Establishment of a nomogram clinical scoring system for the risk of heterotopic ossification in patients undergoing surgery after fracture

doi:10.3969/j.issn.1674-8115.2022.02.005

Abstract

Abstract: Objective

·To establish a nomogram scoring system to predict morbidity of heterotopic ossification (HO) in the patients undergoing surgery after fracture.

Methods

·From August 2018 to October 2020, 124 patients with fractures from department of orthopaedics or brain surgery, including 81 males and 43 females with an average age of (56.48±15.45) years old (ranging from 25?91 years old), were enrolled in the study. Clinical features including gender, age, with brain trauma or not, anesthetic mode, operation duration time, and blood loss during operation were collected. Peripheral blood samples were collected at three time points, i.e. 1 d, 7 d and 15 d after fracture, and the sera levels of bone morphogenetic protein 2 (BMP-2), BMP-4, BMP-5, BMP-7, interleukin 4 (IL-4), IL-6, IL-10, interferon γ (IFN-γ), and transforming growth factor-β (TGF-β) were detected by ELISA. All the patients were divided into HO group and non-HO group according to follow-up outcomes. The variables with statistically significant differences (α=0.15) between the two groups selected from clinical and laboratory indications were included in the univariate Cox regression model. Then the variables selected from univariate Cox regression model (α=0.05) were incorporated into multivariate Cox regression model to screen the independent risk factors of HO and calculate the risk ratios (HR). Finally, the nomogram scoring system was output through rms package in R language.

Results

·The follow-up observation found 13 HO cases after a median time of 71 (38, 292) d. Seven independent risk factors for HO, i.e. brain trauma (HR=2.932, P=0.038), operation duration time (HR=1.005, P=0.007), blood loss during operation (HR=1.004, P=0.022), BMP-2 (15d) (HR=1.009, P=0.044), BMP-4 (15 d) (HR=1.004, P=0.011), TGF-β (15 d) (HR=1.011, P=0.046), and BMP-7 (7 d) (HR=1.004, P=0.008), were selected by comparison between groups, univariate COX regression and multivariate COX regression sequentially. The nomogram to predict morbidity of HO after 90 d, 180 d, and 360 d was generated.

Conclusion

·The seven scoring indexes of nomogram scoring system for predicting the risk of HO in the patients undergoing surgery after fracture are with brain trauma or not, operation duration time, blood loss during operation, levels of BMP-2, BMP-4 and TGF-β in peripheral blood 15 d after fracture and BMP-7 7 d after fracture.

Key words: heterotopic ossification (HO), fracture, nomogram, brain trauma, bone morphogenetic protein (BMP)

CLC Number:

R683

Yekai WANG, Wei CHEN, Yinghui YANG, Jingze WU, Heping WANG, Yanzhen YAO, Zhoujun BAO. Establishment of a nomogram clinical scoring system for the risk of heterotopic ossification in patients undergoing surgery after fracture[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2022, 42(2): 166-172.

Figures/Tables 4

TrendMD

References 14

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Index	HO group（n=13）	Non-HO group （n=111）	χ² /t/z value	P value
Male/n（%）	10 （76.92）	71 （63.96）	0.863	0.353
Age/year	63.38±15.08	55.67±15.37	1.715	0.089
Brain injury/n（%）	6 （46.15）	14 （12.61）	7.357	0.007
Spinal cord injury/n（%）	1 （7.69）	3 （2.70）	‒	0.362
Undergoing the anesthesia modes^①/n（%）	2 （15.38）	19 （8.10）	0.000	1.000
Operation duration time/min	202.00 （110.50， 332.50）	130.50 （79.00， 203.50）	-1.903	0.057
Blood loss during operation/mL	150.00 （17.50， 389.50）	50.00 （20.00， 100.00）	-1.745	0.081
BMP-2（1 d）/（ng·L^-1）	73.38±20.88	43.41±16.59	5.991	0.000
BMP-2（7 d）/（ng·L^-1）	103.61±26.92	80.45±29.46	2.703	0.008
BMP-2（15 d）/（ng·L^-1）	197.46±62.47	81.12±12.33	17.385	0.000
BMP-4（1 d）/（ng·L^-1）	260.15±95.12	120.47±51.88	5.205	0.000
BMP-4（7 d）/（ng·L^-1）	352.53±125.83	235.96±71.89	3.278	0.006
BMP-4（15 d）/（ng·L^-1）	527.07±141.15	261.50±97.32	6.602	0.000
BMP-5（1 d）/（ng·L^-1）	408.00 （309.00， 702.00）	679.00 （590.00， 781.00）	-2.056	0.040
BMP-5（7 d）/（ng·L^-1）	629.43±234.93	524.45±254.80	1.417	0.159
BMP-5（15 d）/（ng·L^-1）	615.61±260.32	503.643±215.77	1.492	0.158
BMP-7（1 d）/（ng·L^-1）	352.92±128.95	260.50±154.56	2.071	0.040
BMP-7（7 d）/（ng·L^-1）	492.23±206.31	367.28±153.97	2.116	0.053
BMP-7（15 d）/（ng·L^-1）	514.46±172.83	418.09±190.83	1.734	0.085
IL-6（1 d）/（ng·L^-1）	82.07±30.60	39.31±8.64	11.548	0.000
IL-6（7 d）/（ng·L^-1）	97.07±26.05	51.79±14.97	9.419	0.000
IL-6（15 d）/（ng·L^-1）	77.00±12.70	54.72±15.11	5.100	0.000
IFN-γ（1 d）/（ng·L^-1）	658.00 （241.00， 776.00）	827.00 （335.00， 994.00）	-1.485	0.138
IFN-γ（7 d）/（ng·L^-1）	513.23±285.90	398.43±270.57	1.439	0.153
IFN-γ（15 d）/（ng·L^-1）	420.46±235.85	344.40±178.52	1.126	0.280
IL-4（1 d）/（ng·L^-1）	817.07±238.78	935.24±339.04	-1.220	0.225
IL-4（7 d）/（ng·L^-1）	835.38±333.24	988.07±320.89	-1.617	0.108
IL-4（15 d）/（ng·L^-1）	803.00±208.30	839.97±271.67	-0.473	0.637
IL-10（1 d）/（ng·L^-1）	466.07±255.66	421.84±237.69	0.594	0.561
IL-10（7 d）/（ng·L^-1）	360.38±142.80	411.09±137.35	-1.255	0.212
IL-10（15 d）/（ng·L^-1）	412.23±225.11	431.56±143.01	-0.431	0.667
TGF-β（1 d）/（μg·L^-1）	4.20±1.53	2.97±0.96	4.063	0.000
TGF-β（7 d）/（μg·L^-1）	3.91±1.36	3.06±1.05	2.662	0.009
TGF-β（15 d）/（μg·L^-1）	4.13±1.10	2.84±0.90	4.726	0.000

Index	HO group（n=13）	Non-HO group （n=111）	χ² /t/z value	P value
Male/n（%）	10 （76.92）	71 （63.96）	0.863	0.353
Age/year	63.38±15.08	55.67±15.37	1.715	0.089
Brain injury/n（%）	6 （46.15）	14 （12.61）	7.357	0.007
Spinal cord injury/n（%）	1 （7.69）	3 （2.70）	‒	0.362
Undergoing the anesthesia modes^①/n（%）	2 （15.38）	19 （8.10）	0.000	1.000
Operation duration time/min	202.00 （110.50， 332.50）	130.50 （79.00， 203.50）	-1.903	0.057
Blood loss during operation/mL	150.00 （17.50， 389.50）	50.00 （20.00， 100.00）	-1.745	0.081
BMP-2（1 d）/（ng·L^-1）	73.38±20.88	43.41±16.59	5.991	0.000
BMP-2（7 d）/（ng·L^-1）	103.61±26.92	80.45±29.46	2.703	0.008
BMP-2（15 d）/（ng·L^-1）	197.46±62.47	81.12±12.33	17.385	0.000
BMP-4（1 d）/（ng·L^-1）	260.15±95.12	120.47±51.88	5.205	0.000
BMP-4（7 d）/（ng·L^-1）	352.53±125.83	235.96±71.89	3.278	0.006
BMP-4（15 d）/（ng·L^-1）	527.07±141.15	261.50±97.32	6.602	0.000
BMP-5（1 d）/（ng·L^-1）	408.00 （309.00， 702.00）	679.00 （590.00， 781.00）	-2.056	0.040
BMP-5（7 d）/（ng·L^-1）	629.43±234.93	524.45±254.80	1.417	0.159
BMP-5（15 d）/（ng·L^-1）	615.61±260.32	503.643±215.77	1.492	0.158
BMP-7（1 d）/（ng·L^-1）	352.92±128.95	260.50±154.56	2.071	0.040
BMP-7（7 d）/（ng·L^-1）	492.23±206.31	367.28±153.97	2.116	0.053
BMP-7（15 d）/（ng·L^-1）	514.46±172.83	418.09±190.83	1.734	0.085
IL-6（1 d）/（ng·L^-1）	82.07±30.60	39.31±8.64	11.548	0.000
IL-6（7 d）/（ng·L^-1）	97.07±26.05	51.79±14.97	9.419	0.000
IL-6（15 d）/（ng·L^-1）	77.00±12.70	54.72±15.11	5.100	0.000
IFN-γ（1 d）/（ng·L^-1）	658.00 （241.00， 776.00）	827.00 （335.00， 994.00）	-1.485	0.138
IFN-γ（7 d）/（ng·L^-1）	513.23±285.90	398.43±270.57	1.439	0.153
IFN-γ（15 d）/（ng·L^-1）	420.46±235.85	344.40±178.52	1.126	0.280
IL-4（1 d）/（ng·L^-1）	817.07±238.78	935.24±339.04	-1.220	0.225
IL-4（7 d）/（ng·L^-1）	835.38±333.24	988.07±320.89	-1.617	0.108
IL-4（15 d）/（ng·L^-1）	803.00±208.30	839.97±271.67	-0.473	0.637
IL-10（1 d）/（ng·L^-1）	466.07±255.66	421.84±237.69	0.594	0.561
IL-10（7 d）/（ng·L^-1）	360.38±142.80	411.09±137.35	-1.255	0.212
IL-10（15 d）/（ng·L^-1）	412.23±225.11	431.56±143.01	-0.431	0.667
TGF-β（1 d）/（μg·L^-1）	4.20±1.53	2.97±0.96	4.063	0.000
TGF-β（7 d）/（μg·L^-1）	3.91±1.36	3.06±1.05	2.662	0.009
TGF-β（15 d）/（μg·L^-1）	4.13±1.10	2.84±0.90	4.726	0.000

Variant	Univariate				Mutivariate
Variant	β	P	HR	95%CI	β	P	HR	95%CI
Age	0.036	0.056	1.037	0.923‒1.075	‒	‒	‒	‒
Brain injury	1.622	0.004	5.063	1.695‒15.129	1.076	0.038	2.932	1.063‒8.083
Operation duration time	0.001	0.017	1.001	1.000‒1.002	0.005	0.007	1.005	1.001‒1.008
Blood loss during operation	0.003	0.027	1.003	1.000‒1.006	0.003	0.022	1.004	1.001‒1.007
BMP-2（1 d）	0.058	0.000	1.059	1.036‒1.084	0.059	0.168	1.060	0.976‒1.152
BMP-2（7 d）	0.018	0.003	1.018	1.006‒1.031	0.019	0.416	1.019	0.974‒1.067
BMP-2（15 d）	0.041	0.000	1.042	1.026‒1.058	0.009	0.044	1.009	1.001‒1.021
BMP-4（1 d）	0.020	0.000	1.020	1.012‒1.027	-0.009	0.124	0.991	0.979‒1.003
BMP-4（7 d）	0.013	0.000	1.013	1.007‒1.020	0.002	0.645	1.002	0.995‒1.008
BMP-4（15 d）	0.009	0.000	1.009	1.006‒1.012	0.004	0.011	1.004	1.001‒1.008
BMP-5（1 d）	0.001	0.183	1.001	0.999‒1.003	‒	‒	‒	‒
BMP-7（1 d）	0.003	0.032	1.003	1.000‒1.005	0.006	0.128	1.006	0.998‒1.014
BMP-7（7 d）	0.003	0.017	1.003	1.001‒1.006	0.004	0.008	1.004	1.000‒1.007
BMP-7（15 d）	0.002	0.205	1.002	0.999‒1.005	‒	‒	‒	‒
IL-6（1 d）	0.052	0.000	1.054	1.037‒1.071	0.003	0.764	1.003	0.983‒1.024
IL-6（7 d）	0.054	0.000	1.055	1.038‒1.074	0.039	0.082	1.039	0.995‒1.086
IL-6（15 d）	0.171	0.000	1.187	1.108‒1.271	0.020	0.282	1.020	0.983‒1.059
IFN-γ（1 d）	0.002	0.044	1.002	1.000‒1.004	0.001	0.471	1.001	0.998‒1.005
IL-4（7 d）	-0.002	0.063	0.998	0.997‒1.000	‒	‒	‒	‒
TGF-β（1 d）	0.117	0.000	1.116	1.107‒1.131	0.003	0.122	1.003	0.992‒1.015
TGF-β（7 d）	0.103	0.042	1.104	1.067‒1.148	0.002	0.670	1.001	0.999‒1.003
TGF-β（15 d）	0.126	0.000	1.136	1.123‒1.152	0.008	0.046	1.011	1.008‒1.014

Variant	Univariate				Mutivariate
Variant	β	P	HR	95%CI	β	P	HR	95%CI
Age	0.036	0.056	1.037	0.923‒1.075	‒	‒	‒	‒
Brain injury	1.622	0.004	5.063	1.695‒15.129	1.076	0.038	2.932	1.063‒8.083
Operation duration time	0.001	0.017	1.001	1.000‒1.002	0.005	0.007	1.005	1.001‒1.008
Blood loss during operation	0.003	0.027	1.003	1.000‒1.006	0.003	0.022	1.004	1.001‒1.007
BMP-2（1 d）	0.058	0.000	1.059	1.036‒1.084	0.059	0.168	1.060	0.976‒1.152
BMP-2（7 d）	0.018	0.003	1.018	1.006‒1.031	0.019	0.416	1.019	0.974‒1.067
BMP-2（15 d）	0.041	0.000	1.042	1.026‒1.058	0.009	0.044	1.009	1.001‒1.021
BMP-4（1 d）	0.020	0.000	1.020	1.012‒1.027	-0.009	0.124	0.991	0.979‒1.003
BMP-4（7 d）	0.013	0.000	1.013	1.007‒1.020	0.002	0.645	1.002	0.995‒1.008
BMP-4（15 d）	0.009	0.000	1.009	1.006‒1.012	0.004	0.011	1.004	1.001‒1.008
BMP-5（1 d）	0.001	0.183	1.001	0.999‒1.003	‒	‒	‒	‒
BMP-7（1 d）	0.003	0.032	1.003	1.000‒1.005	0.006	0.128	1.006	0.998‒1.014
BMP-7（7 d）	0.003	0.017	1.003	1.001‒1.006	0.004	0.008	1.004	1.000‒1.007
BMP-7（15 d）	0.002	0.205	1.002	0.999‒1.005	‒	‒	‒	‒
IL-6（1 d）	0.052	0.000	1.054	1.037‒1.071	0.003	0.764	1.003	0.983‒1.024
IL-6（7 d）	0.054	0.000	1.055	1.038‒1.074	0.039	0.082	1.039	0.995‒1.086
IL-6（15 d）	0.171	0.000	1.187	1.108‒1.271	0.020	0.282	1.020	0.983‒1.059
IFN-γ（1 d）	0.002	0.044	1.002	1.000‒1.004	0.001	0.471	1.001	0.998‒1.005
IL-4（7 d）	-0.002	0.063	0.998	0.997‒1.000	‒	‒	‒	‒
TGF-β（1 d）	0.117	0.000	1.116	1.107‒1.131	0.003	0.122	1.003	0.992‒1.015
TGF-β（7 d）	0.103	0.042	1.104	1.067‒1.148	0.002	0.670	1.001	0.999‒1.003
TGF-β（15 d）	0.126	0.000	1.136	1.123‒1.152	0.008	0.046	1.011	1.008‒1.014

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