Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with meta-analysis

Table 3 Selected studies

Ref.	Study design	Publication	Spine deformity	Age (mean/range)	Gender	n	Treatment	Initial Cobb angle(degree)	Follow-up	Drop out	Progression of deformitycriteria	Analysis/Method ofprediction	Indicesused	Prediction validity(progressive vs stable spine deformities)
Upadhyay et al[73]	RCS	Art.	Thoracic, thoracolumbar, lumbar	< 18 Risser sign ≤ 2	NS	85	Brace	20-45	Until skeletal maturity or surgical tretment	NS	Cobb increasing ≥ 5o, and/or vertebral rotation ≥ 5o	Comparative analysis of progress vs stable cases	Predictor: Increase of Cobb angle and/or vertebral rotation ≥ 5o at 1-2 mo follow-up during brace treatment	OR = 33.23 (95%Cl: 4.0-270.4) P < 0.001 (1) Sensitivity: 39%; (2) Specificity: 98%; (3) +PV: 93%; and (4) -PV: 72%
Peterson et al[62]	PChS	Art.	Thoracic, thoracolumbar	10-15	F (100%)	159	Observation (120) Electrical stimulation (39)	25-30	Until skeletal maturity	NS	Cobb increasing ≥ 6o	Multiple logistic regression modeling	Predictors: (1) Risser sign (0-1); (2) Apical level (uperTh12); (3) Imbalance (10 mm); and (4) Age	(1) Sensitivity: 81%2; (2) Specificity: 81%; (3) +PV: 82%; and (4) -PV: 80%
Ajemba et al[60]	RChS	Art.	NS	12.3 (10-15)	F (87%) M (14%)	44	Observation (30) Brace (14)	18-49	1 yr - skeletal maturity	NS	Cobb increasing ≥ 5o	6 multiple support vector classifier models	Predictors: (1)16 Lenke Rad. Indices; (2)Wrist X-ray; (3) Age; (4) Sex; and (5) Growing index	(1) Sensitivity: 67%-91%2; (2) Specificity: 22%-67%; (3) +PV: 73%-86%; and (4) -PV: 43%-67%
1Cheung et al[64]	PCS	Art.	Right thoracic	10-16	F (87%) M (13%)	30	NS	10-60	4-5 mo	NS	Cobb increasing >10o	Multiple regression modeling, nomogram	Predictor: (1) Spinal grows velocity (≥ 11 mm/yr); (2) Paraspinal EMG activity concave/convex ≥ 1.3	(1) Sensitivity: 69%-79%2; (2) Specificity: 69%-79%; and (3) +PV: 60%-89%
1Danielsson et al[63]	PChS	Art.	Thoracic, Thoracolumbar	10-15 (skeletal)	F (100%)	92	Observation Brace and electrical stimulation	25-35	16 yr	14%	Cobb increasing ≥ 6o	Rate comparison	Predictor: Premenarche at inclusion vs menarche at inclusion	OR = 2.523 (95%Cl: 1.0-6.11) P = 0.05 (1) Sensitivity: 60%; (2) Specificity: 63%; (3) +PV: 53%; and (4) -PV: 70%
Kindsfater et al[46]	RCS	Art.	Thoracic, thoracolumbar	11-20	F (71%) M (29%)	17	Observation (7) Brace (10)	34 (15-90)	< 1 yr	NS	Cobb > 30o; Increasing > 10o /yr	Comparative analysis of progress vs stable cases	Predictor: Level of platelet calmodulin (ng/μg of protein): progressive 1.4-10.7; stable < 1.4 (P = 0.001)	OR = 275.03 (95%Cl: 4.8-15724.2) P = 0.007 (1) Sensitivity: 100%; (2) Specificity: 100%; (3) +PV: 100%; and (4) -PV: 100%
1Lowe et al[47]	PChS	Art.	King I-V	Adolescents	F (93%) M (7%)	55	Observation (28) Brace (17) Fusion(10)	≤ 25	1-3 yr	9.80%	Cobb increasing > 10o /yr	Comparative analysis of progress vs stable cases	Predictor: Increasing of platelet calmodulin level during first year of observation	OR = 11.03 (95%Cl: 1.7-69.9) P = 0.02 (1) Sensitivity: 69%; (2) Specificity: 83%; (3) +PV: 85%; and (4) -PV: 67%
Sun et al[67]	RCS	Art.	Thoracic, thoracolumbar, lumbar	10-16	F (100%)	142	Brace	20-40	0.6-5.9 yr	NS	Cobb exceeding 45o, surgical tretment	Multiple logistic regression modeling	Predictors: (1) Premenarche; (2) Curve > 30o; and (3) Risser sign: 0-1	OR: 5.1-11.52P ≤ 0.002 (1) Sensitivity 72%-89%3; (2) Specificity 48%-77%; (3) +PV: 20%-33%; and (4) -PV: 94%- 97%
1Sun et al[66]	RCS	Art.	Thoracic, thoracolumbar	10-15	F (100%)	68	Brace	20-40	3-6 mo	NS	Cobb increasing > 6o, or exceeding 45o	Comparative analysis of progress vs stable cases	Predictors: (1) Premenarche; (2) Curve > 30o; (3) L2-L4 BMD < 0.76 g/cm2; and (4) Thoracic curve	OR: 6.6-11.22 (0.001 > P < 0.072) (1) Sensitivity: 74.5%; (2) Specificity: 64.7%
Hung et al[65]	PCS	Art.	Thoracic, thoracolumbar, lumbar	11-16	F (100%)	324	Observation	20-30	0.5-3.5 yr	NS	Cobb increasing > 6o,	Multiple logistic regression modeling	Predictors: (1) Age at diagnosis < 13 yr; (2) Premenarche; (3) Risser sign: 0-1; (4) Curve pattern: thoracic or thoracolumbar; and (5) Initial Cobb angle > 30o; Osteopenia: decreased hip neck BMD at concave side	OR: 2.1-4.62 (0.001 > P < 0.044) (1) Sensitivity: 76% (95%Cl: 69-83); (2) Specificity: 70% (95%Cl: 62-77)
Lam et al[74]	PChS	Art.	NS	11-16	F (100%) Chinese population	294	Observation (192), Brace (102)	> 10; Mean: 26 (St. D, 8.2o)	Mean, 3.4 yr (St. D, 1.57o)	NS	Cobb increasing > 6o	Multiple logistic regression modeling	Predictors: (1)Age at diagnosis 11-13 yr, (2) Premenarche; (3) Initial Cobb angle > 25o; and (4) Ultrasound bone stiffness index (calcaneus) Z-score ≤ 0	OR: 2.0-8.62 (0.0001 > P < 0.2) (1) Sensitivity: 84.7%; (2) Specificity: 66.5%
Lee et al[68]	RCS	Art.	NS	10-17	F (82.3%) M (17.7%)	1858 450	Brace (331)	10-30	NS	NS	Cobb > 30o	Risk assessment	Predictor: Initial Cobb angle ≥ 26ovs 8o-10o	Hazard ratio, 8.82 (95%Cl: 6.85-11.31)
Tan et al[36]	PCS	Art.	NS	7-14	F (84.9%) M (15.1%)	186	Observation Brace	> 10	1-8 yr	18%	Cobb ≥ 30o	Risk assessment	Predictor: Initial Cobb angle ≥ 25ovs < 25o	OR = 24.62 (95%Cl: 9.9-60.6) P < 0.001 (1) Sensitivity: 68%3; (2) Specificity: 92%; (3) +PV: 68%; and (4) -PV: 92%
Modi et al[77]	RCS	Art.	Thoracic, thoracolumbar	10-15	F (84%) M (16%)	113	Brace	40-56	Until skeletal maturity (Risser sign ≥ 4); average: 34 ± 13 mo	NS	Cobb increasing ≥ 5o	Comparative analysis of progress vs stable cases	Predictor: Rib-vertebral angle at convex side of the curve apex after brace treatment (< 65ovs≥ 65o )	OR = 5.63 (95%Cl: 2.2-13.9) P < 0.001 (1) Sensitivity: 45%; (2) Specificity: 87%; (3) +PV: 69%; and (4) -PV: 71%
Qiu et al[69]	RCS	Art.	Thoracic, thoracolumbar	10-20	Chinese population	120	Brace	25-40	2.5 ± 0.35 yr	NS	Cobb increasing ≥ 5o	Comparative analysis of progress vs stable cases	Predictor: NTF3 gene: rs11063714, genotype GG vs AA	OR = 3.33 (95%Cl: 1.0-10.9) P = 0.08 (1) Sensitivity: 43%; (2) Specificity: 82%; (3) +PV: 56%; and (4) -PV: 72%
Xu et al[70]	RCS	Art.	Thoracic, thoracolumbar, lumbar	10-15	F (87%) M (13%)	312	Brace	20-40	0.6-2.2 yr	NS	Cobb increasing ≥ 5o and/or surgical correction	Logistic regression modeling	Predictors: (1) ERα gene: rs9340799, allele G; (2) TPH1 gene: rs10488682, allele A; (3) Risser sign O-1; and (4) Curve ≥ 30o	OR: 1.2-3.62 0.0001 > P < 0.1 (1) Sensitivity: 51%; (2) Specificity: 82%; and (3) Correct predictions: 75%
Yeung et al[75]	RCS	Art.	NS	12-16	F (100%) Chinese population	340	Observation	> 20	Until skeletal maturity, 16 years old or surgical intervention	NS	NS	Comparative analysis of Cobb angle in following genotypes of IGF1 SNP rs5742612: TT; TC; and CC	Predictor: TT (mean Cobb, 38 ± 12.1, n = 169) vs CC (mean Cobb, 33o± 9.0, n = 33), P = 0.01 Cut-point: Cobb, 35.7o	OR = 2.13 (95%Cl:1.0-4.4) P = 0.1 (1) Sensitivity: 88%; (2) Specificity: 22%; (3) +PV: 57%; and (4) -PV: 61%
1Ward et al[58]	RChS	Art.	Severe: 8% Moderate/ mild: 92%	9-13 at diagnosis	F (100%) F (100%) M (100%)	277 257 163	NS	> 10	Till skeletal maturity or severe deformity	NS	Severe: Cobb > 40o Moderate: Cobb 25o-40o	Multiple logistic regression modeling	Predictor: Scale (1-200 ) based on 53 SNP markers; cut point, 40: 1-40 ( ≤ 1% risk of progression)	OR=16.83 (95%Cl: 6.6-42.7) P < 0.001 (1) Sensitivity: 91%; (2) Specificity: 63%; (3) +PV: 17%; and (4) -PV: 99%
1Bohl et al[59]	RCS	Art	NS	≥ 10	F (81%) M (19%)	16	Brace	20-40	1 yr after brace discontinuation or skeletal maturity	36%	Cobb > 45o	Comparative analysis: patients with Cobb > 45ovs Cobb < 45o logistic regression modeling	Predictor: Scale (1-200 ) based on 53 SNP markers and initial Cobb angle: cut-point, 160: 160-200 (high risk of curve progression with Cobb > 45o) vs < 160 (low risk of curve progression with Cobb > 45o)	OR = 21.03 (95%Cl:1.5-293.3) P = 0.05 (1) Sensitivity: 78%; (2) Specificity: 86%; (3) +PV: 88%; and (4) -PV: 75%
Zhao et al[71]	RChS	Art	Double curves: thoracic, thoracolumbar or lumbar	10-20	Cases (AIS): F (90%) M (10%) Controls: F (75%) M (25%) Chinese population	67 100	Surgical correction	30-90	NS	NS	Cobb ≥ 30o	Comparative analysis of cases vs healthy controls	Predictors: (1) ER1 gene: rs2234693, allele T; (2) CALM 1 gene: rs12885713, allele T	OR: 1.7-1.83 0.01 > P < 0.05 (1) Sensitivity: 28%-69%; (2) Specificity: 44%-82%; (3) +PV: 45%-51%; and (4) -PV: 63%-68%
Zhou et al[72]	RCS	Art.	NS	11-18	F (100%) Chinese population	241	NS	20-100	Until skeletal maturity	54%	NS	Comparative analysis of severe cases (mean Cobb, 36o± 13o) vs moderate cases (mean Cobb, 29o± 7.4o)	Predictor: Il-17RC gene: rs708567, genotype GG, Cut-point: Cobb angle, 32.5o	OR = 3.43 (95%Cl: 1.4-8.3) P = 0.007 (1) Sensitivity: 94%; (2) Specificity: 17%; (3) +PV: 60%; and (4) -PV: 69%
Moreau et al[44]	RChS	Art.	Thoracic, thoracolumbar, lumbar	13-20	Cases (AIS): F (83%) M (17%) Controls: F (65%) M (35%)	41 17	Surgical correction	30-90	NS	NS	NS	Comparative analysis of AIS cases (mean Cobb, 54o± 14o) vs controls (non- idiopathic deformities)	Predictor: low inhibition of forskolin stimulated cAMP by melatonin in osteoblasts vs significant inhibition of forskolin stimulated cAMP by melatonin in osteoblasts	OR=3.93 (95%Cl: 0.45-33.7) P = 0.3 (1) Sensitivity: 20%; (2) Specificity: 94%; (3) +PV: 89%; and (4) -PV: 33%
Akoume et al[16]	PCS	Art	Asymptomatic subjects at-risk of AIS	5-15	F (65%) M (35%)	31	Observation	≤ 10	2 yr	NS	Cobb > 10o	Comparative analysis of cases with developed AIS spine deformity (mean Cobb, > 10o) vs subjects at risk, but without deformity	Predictor: peripheral blood mononuclear cells electrical impedance after melatonin or iodomelatonin administration: < 120 ohms vs≥ 120o homs	OR = 18.53 (95%Cl: 8.7-392.5) P = 0.03 (1) Sensitivity: 33%; (2) Specificity: 100%; (3) +PV: 100%; and (4) -PV: 70%
Akoume et al[61]	RChS	Art	NS	NS	NS	162 794	NS	NS	NS	NS	Cobb angle ≥ 45o Cobb angle 10o-44o	Comparative analysis of the G proteins functional status	Predictor: type of peripheral blood mononuclear cells G protein response to electrical stimulation: FG2 vs FG1 or FG3	OR = 2.63 (95%Cl: 1.9-3.7) P < 0.001 (1) Sensitivity: 26%; (2) Specificity: 88%; (3) +PV: 56%; and (4) -PV: 67%
Yamamoto et al[76]	RCS	Art.	NS	9-15	F (100%)	28	Analysis of curve history	5-59	05-2 yr	NS	Cobb increasing > 4o	Comparative analysis of progressive cases vs stable	Predictor: Brain stem function, abnormal vestibular-eye test vs normal	OR = 24.03 (95%Cl: 2.4-240.6) P = 0.007 (1) Sensitivity: 91%; (2) Specificity: 71%; (3) +PV: 67%; and (4) -PV: 92%

¹Study used industrial or other sponsorship;

²Predictive characteristics reported in the collected publication;

³Predictive characteristics calculated by authors of current review using extracted results. PChS: Prospective cohort study; RChS: Retrospective cohort study; PCS: Prospective case series; RCS: Retrospective case series; +PV: Positive predictive value; -PV: Negative predictive value; NS: Not specified; EMG: Electromyography; SNP: Single nucleotide polymorphism; NTF3: Neurotropin-3; IGF1: Insulin-like growth factor 1; ERα: Estrogen receptor alpha; Il-17RC: Interleukin 17 receptor C; CALM1: Calmodulin1.