Literature DB >> 31601901

The age distribution of facial metrics in two large Korean populations.

Hae-Young Lee1, Seongwon Cha2, Hyo-Jeong Ban2, In-Young Kim1, Bo-Reum Park1, Ig-Jae Kim3, Kyung-Won Hong4.   

Abstract

Growth and alterations in craniofacial morphology have attracted interest in many fields of science, especially physical anthropology, genetics and forensic sciences. We performed an analysis of craniofacial morphology alterations by gender and ageing stage in Korean populations. We studied 15 facial metrics using two large Korean populations (1,926 samples from the Korea Medicine Data Center cohort and 5,643 samples from the Ansan-Ansung cohort). Among the 15 metrics, 12 showed gender differences and tended to change with age. In both of the independent populations, brow ridge height, upper lip height, nasal tip height, and profile nasal length tended to increase with age, whereas outer canthal width, right palpebral fissure height, left palpebral fissure height, right upper lip thickness, left upper lip thickness, nasal tip protrusion, facial base width, and lower facial width tended to decrease. In conclusion, our findings suggest that ageing (past 40 years of age) might affect eye size, nose length, upper lip thickness, and facial width, possibly due to loss of elasticity in the face. Therefore, these facial metric changes could be applied to individual age prediction and aesthetic facial care.

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Year:  2019        PMID: 31601901      PMCID: PMC6786987          DOI: 10.1038/s41598-019-51121-z

Source DB:  PubMed          Journal:  Sci Rep        ISSN: 2045-2322            Impact factor:   4.379


Introduction

The appearance of the face typically changes in different dimensions and directions with age[1,2]. This phenomenon, known as allometry, is the reason why young faces are distinct from old faces[3]. Growth and alteration in craniofacial morphology have generated interest in many fields of science, especially physical anthropology[4,5] and genetics[6,7]. Additionally, alternative applications of craniofacial morphology, such as forensic science, have received considerable attention[8]. In the field of Korean Oriental medicine, facial metrics are regarded as representative and reliable characteristics for diagnosing a person’s Sasang constitution[9]. Previously, we performed a two-stage genome-wide association study of facial morphological traits in two large Korean populations (1,926 samples from the Korea Medicine Data Center (KDC) cohort and 5,643 samples from the Ansan-Ansung cohort)[6]. We speculated that the ageing-related trends in each facial metric might be important for human evolution and appearance. In this study, we compared 15 facial metrics – (a) BRH, brow ridge height; (b) IW, intercanthal width; (c) OW, outer canthal width; (d) RPFH, right palpebral fissure height; (e) LPFH, left palpebral fissure height; (f) NBH, nasal bridge height; (g) ULH, upper lip height; (h) RULT, right upper lip thickness; (i) LULT, left upper lip thickness; (j) SW, subnasal width; (k) PNL, profile nasal length; (l) FBW, facial base width; (m) NTH(V), nasal tip height (vertical); (n) NTP(H), nasal tip protrusion (horizontal); and (o) LFW, lower facial width – for each of four age groups (40 s, 50 s, 60 s and over 70 s) using the KDC and Ansan-Ansung cohorts as the replication set (Fig. 1). For example, the brow ridge is the nodule or crest of bone that is situated on the frontal bone of the skull[10], forming the boundary between the forehead itself and the tops of the eye sockets. Normally, in humans, the ridges arch over each eye, offering mechanical protection[11]. Typically, the arches are more prominent in men than in women and vary between different ethnic groups[12].
Figure 1

Facial changes from age 40 years to age 70+ years. (a) BRH, brow ridge height; (b) IW, intercanthal width; (c) OW, outer canthal width; (d) RPFH, right palpebral fissure height; (e) LPFH, left palpebral fissure height; (f) NBH, nasal bridge height; (g) ULH, upper lip height; (h) RULT, right upper lip thickness; (i) LULT, left upper lip thickness; (j) SW, subnasal width; (k) PNL, profile nasal length; (l) FBW, facial base width; (m) NTH(V), nasal tip height; (n) NTP(H), nasal tip protrusion; and (o) LFW, lower facial width.

Facial changes from age 40 years to age 70+ years. (a) BRH, brow ridge height; (b) IW, intercanthal width; (c) OW, outer canthal width; (d) RPFH, right palpebral fissure height; (e) LPFH, left palpebral fissure height; (f) NBH, nasal bridge height; (g) ULH, upper lip height; (h) RULT, right upper lip thickness; (i) LULT, left upper lip thickness; (j) SW, subnasal width; (k) PNL, profile nasal length; (l) FBW, facial base width; (m) NTH(V), nasal tip height; (n) NTP(H), nasal tip protrusion; and (o) LFW, lower facial width.

Results

Gender differences

The distribution characteristics of 15 facial metrics are described in Table 1 and plotted in Fig. 1 by gender and age group in the KDC and Ansan-Ansung cohorts. The prominent gender differences were identified by the sex differences in the overall sample, as shown in Table 1, and the age distribution of sex differences, as shown in Fig. 1. Among the 15 facial metrics, six metrics (OW, NBH, ULH, SW, FBW, and LFW) appeared to be greater in males than in females in the overall sample comparison in both the KDC and Ansan-Ansung cohorts. In the age distribution of gender differences in Fig. 1, 12 metrics (BRH, OW, NBH, ULH, RPFH, LPFH, SW, PNL, FBW, NTH(V), NTP (H), LFW) showed gender differences. Interestingly, 4 metrics (RPFH, LPFH, RULT, LULT) were larger in females than in males.
Table 1

Means and standard deviations of facial metrics in KDC and Ansan-Ansung populations.

Coordinate*PhenotypePhenotype descriptionSexPopulationMeans and standard deviations of facial metrics in each age group (mm)ANOVA testLinear regression
Total40506070p-valueAdjusted for ageAdjusted by age and BMI
NMeanSDNMeanSDNMeanSDNMeanSDNMeanSDBetaStd. errorSig.BetaStd. errorSig.
(a) BRH Brow ridge height Male KDC 670 29.84.3 145 29.8 4 147 29.54.6 106 30.64.5 73 31.14.9<0.050.100.02<0.050.110.02<0.05
Ansan-Ansung 2541 29.74.3 245 29.33.8 1222 29.5 4 658 30.14.8 416 30 4.7<0.010.070.01<0.0010.110.01<0.001
Female KDC 1164 28.7 4 255 28.23.6 250 28.53.9 178 28.54.4 123 29.9 5 <0.010.120.01<0.010.100.01<0.01
Ansan-Ansung 2721 29 3.9 216 28.43.6 1191 28.43.5 808 29.23.9 506 30.44.3<0.0010.180.01<0.0010.180.01<0.001
(b)IWIntercanthal widthMaleKDC70836.53.815536.63.616035.93.311335.74.17434.84.5<0.01−0.180.02<0.001−0.170.02<0.001
Ansan-Ansung260435.63.824835.93.3125235.73.567435.43.943035.74.50.233−0.030.010.16−0.030.010.13
FemaleKDC126336.43.527536.73.327435.93.619035.33.813135.53.5<0.001−0.150.01<0.001−0.150.01<0.001
Ansan-Ansung297835.83.524535.63128635.63.187135.83.657636.24.2<0.010.050.01<0.050.050.01<0.01
(c) OW Outer canthal width Male KDC 716 99.7 7 156 99.76.7 160 99.46.8 117 99.97.2 77 97 8.7<0.05−0.120.03<0.01−0.100.03<0.05
Ansan-Ansung 2624 99 6.5 249 100.45.2 1254 100.35.9 686 97.96.6 435 96.47.3<0.001−0.250.01<0.001−0.170.01<0.001
Female KDC 1275 95.36.2 275 95.85.2 274 94.56.1 193 94.8 7 140 93 7.3<0.001−0.140.02<0.001−0.160.02<0.001
Ansan-Ansung 2982 95 5.9 246 96.34.9 1286 96.15.3 874 94.6 6 576 92.96.8<0.001−0.210.01<0.001−0.220.01<0.001
(d) RPFH Right palpebral fissure height Male KDC 717 7.71.4 155 7.91.4 162 7.71.5 117 7.51.3 77 7.21.5<0.001−0.170.01<0.001−0.180.01<0.001
Ansan-Ansung 2629 7.51.4 249 7.81.4 1254 7.71.4 689 7.31.5 437 7.11.5<0.001−0.190.00<0.001−0.210.00<0.001
Female KDC 1277 8.51.7 275 8.91.5 276 8.31.6 195 7.61.5 141 7 1.7<0.001−0.400.00<0.001−0.390.00<0.001
Ansan-Ansung 2986 7.71.6 245 8.51.4 1285 8.31.4 876 7.41.5 580 6.81.4<0.001−0.400.00<0.001−0.400.00<0.001
(e) LPFH Left palpebral fissure height Male KDC 715 7.91.5 155 8 1.4 162 8 1.6 116 7.41.4 75 7.21.6<0.001−0.210.01<0.001−0.220.01<0.001
Ansan-Ansung 2626 7.71.5 250 7.91.3 1252 8 1.4 688 7.51.5 436 7.21.6<0.001−0.210.00<0.001−0.220.00<0.001
Female KDC 1279 8.51.7 275 8.91.4 276 8.31.6 194 7.61.7 142 7.31.6<0.001−0.370.00<0.001−0.350.00<0.001
Ansan-Ansung 2977 7.81.6 246 8.61.5 1283 8.41.5 872 7.41.5 576 6.91.6<0.001−0.400.00<0.001−0.400.00<0.001
(f)NBHNasal bridge heightMaleKDC68035.84.115035.83.9149363.711035.94.57435.44.40.609−0.020.020.59−0.030.020.48
Ansan-Ansung256136.13.924635.93.51229363.866736.1441936.44.40.1120.040.01<0.050.000.010.89
FemaleKDC121033.33.826433.53.426033.33.918532.83.813432.44.3<0.01−0.100.01<0.01−0.090.01<0.05
Ansan-Ansung282632.93.623032.83.51224333.483132.93.754132.840.372−0.020.010.41−0.010.010.52
(g)ULHUpper lip heightMaleKDC67529.5314729.42.915429.82.911230.53.26730.13.6<0.050.110.01<0.050.120.01<0.01
Ansan-Ansung252430.22.824229.62.5122630.32.764930.22.940730.43.20.06120.040.010.050.050.01<0.01
FemaleKDC125227.92.627027.82.327128.52.619028.62.713828.73.1<0.0010.110.01<0.0010.100.01<0.01
Ansan-Ansung294128.92.624328.42.2127928.92.385929.12.756028.830.2450.020.010.290.020.010.33
(h)RULTRight upper lip thicknessMaleKDC6772.10.21502.20.21552.10.21082.10.36620.3<0.001−0.180.00<0.001−0.180.00<0.001
Ansan-Ansung24762.10.22422.10.212162.10.263120.238720.3<0.001−0.220.00<0.001−0.220.00<0.001
FemaleKDC12562.20.22722.20.22722.10.21902.10.21332.10.2<0.001−0.130.00<0.001−0.130.00<0.001
Ansan-Ansung29412.10.22452.20.212822.20.28552.10.25592.10.3<0.001−0.250.00<0.001−0.250.00<0.001
(i)LULTLeft upper lip thicknessMaleKDC6832.10.21522.10.21532.10.21082.10.26920.3<0.001−0.180.00<0.001−0.180.00<0.001
Ansan-Ansung247620.22412.10.212122.10.263420.238920.3<0.001−0.190.00<0.001−0.190.00<0.001
FemaleKDC12552.20.22722.20.22722.20.21902.10.21322.10.2<0.01−0.120.00<0.001−0.130.00<0.001
Ansan-Ansung29462.10.22442.20.212832.20.28592.10.256020.3<0.001−0.250.00<0.001−0.250.00<0.001
(j)SWSubnasal widthMaleKDC682273148272.815727.33.310927.42.97227.32.50.4370.020.010.600.030.010.46
Ansan-Ansung255627.92.624427.92.71228282.766127.92.642327.72.50.0811−0.040.01<0.05−0.010.010.51
FemaleKDC125324.62.726924.62.527224.82.619225.52.613624.92.8<0.050.090.01<0.050.060.010.07
Ansan-Ansung295725.32.424424.52.21280252.286725.62.4566262.5<0.0010.200.01<0.0010.190.00<0.001
(k)PNLProfile nasal lengthMaleKDC6853.90.11513.90.11493.90.111140.17540.1<0.050.080.000.080.080.000.09
Ansan-Ansung25663.90.12443.90.112353.90.16693.90.141840.1<0.0010.130.00<0.0010.120.00<0.001
FemaleKDC12113.90.12633.90.12623.90.11823.90.11353.90.10.556−0.020.000.50−0.020.000.56
Ansan-Ansung28093.80.12263.80.112283.80.18323.80.15233.90.1<0.0010.090.00<0.0010.090.00<0.001
(l)FBWFacial base widthMaleKDC7031569.1154157.69.1159156.79.3117155.28.776151.810.4<0.001−0.220.04<0.001−0.200.03<0.001
Ansan-Ansung2609156.48.6246158.77.41244158.28.1681154.38.5438153.39.4<0.001−0.260.02<0.001−0.130.02<0.001
FemaleKDC1258148.17.6271148.36.9269147.87.4194147.88.4142147.39.30.237−0.040.020.23−0.090.02<0.01
Ansan-Ansung2975148.87.42451496.81281149.56.9869148.67.5580147.68.4<0.001−0.090.02<0.001−0.100.01<0.001
(m)NTH(V)Nasal tip heightMaleKDC6892.70.21482.60.21532.70.11162.70.2762.70.2<0.0010.180.00<0.0010.190.00<0.001
Ansan-Ansung25632.60.12452.60.112362.60.16662.60.14162.70.2<0.0010.150.00<0.0010.180.00<0.001
FemaleKDC12022.60.12602.60.12612.60.11822.60.11332.70.2<0.0010.150.00<0.0010.130.00<0.001
Ansan-Ansung27752.60.12282.50.112152.60.18182.60.15142.60.1<0.0010.130.00<0.0010.130.00<0.001
(n)NTP (H)Nasal tip protrusionMaleKDC6822.60.21452.60.21562.60.21112.60.2762.50.2<0.01−0.130.00<0.01−0.130.00<0.01
Ansan-Ansung25782.60.22482.60.212382.60.16692.50.24232.50.2<0.001−0.110.00<0.001−0.120.00<0.001
FemaleKDC11832.50.22602.50.12542.50.21832.50.21242.40.2<0.001−0.240.00<0.001−0.220.00<0.001
Ansan-Ansung28142.40.22272.40.212292.50.28292.40.25292.40.2<0.001−0.150.00<0.001−0.150.00<0.001
(o)LFWLower facial widthMaleKDC697136.510.3153138.7101561389.5116135.69.974134.511.5<0.001−0.190.04<0.001−0.160.04<0.001
Ansan-Ansung2592138.19.7246140.58.81245140.19.2674136.19.74271349.9<0.001−0.260.02<0.001−0.130.02<0.001
FemaleKDC1256128.48.7270128.98.32691298.3193129.69.2142128.79.70.8050.000.030.96−0.070.02<0.05
Ansan-Ansung2971130.582461317.71280131.27.5868130.58.1577128.48.7<0.001−0.120.02<0.001−0.130.01<0.001
Means and standard deviations of facial metrics in KDC and Ansan-Ansung populations.

Age group comparison

Age group differences were analysed by Student’s t-tests comparing the 40 s age group to the 50 s, 60 s and 70 s age groups. BRH, ULH, and NTH (v) are slightly increased in the 60 s age group in both cohorts and in both genders (Fig. 1a,g,m). OW, RULT, LULT, and NTP (H) were slightly decreased in the 60 s age group in both cohorts and in both genders (Fig. 1c,h,I,n). RPFH and LPFH showed a considerably decreased pattern in both cohorts and in both genders, and the pattern was prominent in females in both cohorts (Fig. 1d,e). Although FBW and LFW showed a considerably decreased pattern in both cohorts and in both genders, the pattern was prominent in males in both cohorts (Fig. 1l,o). PNL showed a slight increase in both cohorts, but only in males (Fig. 1k). IW, NBH, and SW seemed to have no clear pattern (Fig. 1b,f,j). To understand in greater detail the effect of ageing on facial metrics, we constructed linear regression models with age and/or body mass index as covariates. We identified a significant linear increasing tendency of BRH and NTP and a decreasing tendency of OW, RPFH, LPFH, RULT, LULT, NTH, and NTP in both cohorts and in both sexes (Table 1).

Ethnic comparison of the human orbital region

Facial metrics in the orbital region, including PFH, IW, and OW, were compared between Koreans and other ethnicities (Fig. 2). RPFH and LPFH were relatively low among non-Asians relative to Asians (Fig. 2A). The Korean subjects had a large OW, ranking between those of Japanese and Indian individuals, whereas the IW was of Koreans was smaller than those of other Asian populations, such as Japanese and Chinese (Fig. 2B,C). Interestingly, the gender difference in IW was no more prominent in Koreans than in other ethnic groups.
Figure 2

Ethnic comparison of the human orbital region. (A) Palpebral fissure height, (B) intercanthal width, and (C) outer canthal width. The data on ethnicities other than Korean were obtained from Vasanthakumar et al.[14].

Ethnic comparison of the human orbital region. (A) Palpebral fissure height, (B) intercanthal width, and (C) outer canthal width. The data on ethnicities other than Korean were obtained from Vasanthakumar et al.[14].

Discussion

In this study, we analysed 15 facial metrics for gender differences and for ageing-related changes in two large Korean cohorts. Among these 15 metrics, 12 showed gender differences and tendencies toward age-related change. Increasing tendencies were observed in BRH, ULH, NTH, and PNL, and decreasing tendencies were observed in OW, RPFH, LPFH, RULT, LULT, NTP, FBW, and LFW. The decreasing tendencies were not changed even when adjusted for body mass index, indicating that some other structures under the skin (such as collagen and muscle) were reduced in the aged population. In the orbital region, BRH showed a tendency to increase with age in both the KDC and Ansan-Ansung cohorts. The BRH is the nodule or crest of bone situated on the frontal bone of the skull[10]; this ridge separates the forehead itself from the tops of the eye sockets. Normally, in humans, the ridges arch over each eye, offering mechanical protection[11]. Typically, the arches are more prominent in men than in women and vary between different ethnic groups[12]. “RPFH” and “LPFH” are abbreviations for the right and left palpebral fissure height. The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eyelids. There are many studies of palpebral fissure height; this metric is approximately 10 mm in adults and is smaller in East Asian populations than in white populations[13,14]. The gender differences in palpebral fissure height have been well summarized in reports on a South Indian population[14]. The bilateral orbital region, which is part of the upper face, acts as a key determinant of the perception of facial attractiveness, youthfulness and health[14]. Our comparison of palpebral fissure height implies that a very small PFH is a typical Korean facial characteristic (Fig. 2A). IW did not show any alteration with age, but OW showed a prominent decreasing pattern. The ethnic comparison of Fig. 2B,C showed that our study group had a shorter IW than Japanese or Chinese individuals, but the gender difference was no more prominent in Koreans than in other ethnic groups. In contrast, the OW of our study population was relatively large and was similar to that of the Japanese population. Therefore, the characteristics of the orbital region of Koreans are a small palpebral height and a wide canthal region. In the nasal area, the NTH slightly increased with age, and the NTP slightly decreased with age, but the NBH did not show any tendency to change. Additionally, the profile nasal length increased slightly with ageing only in males. The nasal tip is a challenging part of the nose for plastic surgeons because of variations in the anatomy of the lower lateral cartilage[15]. Therefore, our results help to clarify the direction of surgical correction for nasal tip deformities. In the orthodontic region, the ULH slightly increased with ageing, and the RULT and LULT showed slight decreases with ageing. The upper lip is an important attractive point for the smile. According to Hulsey, the “smile is one of the most effective means by which people convey their emotions”[16]. The ULH is affected by the gingival margin of the upper central incisors and influences the attractiveness of a smile[16]. Generally, a shorter ULH indicates a higher smile line. On average, the smile line was found to be 1.5 mm higher in women than in men[17]; similarly, in the current study, the ULH was greater in males than in women, indicating a shorter smile line in women (see Table 1g). Although the concept of beauty has changed throughout the centuries, the thickness of the upper lip has always been a subject of interest and has importance in every culture[18]. These results may be beneficial to forensic anthropologists, plastic and reconstructive surgeons, and orthodontists. Regarding overall facial width, both FBW and LFW slightly decreased with ageing, and the tendency was more prominent in male than female subjects. Facial width is reportedly associated with testosterone levels in males[19]. Therefore, the decrease in testosterone in elderly males may decrease the facial width.

Conclusion

Our study found that 12 of 15 facial metrics changed with age in subjects of both genders. The changes in eye size, nose length, upper lip thickness, and facial width might be general trends in Koreans because of the consistent tendencies in two large independent cohorts. Changes in facial metrics could serve as indicators to predict age from photographs and would be helpful for aesthetic facial care. To our knowledge, there are very few studies on the alteration of facial metrics with ageing, particularly in groups over 40 years old. Moreover, our study did not analyse the facial ageing of other ethnic populations. Therefore, we hope that the currents results will be validated in other ethnic groups and applied to diverse fields.

Materials and Methods

Study participants

A total of 1,926 participants in the KDC cohort were recruited from 19 sites (Korean Oriental Medical Clinics) between 2007 and 20106, and a total of 5,643 participants in the Ansan-Ansung cohorts were recruited from two regions in southern Korea from 2009 to 2012 for the Korean Genome and Epidemiology Study (KoGES)[6,20] (Table 2). The subjects were photographed with a neutral expression in both frontal and profile views under the following standard conditions: the hair should be pulled back with a hair band; the centre points of the two pupils should be horizontally aligned, as should the upper auricular perimeters; and a ruler should be placed approximately 10 mm below the chin to convert pixels into millimetres. All participants provided written informed consent to participate in the study. This protocol was approved by the Korea Institute of Oriental Medicine Institutional Review Board (I-0910/02-001), and all research was performed in accordance with the relevant guidelines/regulations.
Table 2

Study Population Characteristics.

PhenotypesPopulationTotalMaleFemale
N Mean SD N Mean SD N Mean SD
BMI (kg/m2)KDC1,40823.83.172424.03.11,28423.13.3
Ansan-Ansung5,64324.43.12,64824.32.92,99524.63.2
Age (years)KDC1,40857.110.872456.910.51,28457.211.0
Ansan-Ansung5,64360.48.52,64859.98.42,99560.98.6
Study Population Characteristics.

Craniofacial measurements

Detailed descriptions of candidate feature variables and the corresponding measurement methods have been provided in a previous report[6,9]. Briefly, the facial variables were limited to those that could be easily quantified. Facial feature points in frontal and lateral images were automatically extracted by detecting and analysing the face, eyes, nose, mouth, and contours via an in-house program in Visual Studio C++ using OpenCV (Open Source Computer Vision Library). The positions of the extracted points were confirmed by a well-trained operator (accuracy: 98.8% on average). Fifteen facial metrics, each defined by the distance between two facial points, were derived from the photographs by converting pixels into millimetres using MATLAB software[21]. For statistical analysis, 5 severely skewed facial variables, including PNL, NTH(V), NTP(H), RULT, and LULT, were ln transformed. We removed the outliers, which were defined using the first and third quartiles and the interquartile range of each facial variable. In each facial variable, measurements below the first quartile – 2.0 × interquartile range or above the third quartile + 2.0 × interquartile range were defined as outliers and excluded.

Statistical analysis

For each facial variable, the mean length was compared between age groups (40 s vs 50 s, 60 s or 70+) using Student’s t-test. Additionally, the mean lengths of male and female facial variables were plotted (Fig. 1) for both the KDC and Ansan-Ansung cohorts. We used the following criteria to identify phenotypes that tended to change with age: the mean underwent a significant gradual increase or decrease (p < 0.05), and the pattern appeared to be similar between the KDC and Ansan-Ansung cohorts.
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8.  Analysis of Sasang constitutional types using facial features with compensation for photographic distance.

Authors:  Jun-Hyeong Do; Boncho Ku; Jun-Su Jang; Honggie Kim; Jong Yeol Kim
Journal:  Integr Med Res       Date:  2012-10-16

9.  Identification of five novel genetic loci related to facial morphology by genome-wide association studies.

Authors:  Seongwon Cha; Ji Eun Lim; Ah Yeon Park; Jun-Hyeong Do; Si Woo Lee; Chol Shin; Nam Han Cho; Ji-One Kang; Jeong Min Nam; Jong-Sik Kim; Kwang-Man Woo; Seung-Hwan Lee; Jong Yeol Kim; Bermseok Oh
Journal:  BMC Genomics       Date:  2018-06-19       Impact factor: 3.969

10.  A classification method of normal and overweight females based on facial features for automated medical applications.

Authors:  Bum Ju Lee; Jun-Hyeong Do; Jong Yeol Kim
Journal:  J Biomed Biotechnol       Date:  2012-08-05
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