, B) and for each of the DHS1 subjects (C) (n = 2687). Indices are measured at the point of maximal sternal deformity, that is, at the point of maximal sternal depression for the PE cases and the point of maximal sternal protrusion for the PC cases (A), or at the superior xiphoid (B, C). Dashed lines indicate a Haller Index of 3.25 or a Correction Index of 10%. Note the different axes.

Measurement of chest wall shape in a multi-ethnic population-based cohort

Thoracic imaging was analyzed for the Dallas Heart Study, a multi-ethnic, adult population based cohort from Dallas, Texas. The subjects included those who participated in the initial study (DHS1) (n = 2687) as well as the follow up study (DHS2) 6–7 years later. Participants in DHS2 included a subset from DHS1 who had repeat imaging (n = 992) and an unrelated group who were newly enrolled (n = 788) (S1 Table).

The Haller index measures the ratio of the longitudinal to transverse dimension of the thorax in the axial plane. A smaller Haller index correlates to a more circular shape and a larger one correlates with a more oval shape. A larger Haller index, thus, a more oval shape, is found in females as compared to males at the T6, T8 and superior xiphoid in DHS1 (Fig 2A, S2 Table). The Correction index measures the position of the sternum relative to the lateral rib cage. A larger Correction index indicates a more “sunken” position of the sternum relative to the lateral ribs. A negative Correction index indicates a more “peaked” position of the sternum. A larger Correction index, thus, a more “sunken” position of the sternum is seen in females as compared to males at all axial levels in DHS1 (Fig 2B, S2 Table). Although the magnitude of change is small in the DHS, these findings are consistent at multiple levels (T6, T8 and Superior Xiphoid) and in both the DHS1 and the DHS2 cohorts (S2 Table). In general, females have a more oval axial thoracic shape with a more sunken position of the sternum.

Prevalence of severe pectus excavatum in population-based cohort

There is more separation between the cases and population-based controls at the level of the superior xiphoid than at T6 or T8 (Fig 2). When the Haller index is plotted against the Correction index, the cases with pectus excavatum are distinguished from those with carinatum at the level of maximal sternal deformity (Fig 3A) and the superior xiphoid (Fig 3B). Most pectus excavatum cases have a Haller index >3.25 and a Correction index >10%. When we apply these same thresholds to the DHS1 cohort, we find that 0.5% have a Haller index >3.25 and 5% have a Correction index >10% (Fig 3C, Table 1). When we use a combination of these thresholds to define pectus excavatum at the level of the superior xiphoid, we find a prevalence of 0.4%, or 1 in 250 individuals, in the DHS1 cohort. A higher prevalence is found in women (0.5%; 1 in 200) than men (0.3%; 1 in 333). Similar estimates of prevalence are found in the DHS2 cohort that incudes unrelated subjects (Table 1) or when assessed at T6 or T8 (S3 Table).

Table 1. Prevalence of pectus excavatum in cases and population-based cohorts at the level of the superior xiphoid.

Pectus Cases Male Female
Population Pectus Definition N N (%) N N (%) N N (%)
All Pectus Cases HI>3.25 297 215 (72) 231 164 (71) 66 51 (77)
(including PE and PC) CI>10% 297 265 (89) 231 206 (89) 66 59 (89)
HI>3.25 and CI>10% 297 213 (72) 231 162 (70) 66 51 (77)
DHS1 HI>3.25 2687 14 (0.5) 1158 6 (0.5) 1529 8 (0.5)
CI>10% 2687 143 (5) 1158 43 (4) 1529 100 (6)
HI>3.25 and CI>10% 2687 12 (0.4) 1158 4 (0.3) 1529 8 (0.5)
DHS2 HI>3.25 788 4 (0.5) 249 0 (0) 539 4 (1)
(Not in DHS1) CI>10% 788 53 (7) 249 7 (3) 539 46 (8)
HI>3.25 and CI>10% 788 3 (0.4) 249 0 (0) 539 3 (0.6)
DHS2 HI>3.25 992 7 (0.7) 278 1 (0.4) 714 6 (0.8)
(Subset of DHS1) CI>10% 992 77 (7.8) 278 11 (4) 714 66 (9.2)
HI>3.25 and CI>10% 992 7 (0.7) 278 1 (0.4) 714 6 (0.8)
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P-values calculated using Fisher exact test.

Abbreviations: Pectus Excavatum (PE), Pectus Carinatum (PC), Haller Index (HI), Correction Index (CI).

Chest wall measurements independently associated with ethnicity, age and weight

The chest wall shape of the Dallas Heart Study cohorts differ by ethnicicty (S4 Table). In general, Non-Hispanic blacks have a smaller CI than non-Hispanic whites or Hispanics, indicating less likelihood of a posteriorly-depressed sternum. These findings were seen in both the DHS1 and DHS2 cohorts. Although not consistent across all axial levels, Non-Hispanic Blacks tend to have a lower Haller index than whites in the DHS1 cohort. This suggests a larger anterior-posterior depth relative to the lateral dimension, or a more circular rather than oval axial thoracic shape.

We find that there are significant associations between chest wall shape, age and weight in the DHS1 cohort (Fig 4A and 4B). There is a negative association between the Haller index and weight (p<0.0001), BMI (p<0.0001) and age (p<0.0001). There is a similar negative association between the Correction index and weight (p<0.0001) or BMI (p<0.0001). In contrast with the Haller index, the Correction index was positively, but modestly, correlated with age (p = 0.0045).

Fig 4. Haller and correction indices of the Dallas Heart Study subjects.

Fig 4

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Haller index (A) and Correction Index (B) measured at the superior xiphoid axial level is plotted against the age in years, height in cm, weight in kg and BMI in kg/m2 for DHS1 (n = 2687) subjects. Individual subjects are represented as gray circles; the trend line is superimposed. Correlation (C) and box and whisker plots (D) of Haller and Correction indices for DHS Subjects (n = 992) with available imaging from DHS1 and DHS2. A DHS subject (E) demonstrating an increase in the Haller index in the repeat imaging study at the level of the superior xiphoid. The magnitude of Haller index increase is within the top 1%. Imaging shows the development of a more circular, and less oval, axial chest wall shape.

Multivariable models of chest wall shape of DHS1 demonstrate independent associations of ethnicity, gender, age, height and weight with the Haller and Correction indices across different thoracic levels (S5 Table). The indices are associated with height (β [SE], 0.029(0.003), p<0.0001 and 0.022(0.003), p<0.0001, respectively) and weight (-0.024(0.001), p<0.0001 and -0.013(0.001), p<0.0001, respectively) at the superior xiphoid process, independent of age, gender, and ethnicity. Similar results are found when analyzing the unrelated DHS2 cohort (S6 Table).

Change in chest wall measurements in the population over 7 years

We analyzed chest wall measurements for the 992 subjects who underwent repeat imaging. The repeated measures were highly correlated (Fig 4C). There was a small but significant mean decrease in the Haller index from DHS1 to DHS2 (2.19 [2.01–2.40] vs 2.15 [1.99–2.35], p<0.0001) (Fig 4D), indicating a trend toward developing a more circular transverse chest wall shape. There was a decrease of the mean Correction index from DHS1 to DHS2 (4.5 [2.2–6.7] vs 3.6 [1.7–6.1], p<0.0001) indicating a trend toward a less depressed position of the sternum in repeat imaging.

Discussion

Although pectus excavatum has been characterized as one of the most common birth defects[1, 17], its prevalence in adult populations is unknown. In this study we estimate the prevalence of pectus excavatum at ~0.4%, or 1 in 250 individuals, in a large, population-based, multiethnic, adult population with a median age of 44 years. We have used a combination of two, independent and validated radiographic measures of chest wall shape, the Haller and Correction indices, to characterize cohorts of pectus clinical cases and unselected population-based controls. We find significant associations between these indices with age, gender, ethnicity, height and weight. It is striking that the radiographic measurements associated with pectus excavatum differ significantly by gender. Both the Haller and Correction indices are larger in females than males for both the case and control cohorts. Although the absolute numbers are small, we find that more females (0.5%) than males (0.3%) have pectus excavatum in the population cohort as defined by these indices. This finding is surprising since the literature suggests that a greater number of boys, usually 4-fold higher than girls, are referred for evaluation of pectus[6, 18]. Even in the current study, there are 3.5 times more males than females in the pectus case cohort. Thus, there is a strong referral bias to evaluate adolescent boys for pectus as breast development and modesty may mask the underlying chest wall defect in affected females. Future studies will need to determine the generalizability of these findings in unselected cohorts of different ages.

These observations would not be possible without the availability of chest CT scans that allow for unbiased calculation of quantitative indices. Several radiographic metrics have been studied to quantitate the severity of the pectus deformity. The Haller index is the most widely used, although it does not directly measure sternal depression, but rather, the quotient of the transverse and anterior-posterior axial dimensions. The original description of this index in 1987 was without reference to bony thoracic landmarks, but was calculated in the axial plane that generated the largest value[12]. Cross-sectional pediatric cohort studies have found that the Haller index tends to increase with age for the pediatric population, especially at the most cranial (T3-T5) and caudal (T11-T12) levels[14, 15]. Hence, prior studies suggest that the axial thorax tends to flatten from a more circular to a more oval shape during childhood. Perhaps this explains why prevalence of pectus excavatum is lower in a birth cohort (1:400)[1] than in school-aged children[2, 4, 5] (up to 1:40[3]). Also, perhaps this is why most individuals are referred for surgical evaluation of chest wall deformities during adolescence. Here, we find the opposite trend for Haller index with age; namely, it tends to decrease with advancing age in adults. Thus, this study suggests that the axial thorax tends to return to a more circular shape during adulthood.

Although the diagnosis of pectus does not require a chest CT scan, imaging studies provide quantitative measures of severity, thus allowing for comparison across studies. The original descriptions of the Haller and Correction indices suggested cut-offs of >3.25[12] and >10%[13], respectively, as thresholds to define pectus excavatum in children. Ten-fold fewer DHS1 subjects have a Haller index >3.25 than a Correction index >10% at the level of the superior xiphoid. By using a combination of both thresholds, we conservatively estimate the population-based prevalence of pectus excavatum in adults of 0.4%. In comparison, 78% and 96% of the pectus cases have a HI >3.25 or CI >10%, respectively, at the point of maximal sternal deformity. Given the difference in age between the cases and the population-based controls, we are not suggesting that the latter should provide guidance regarding cut-offs for evaluation or treatment of adolescents with pectus. However, the adult population does highlight the extreme nature of the cases evaluated by the surgical centers.

Although there is correlation between the Haller and Correction indices in pectus cases[19], the correlation between the two indices in population-based cohorts is unknown. We find that there is evidence for a more oval axial thorax shape and a greater degree of sternal depression in adult women than men. At three different axial levels, the indices are larger for Whites or Hispanics than Blacks. In light of this observation, it is interesting to note that Whites are the most highly represented amongst the pectus cases. At every axial level, a more oval axial thorax and a more depressed sternum is associated with taller height and decreased weight.

There are a number of limitations of the current study. Because of the cardiac-centric imaging of the DHS, the shape of the chest was measured solely in the mid chest. Only two indices were measured, although others have been used in other studies to quantitate the pectus deformity[20]. Some of the variability in thorax shape in subjects from DHS1 to DHS2 may be due to differences in breath hold techniques[21, 22], although variability due to respiration tends to be less in the mid-chest[15]. Beside respiration, variability may be related to difficulty in identifying bony landmarks and human error. We have not used the axial image that represents the maximal deformity in the population-based cohorts, as is commonly done for evaluation of pectus cases, since this would impart less objectivity in evaluating mild abnormalities. Additional studies will be needed to correlate these quantitative indices with different dysmorphologic varieties of pectus, such as cup, saucer and trench shaped deformities[23].

Although association does not prove causation, the very strong inverse association between the Haller index and weight or BMI suggests that obesity may lead to a more circular axial thoracic shape. These observations are observed across different axial levels, for two independent indices of thoracic shape and in both unrelated subsets of the DHS cohort. Weight and BMI have also been found to be inversely related to severity of the pectus defect in an independent cohort[24]. Obese subjects are at greater risk for inspiratory muscle (i.e., diaphragm) fatigue at rest and with exercise[25–27]. Obesity also changes respiratory compliance and lung volumes. All of these factors may affect the shape of the thorax.

The clinical utility of the current study is that it provides a framework for comparing quantitative chest wall indices in pectus cases to an unselected, large, population-based, multiethnic population. The interval of time, 6 to 7 years, between the imaging studies evaluated in this study is small with regard to the subjects’ lifespans. Additional studies may clarify the progression of thoracic changes over time from birth to adulthood for those with or without pectus. Identification of the factors that influence the temporal plasticity of the thorax may reveal more about the ontogeny of pectus and chest wall defects.

Supporting information

S1 Table. Demographic characteristics of participants.

(DOCX)

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S2 Table. Haller and correction index measurements in pectus cases and DHS cohorts at multiple axial levels (T6, T8 and superior xiphoid) by gender.

(DOCX)

Click here for additional data file. (18.8KB, docx)
S3 Table. Prevalence of pectus excavatum in cases and population-based cohorts.

(DOCX)

Click here for additional data file. (19.6KB, docx)
S4 Table. Chest wall shapes in population-based cohorts by ethnicity.

(DOCX)

Click here for additional data file. (19.2KB, docx)
S5 Table. Linear models of the haller and correction index of the Dallas Heart Study (DHS1) cohort (n = 2685) at three axial levels (T6, T8 and superior xiphoid).

(DOCX)

Click here for additional data file. (19.4KB, docx)
S6 Table. Linear models of chest wall shape for the unrelated Dallas Heart Study (DHS2) cohort (n = 788) at three axial levels (T6, T8 and superior xiphoid).

(DOCX)

Click here for additional data file. (19.4KB, docx)

Acknowledgments

The authors thank Helen Hobbs, MD, and the other members of the Dallas Heart Study steering committee for access to the thoracic imaging studies.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The study was supported by grants UL1TR000451 and KL2TR000453 from the National Center for Advancing Translational Sciences as well as institutional funds. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Decision Letter 0

Agostino Chiaravalloti

28 Jan 2020

PONE-D-19-18160

Prevalence of Pectus Excavatum in an Adult Population-Based Cohort Estimated from Radiographic Indices of Chest Wall Shape

PLOS ONE

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Reviewer #1: This study provided an overview for the prevalence of pectus excavatum (PE) in the general adult population. The measurement protocol is simple, and the large sample size makes for a decent estimation. Currently, PE is most mentioned in neonates and children. Therefore, there lack existing evidence in the literature to effectively evaluate the accuracy of this study. On the other hand, however, this study has the potential to become one of the first in its kind, and could pave the way to future studies in adult PE. There are a few comments that I would like the authors to address.

1.As shown in Table 1, while evaluating the diagnostic indices of PE, was it necessary to include cases with pectus carinatum (PC)? The likelihood of decreased Haller index in PC patients might cause an underestimation in terms of the cases that fits the criteria.

2.What was the diagnostic criteria for the reference pectus cases? Apparently not all referred cases fit both the HI and CI criteria. Providing the detailed diagnostic criteria of these cases could increase the credibility of this sample.

3.While evaluating the paired samples in DHS1 and DHS2, with such a large sample size, parametric tests are usually preferred due to their higher power. Did the samples not follow normal distribution? If so, the possibility of the sample being biased may need to be addressed.

4.The estimated prevalence of undiagnosed, untreated adult pectus excavatum (1 in 250) was higher than the assumed incidence of neonatal pectus excavatum, 1 in 400, in 1975, where CT was much less available. Do the authors have any theory in regard to this phenomenon?

5.What is the clinical significance of this study? Do the authors have any expectation as to what changes this study might lead to in the management of adult PE?

Reviewer #2: The authors present a retrospective analysis of thoracic computed tomography imaging studies, reviewing the Haller index, a measure of thoracic axial shape, and the Correction index. They found that very strong inverse association between the Haller Index and weight or BMI suggests that obesity may lead to a more circular axial thoracic shape.

Overall, the most important problem of this manuscript is its novelty. Similar studies have been done by other investigators before, with the same modality or other modality both. Just to list a few:

Incidence and Classification of Chest Wall Deformities in Breast Augmentation Patients.

Aesthetic Plast Surg (United States), Dec 2017, 41(6) p1280-1290

Relationship between cardiac MR compression classification and CT chest wall indexes in patients with pectus excavatum. J Pediatr Surg (United States), Nov 2018, 53(11) p2294-2298

Szafer D, Taylor JS, Pei A, et al.

A Simplified Method for Three-Dimensional Optical Imaging and Measurement of Patients with Chest Wall Deformities. J Laparoendosc Adv Surg Tech A (United States), Feb 2019, 29(2) p267-271

Reviewer #3: INTRODUCTION

Page 3:

First reference [1] is from 1975! Is there no newer data available?

Page 3:

You describe that radiographic measures can quantify …; but is it always necessary for diagnosis? What added value does CT (radiation exposure) have, especially for patients in adolescence. A small paragraph like diagnosis is based on … would be helpful.

Page 3:

A Correction Index of 10% - do you mean exactly or greater than?

METHODS

Page 4:

The cases referred for evaluation of pectus …; During which period were the patients selected? How many cases were obtained and how many were included in the study? Why did all patients undergo a CT?

Page 5:

Definition of Haller and Correction Index thresholds - taken from the literature?

RESULTS

Page 7:

The Haller Index measures …

The Correction Index measures …; just a repetition of the introduction / methods - can be shortened.

Page 8:

You describe significant associations; do the parameters mentioned have a predictive value?

Page 9:

correlated with age (p=0.0045); for real? Or 0.045?; if you look at the corresponding graph, p does not appear so clearly (see Haller Index / Height; p = 0.074)

Page 9:

992 subjects with repeat imaging; any therapy between imaging?

DISCUSSION

Page 10:

Perhaps this explains why most …; what kind of evaluation? Is a CT always necessary?

Page 11:

Ten-fold fewer DHS1 subjects …; Isn't it better to adjust the threshold for both indices?

In general:

Is the data of clinical relevance? Is there a predictive value from the parameters for the development of the funnel chest deformity? Should every patient undergo a CT?

Spelling:

You mixed up Haller index/Index or Correction index/Index – please unify!

**********

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PLoS One. 2020 May 7;15(5):e0232575. doi: 10.1371/journal.pone.0232575.r002

Author response to Decision Letter 0

14 Feb 2020

The authors wish to thank the reviewers for their thorough evaluation of the submitted manuscript. We are encouraged that the reviewers found the paper to be “one of the first of its kind.” We have addressed each of the reviewers’ comments point-by-point below.

1. Reviewer #1: As shown in Table 1, while evaluating the diagnostic indices of PE, was it necessary to include cases with pectus carinatum (PC)? The likelihood of decreased Haller index in PC patients might cause an underestimation in terms of the cases that fits the criteria.

We agree with the reviewer; the inclusion of the decreased index in pectus carinatum (PC) patients led to an underestimation of pectus excavatum (PE) cases. However, since there is a spectrum of phenotypes, including PE, PC, and mixed PE/PC, seen amongst patients referred to academic centers for pectus, we wanted to include a “real-world” patient cohort to compare against the population-based cohort. If we included only the patients who were categorized as PE by the pediatric surgeons, then the number of cases as defined by a HI>3.25, a CI>10%, or a HI>3.25 and CI>10% was 79%, 96%, and 78%, respectively. We show this graphically in Figure 3A. We have added a sentence to the Results that indicates this point (last sentence in the first Results paragraph): “A Correction index of >10% was found at the point of maximal depression in 96% of the PE cases, whereas a Haller index of >3.25 was found in fewer (78%) cases (Figure 3A).”

2. What was the diagnostic criteria for the reference pectus cases? Apparently, not all referred cases fit both the HI and CI criteria. Providing the detailed diagnostic criteria of these cases could increase the credibility of this sample.

We have included a sentence to the Methods to clarify the criteria for the reference pectus cases. “Cases included those diagnosed with a chest wall defect by a pediatric surgeon. Only those cases with an available thoracic computed tomography (CT) scan were included in the study...” Please also refer to the response to comment #10 below.

3. While evaluating the paired samples in DHS1 and DHS2, with such a large sample size, parametric tests are usually preferred due to their higher power. Did the samples not follow normal distribution? If so, the possibility of the sample being biased may need to be addressed.

The reviewer is correct that the measurements of HI and CI, and their differences between DHS1 and DHS2, did not follow a normal distribution. That is why we chose a conservative approach to use a nonparametric test. Although nonparametric tests can be slightly less powerful than parametric tests when the distribution is indeed normal (asymptotic relative efficiency ~95.5%), they are in fact more powerful when the distribution is non-normal (Lehman EL, Nonparametrics: Statistical Methods Based on Ranks). Furthermore, none of the conclusions changed when we used a paired t-test instead (see figure below). We prefer to use the nonparametric test, because it is a more appropriate approach given the distribution of the data.

At the same time, we would like to note that the distribution of HI and CI among participants with paired data was representative of the larger DHS cohort. That is, the deviation from normality was due to the presence of a small number of extreme observations at the upper end of the distribution. Thus, the deviation from normality is unlikely to reflect some bias in the data.

4. The estimated prevalence of undiagnosed, untreated adult pectus excavatum (1 in 250, or 0.4%) was higher than the assumed incidence of neonatal pectus excavatum, 1 in 400 (0.25%), in 1975, where CT was much less available. Do the authors have any theory in regard to this phenomenon?

As mentioned below in the response to comment #7 below, we have included additional references that demonstrate the wide range of the prevalence of pectus across different cohorts. The highest rate of pectus was found in the Coskun et al study of ~1300 Turkish students between 7-14 years of age, where the prevalence of pectus carinatum was 0.6% and the prevalence of pectus excavatum was 2.6% (or, approximately 1:40). The prevalence of pectus was 1.95% in a study that evaluated ~1300 11-14 year-old students from Brazil. The Rajabi-Mashhadi study found a prevalence of chest deformities of 1% in Iranian children aged 7-14 years. Pectus is one of the most common congenital abnormalities (prevalence of 0.8%) in ~20,000 Turkish schoolchildren, 6-15 years of age. The prevalence of pectus found in this study (1:250, or 0.4%) falls within the range of prevalence described across the five studies (0.25-2.6%) (references 1-5).

We have added text to the 2nd paragraph in the Discussion addressing this point. Cross-sectional studies have found that the Haller index tends to increase with age for pediatric populations. “Perhaps this explains why an estimates of pectus excavatum is lower in birth cohorts (1:400)[1] than in school-aged children[2,4,5] (up to 1:40[3]). Also, perhaps this is why most individuals are referred for surgical evaluation of chest wall abnormalities during adolescence.”

5. What is the clinical significance of this study? Do the authors have any expectation as to what changes this study might lead to in the management of adult PE?

We have modified the first paragraph in the Discussion to state the following: “It is striking that the radiographic measurements associated with pectus excavatum differ significantly by gender. Both the Haller and Correction indices are larger in females than males for both the case and control cohorts. Although the absolute numbers are small, we find that more females (0.5%) than males (0.3%) in the population cohort have pectus excavatum as defined by these indices. This finding is surprising since the literature suggests that a greater number of boys, usually 4-fold higher than girls, are referred for evaluation of pectus[6,19]. Even in the current study, there are 3.5 times more males than females in the pectus case cohort. Thus, there is strong referral bias to evaluate adolescent boys for pectus as breast development and modesty may mask the underlying chest wall defect in affected females. Future studies will need to determine the generalizability of these findings in unselected cohorts of different ages.” We have added the following statements to the Abstract: “Radiographic measures of pectus are more common in female than males… Despite the higher reported prevalence of pectus in adolescent males, this study demonstrates a higher prevalence of radiographic indices of pectus in adult females.”

It is unclear how these findings might lead to changes in the management of adult pectus. However, future studies could determine if there is an association between these quantitative measures with surgical or non-surgical treatment outcomes across the age spectrum.

Reviewer #2: Overall, the most important problem of this manuscript is its novelty. Similar studies have been done by other investigators before, with the same modality or other modality both. Just to list a few: Incidence and Classification of Chest Wall Deformities in Breast Augmentation Patients. Aesthetic Plast Surg (United States), Dec 2017, 41(6) p1280-1290; Relationship between cardiac MR compression classification and CT chest wall indexes in patients with pectus excavatum. J Pediatr Surg (United States), Nov 2018, 53(11) p2294-2298; Szafer D, Taylor JS, Pei A, et al.A Simplified Method for Three-Dimensional Optical Imaging and Measurement of Patients with Chest Wall Deformities. J Laparoendosc Adv Surg Tech A (United States), Feb 2019, 29(2) p267-271.

The authors respectively disagree with the reviewer on this point. The cohorts described in the references provided by the reviewer above include patients who underwent breast augmentation and those referred for evaluation of a chest wall abnormality. While multiple studies have evaluated the degree of deformity in pectus cohorts, we are not aware of one that has screened an unselected, longitudinal, multiethnic, population-based probability sampling of adults for chest wall abnormalities.

7. Reviewer #3: INTRODUCTION Page 3: First reference [1] is from 1975! Is there no newer data available?

The reference (Chung and Myrianthopoulos 1975) is the most cited reference estimating the prevalence of pectus in a birth cohort. We have added four additional references of studies that calculated the prevalence of pectus across different worldwide cohorts of children of various ages (References 2-5). The prevalence of pectus excavatum across all these studies ranges from 1:40 to 1:400. Please see our response to comment #4 above.

8. Page 3: You describe that radiographic measures can quantify …; but is it always necessary for diagnosis? What added value does CT (radiation exposure) have, especially for patients in adolescence. A small paragraph like diagnosis is based on … would be helpful.

We agree with the reviewer regarding this point. We have added a sentence in the Discussion (4th paragraph, 1st sentence) that “Although a CT scan of the chest is not needed to make the diagnosis of pectus, measurements from the imaging study offer metrics for comparison of cases against controls.”

9. Page 3: A Correction index of 10% - do you mean exactly or greater than?

We have edited the sentence as follows “a Correction index of greater than 10% is considered indicative of substantial pectus excavatum.”

10. METHODS Page 4: The cases referred for evaluation of pectus …; During which period were the patients selected? How many cases were obtained and how many were included in the study? Why did all patients undergo a CT?

Patients were recruited by East Virginia Medical Center from 2009-2017; and by UTSW from 2014-2017. Only patients with a CT scan of the chest that was available for review were included as cases in this manuscript. Thus, fewer patients were included as clinical cases in this study (58% and 17% of the total cohort collected from Virginia and UTSW, respectively). We have added these details to the Methods section.

While we assume that the chest CT scan was ordered to further evaluate the chest wall deformity, we were not able to determine the clinical indication(s) for the chest CT scans for all patients recruited from both centers.

11. Page 5: Definition of Haller and Correction index thresholds - taken from the literature?

Yes. The references are now included in the Methods section describing the index thresholds.

12. RESULTS Page 7: The Haller index measures … The Correction index measures …; just a repetition of the introduction / methods - can be shortened.

Thank you for the comment. We have shortened this section.

13. Page 8: You describe significant associations; do the parameters mentioned have a predictive value?

To determine if the Haller and Correction indices have a predictive value in distinguishing pectus excavatum cases from the general population, we have performed ROC curve analyses (figures shown below). For this analysis, we excluded the pectus carinatum and mixed cases, and compared clinical pectus excavatum cases to the DHS (controls). Pectus excavatum cases with HI > 3.25 and CI > 0.1 were considered as true positives. DHS participants with indices below these thresholds were considered as true negatives. Overall, HI and CI parameters were able to discriminate between PE cases and DHS controls quite well, with areas under the ROC curve (AUROC) greater than 97% for HI and CI measured at the level of superior xiphoid (SX). CI >10% at the level of SX had the best performance, with sensitivity and specificity both greater than 94%. Although these results look promising, we would like to point out that we consider them preliminary, since the comparison populations were very different with respect to age, gender, and ethnicity. Future studies will be required to validate these findings before the HI and CI parameters can be used in the clinic for routine screening or diagnosis of subjects.

14. Page 9: correlated with age (p=0.0045); for real? Or 0.045?; if you look at the corresponding graph, p does not appear so clearly (see Haller index / Height; p = 0.074)

Yes, the p-value as indicated (p=0.0045) is correct. The trend is very modest, but given the sample size, we can detect even a small non-zero trend with relatively high level of significance.

15. Page 9: 992 subjects with repeat imaging; any therapy between imaging?

There was no chest wall specific therapy between imaging. In fact, we excluded DHS scans if there was evidence of chest trauma or a prior thoracic surgical procedure (described in Methods).

16. DISCUSSION Page 10: Perhaps this explains why most …; what kind of evaluation? Is a CT always necessary?

We have revised the sentence to improve its clarity. Comment #4 (above) also described the modification of this sentence.

17. Page 11: Ten-fold fewer DHS1 subjects …; Isn't it better to adjust the threshold for both indices?

We agree with the reviewer that we could adjust the threshold in adults for both indices based upon their distribution found in the normal cohort. A threshold of greater than 2 standard deviations from the mean would be equivalent to a HI > 2.759 and a CI > 0.117. (Under the assumption of a normal distribution, approximately 2.5% of samples would be expected to exceed this value. In DHS-1, 3.46% and 3.42% exceed the threshold for HI and CI, respectively, reflecting the presence of extreme observations and a deviation from a normal distribution.) A threshold of greater than 3 standard deviations from the mean would be equivalent to a HI > 3.05 and a CI > 0.152. (In DHS-1, 0.93% and 1.07% exceed these thresholds, compared to 0.135% expected under the normal distribution). While these thresholds would be applicable to adult multiethnic cohorts, they would not be applicable to adolescent pectus case cohorts.

18. In general: Is the data of clinical relevance? Is there a predictive value from the parameters for the development of the funnel chest deformity? Should every patient undergo a CT?

This question is very similar to question #5 posed by Reviewer #1. Kindly refer to comment #5.

19. Spelling: You mixed up Haller index/Index or Correction index/Index – please unify!

We have revised the text so that capitalization of the word “index” is uniform.

Thank you.

Best regards,

Christine Kim Garcia, MD, PhD

Attachment

Submitted filename: Reponse letter_2.14.2020.doc

Click here for additional data file. (6.3MB, doc)

Decision Letter 1

JJ Cray Jr

20 Apr 2020

Prevalence of Pectus Excavatum in an Adult Population-Based Cohort Estimated from Radiographic Indices of Chest Wall Shape

PONE-D-19-18160R1

Dear Dr. Kim Garcia,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

JJ Cray Jr., Ph.D.

Academic Editor

PLOS ONE

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1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

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Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: N/A

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes: Chai, Jyh-Wen

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Acceptance letter

JJ Cray Jr

28 Apr 2020

PONE-D-19-18160R1

Prevalence of Pectus Excavatum in an Adult Population-Based Cohort Estimated from Radiographic Indices of Chest Wall Shape

Dear Dr. Kim Garcia:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. JJ Cray Jr.

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Demographic characteristics of participants.

    (DOCX)

    Click here for additional data file. (16KB, docx)
    S2 Table. Haller and correction index measurements in pectus cases and DHS cohorts at multiple axial levels (T6, T8 and superior xiphoid) by gender.

    (DOCX)

    Click here for additional data file. (18.8KB, docx)
    S3 Table. Prevalence of pectus excavatum in cases and population-based cohorts.

    (DOCX)

    Click here for additional data file. (19.6KB, docx)
    S4 Table. Chest wall shapes in population-based cohorts by ethnicity.

    (DOCX)

    Click here for additional data file. (19.2KB, docx)
    S5 Table. Linear models of the haller and correction index of the Dallas Heart Study (DHS1) cohort (n = 2685) at three axial levels (T6, T8 and superior xiphoid).

    (DOCX)

    Click here for additional data file. (19.4KB, docx)
    S6 Table. Linear models of chest wall shape for the unrelated Dallas Heart Study (DHS2) cohort (n = 788) at three axial levels (T6, T8 and superior xiphoid).

    (DOCX)

    Click here for additional data file. (19.4KB, docx)
    Attachment

    Submitted filename: Reponse letter_2.14.2020.doc

    Click here for additional data file. (6.3MB, doc)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

    Articles from PLoS ONE are provided here courtesy of PLOS

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