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CN106943192A - The method for building up of the preoperative forecast model of the expression index of lung carcinoma cell KI 67 - Google Patents

The method for building up of the preoperative forecast model of the expression index of lung carcinoma cell KI 67 Download PDF

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CN106943192A
CN106943192A CN201710151411.4A CN201710151411A CN106943192A CN 106943192 A CN106943192 A CN 106943192A CN 201710151411 A CN201710151411 A CN 201710151411A CN 106943192 A CN106943192 A CN 106943192A
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expression index
ggo
forecast model
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lung carcinoma
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彭明政
王金武
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Ninth Peoples Hospital Shanghai Jiaotong University School of Medicine
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Abstract

The invention provides a kind of method for building up of the preoperative forecast model of the expression index of lung carcinoma cell KI 67.Comprise the following steps:Step (1):Case is screened, standard compliant patient is obtained;Step (2):The described expression index of patient KI 67 of detection;Step (3):CT image scans and three-dimensional reconstruction are carried out to described patient lungs, each CT supplemental characteristics and 3-D view is obtained;Step (4):Statistical procedures analysis and cross validation are carried out to described CT supplemental characteristics and the expression index of KI 67, and set up KI 67 forecast model.Of the invention initiative is associated related CT parameters measured in the GGO Three-dimension Reconstruction Models with preferable objectivity and accuracy with the expression index of lung carcinoma cell ki 67 in Pathologic specimen, is set up by studying the quantization correlation of the two with the LI of three-dimensional reconstruction parameter prediction KI 67 multivariate regression models.

Description

The method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index
Technical field
Three-dimensional measurement iconography parameter lung carcinoma cell KI-67 tables are based on the present invention relates to medical domain, more particularly to one kind Up to the method for building up of the preoperative forecast model of index.
Background technology
With high-resolution ct (High resolution CT, HRCT) development and popularization, lung ground glass tubercle The recall rate of (Ground-glass opacity, GGO) is significantly improved.Research shows focal GGO mostly adenocarcinomas of lung both at home and abroad Early lesion.GGO is a non-specific focus, can be performance of a variety of diseases on CT, be found on HRCT The focal shadow of lung, is generally described as clouding lung density by scholar and increases shadow, while inside can still show bronchus or blood vessel knot Structure image.But generally acknowledge that it tends to lung's infantile tumour more both at home and abroad at present.Existing multinomial domestic and international research and clinical pathology money Material prompting, most GGO histopathologies are early stage adenocarcinoma of lung.The histological type of early stage adenocarcinoma of lung presses evolution evolution, can divide For atypical adenoma sample hyperplasia (Atypical adenomatous hyperplasia, AAH), in situ adenocarcinoma (Adenocarcinoma in situ, AIS), it is micro- infiltration gland cancer (minimally invasive adenocarcinoma, ) and adenocarcinoma infiltrating (Invasive adenocarcinoma, IAC) MIA.Even follow-up observation, only by two-dimensional ct iconography It is general levy as including traditional edge, size, whether pleura pulls, has impulse- free robustness etc. is difficult accurately to differentiate its histological type. As a kind of quantizating index, CT iconography parameters are in studying GGO increasingly by the favor of scholars.In addition, three dimensional CT Sensitivity and accuracy are had more to the evaluation of Small pulmonary nodule compared to conventional two-dimensional CT.
On the other hand, from the perspective of pathology, the increase of cell-proliferation activity is to create a bad precedent the beginning that lung cancer develops Person.And cell nuclear proliferating antigen ki-67 often is used for detecting the proliferation activity of cell in sample by clinical pathologist, it is expressed in more In the nucleus of the active cell of propagation, to regulate and control the cell cycle associated regulatory genes of division growth cell, its expression index It is proportionate with cell-proliferation activity, many height are expressed in malignant cell, the generation development relationship with tumour is close, multinomial It is used to explore the biological behaviour of malignant tumour propagation in research.It is thin expressed by researchers' prediction ki-67 both domestic and external Born of the same parents' proliferation activity has good correlation with the prognosis of patients with lung cancer.It is documented that, Ki-67 albumen is originally defined as standard Monoclonal antibody Ki-67, is obtained by Hodgkin lymphoma cell line L428 nucleus immune mouse.In fact Ki-67 eggs All active periods (G1, S, G2, mitosis) of cell cycle are appeared in vain, but are not often expressed in akinete (G0 phases), This becomes detection specific cell colony proliferation activity or the fabulous mark of growth fraction.High value-added rate is that tumour is most significant Feature, therefore proliferation activity is used to estimation Huppert's disease, prostate cancer, the prognosis of breast cancer in multinomial research.
Although the CT features for having researched and analysed different pathological types GGO of a large amount of domestic and foreign scholars, seldom research GGO tri- Relation in dimension reconstruction between iconography parameter and the pathological parameters such as cell-proliferation activity mark Ki-67LI of quantization.Cross Performed an analysis toward diagnostic method and be only limitted to iconography level, be not directed to evaluate the Pathological levels situation as diagnosis goldstandard, make Excessively subjectivity must be diagnosed and accuracy is not high.
So, if can be associated KI-67 indexes to related CT parameters, preoperative forecast model is obtained, is extremely to have Practical value, but prior art, this part also still belongs to blank.
The content of the invention
In order to overcome the above-mentioned deficiencies of the prior art, Lung neoplasm CT three-dimensional reconstruction iconographies are based on the invention provides one kind The preoperative forecast model of the lung carcinoma cell KI-67 expression index of parameter.
The method for building up of the preoperative forecast model for the lung carcinoma cell KI-67 expression index that the present invention is provided, it is characterised in that Comprise the following steps:
Step (1):Case is screened, standard compliant patient is obtained;
Step (2):The described patient's KI-67 expression index of detection;
Step (3):CT image scans and three-dimensional reconstruction are carried out to described patient lungs, each CT supplemental characteristics and three are obtained Tie up image;
Step (4):Described CT supplemental characteristics and KI-67 expression index are carried out statistical procedures analysis and intersected to test Card, and set up KI-67 forecast model.
It is preferred that described patient is to meet following standard:
Preoperative row CT examination and GGO patient is diagnosed as first;
It is postoperative to have clear and definite pathological diagnosis result;
Diameter is less than 3cm pure GGO and Combination GGO.
It is preferred that the detection of KI-67 expression index uses SABC two step method.
It is preferred that described CT supplemental characteristics are average diameter, cumulative volume, maximum CT values, mean CT-number and CT Distribution values Standard deviation.
It is preferred that the step (5) is further comprising the steps of:
Step (5.1):Using Levene inspection CT supplemental characteristics and KI-67 expression index homogeneities of variance;
Step (5.2):Examine and calculate between each group with Kruskal-Wallis for the CT supplemental characteristics of heterogeneity of variance Whether supplemental characteristic has significant difference;
Step (5.3):KI-67 expression index for homogeneity of variance then analyzes group difference with single factor test variance, and Pair test two-by-two between group with LSD inspections to carry out kI-67;
Step (5.4):Between being carried out two-by-two to CT supplemental characteristics and ki-67 expression index predicted value with Tamhane ' s T2 Pair test;
Step (5.5):Each CT supplemental characteristics and ki-67 expression index pair are detected with Receiver operating curve's analysis In the sensitivity and specificity of the GGO focuses for differentiating different pathological types;
Step (5.6):KI- is set up using Spearman correlation analysis and multiple regression analysis and ten folding cross validations The forecast model of 67 expression index.
Compared with prior art, beneficial effects of the present invention are as follows:
It is of the invention initiative will be measured related in the GGO Three-dimension Reconstruction Models of accuracy with preferable objectivity CT parameters are associated with lung carcinoma cell ki-67 expression index (Labeling index, LI) in Pathologic specimen, pass through both research Quantization correlation set up with three-dimensional reconstruction parameter prediction KI-67LI multivariate regression models so as to preoperative GGO pathology The antidiastole of property provides more accurate quantifiable assessment, judges to provide a preferable median for doctor.Will than with Toward merely more accurate come subjective judgement by Features.
Brief description of the drawings:
Figure 1A and Figure 1B be the embodiment of the present invention in KI-67 expression index SABC quantitative measurment figure.
Fig. 2A, Fig. 2 B and Fig. 2 C are the three-dimensional reconstruction processing and parameter measurement of lung ground glass tubercle in the embodiment of the present invention Figure;
Fig. 3 is non-infiltration gland cancer (PIA), micro- adenocarcinoma infiltrating (MIA) and adenocarcinoma infiltrating (IAC) in the embodiment of the present invention Between each parameter comparison figure;
Fig. 4 is expression lung ground glass tubercle (GGO) diameter, volume (TV), maximum CT values in the embodiment of the present invention (MAX), the curve of Receiver operating curve (ROC) analysis of mean CT-number (AVG) and CT Distribution values standard deviation (STD) Figure.
Fig. 5 is the diameter of lung ground glass tubercle (GGO) in the embodiment of the present invention, volume (TV), maximum CT values (MAX), put down The scatter diagram of equal CT values (AVG) and CT Distribution values standard deviation (STD) the Spearman correlation analysis between ki-67Li.
Fig. 6 is that ki-67 expression index (LI) actual value in the embodiment of the present invention and predicted value are ground in different pathological types lung Glass tubercle (GGO) includes the case line ratio between non-infiltration gland cancer (PIA), micro- infiltration gland cancer (MIA) and adenocarcinoma infiltrating (IAC) Relatively scheme.
Fig. 7 is the KI-67 of different pathological types lung ground glass tubercle in embodiment of the present invention ROC curve figure.
Embodiment
The present invention is further described with reference to specific embodiment, to more fully understand the present invention.
First, method
1st, clinical data is gathered
Collect have clear and definite pathological examination in October, 2012 in October, 2014 after surgery excision to hospital and art Before have complete HRCT and three-dimensional reconstruction 160 GGO patients clinical medical history, pathological replacement, operation record and CT image datas, To the age of patient, sex, pathological, GGO shapes, edge, diameter (diameter), volume (total volume, TV), Maximum CT values (the maximum CT attenuation value, MAX), mean CT-number (average CT Attenuation, AVG) and GGO entirety CT Distribution values standard deviation (standard deviation of the Distribution of CT attenuation within the whole GGO, STD) carry out sorting-out in statistics.All cases Receive anti-inflammatory treatment after being detected first as GGO 2 weeks, CT is checked after follow-up in 3 months.GGO focuses are contrasted only after follow-up The case that stable or diameter reduces can include research, and the case for foci disappearance after anti-inflammatory should give exclusion, mostly inflammatory Focus.
Case is included into the standard of research:
1. it is preoperative to be diagnosed as in the court's row CT examination and first GGO patient;
2. it is postoperative to have clear and definite pathological diagnosis result;
3. diameter is less than 3cm pure GGO and Combination GGO.
Henschke et al. research reports GGO is than full reality Small pulmonary nodule (Full-solid nodules) grade malignancy Higher, Feng Li et al. researchs are found in 137 full reality Small pulmonary nodules, and only 15 are pernicious focus, remaining 122 It is all benign focus, and polygonal, the smooth of the edge or the pernicious person of slightly smooth case are substantially fewer than benign person in full solid nodules (polygonal:Pernicious benign 38%, the p=0.02 of 7%-;The smooth of the edge is slightly smooth:Pernicious benign 63%, the p=0.001 of 0%-); 98% polygonal solid nodules (46/47) and the solid nodules (77/77) of 100% the smooth of the edge are benign lesion.Therefore This research eliminates the case of full solid nodules.
The standard of Excluded cases:
1. the GGO or focus on CT images with diameter greater than 3cm are regression after full reality lesser tubercle person or follow-up anti-inflammatory treatment Person;
2. the pathological examination person that is pulmonary metastasis, pathological examination are squamous carcinoma or small cell carcinoma person and though pathology is gland cancer, By stages more than T1N0M0 person;
3. (some patientss are after local hospital CT is diagnosed to preoperative CT scan data person without postoperative pathological result or without the court Go to the court);
4. it is preoperative to receive lung's chemicotherapy and Biopsy person, iconography parameter measurement can be caused inaccurate;
5. there is the outer cancer medical history person of Lung Cancer in the past.
Final 160 GGO cases include research, wherein male 54, women 106, and average age is 56.59 ± 9.9 Year.All cases carry out three-dimensional reconstruction parameter measurements CT scan obtained to performing the operation the time-interval averaging of Pathologic specimen for 11 ± 4 days (1-23 days).All case pathological diagnosis results for including research include atypical adenoma sample hyperplasia (Atypical Adenomatous hyperplasia, AAH) 26, it is in situ adenocarcinoma (Adenocarcinoma in situ, AIS) 11, micro- Infiltrate gland cancer (Minimally invasive adenocarcinoma, MIA) 106 and adenocarcinoma infiltrating (Invasive Adenocarcinoma, IAC) 17.Table 1 summarizes clinical data, imaging data and the pathology for including research case Data.
Clinic, iconography and the pathologic data statistics (160) of the GGO cases of the different pathological types of table 1
Note:
Classified according to the international multidisciplinary adenocarcinoma of lung categorizing systems of newest U.S. IASLC/ATS/ERS;
All data are recorded with mean+SD (SD), and * represents p<0.05;
Sex, smoking history and GGO classifications are analyzed by Chi-square Test;
Average age, diameter, cumulative volume (TV), maximum CT values (MAX), mean CT-number (AVG), CT Distribution value standard deviations (STD) and ki-67 expression index predicted value is by Kruskal-Wallis and Tambane ' sT2 examine analyzed;
Ki-67 expression index passes through one-way analysis of variance (one-way ANOVA) least significant difference test (LSD Test) analyzed;
P represents the p value of all GGO cases the results of analysis of variance;
P1 represents the p value of significant difference between non-infiltration adenocarcinoma of lung (PIA) and micro- infiltration adenocarcinoma of lung (MIA) group;
P2 represents the p value of significant difference between micro- infiltration adenocarcinoma of lung (MIA) and infiltration adenocarcinoma of lung (IAC) group;
2nd, Immunohistochemical Method detection Ki-67 expression index
The SABC two step method that Ki-67 detection is adopted international standards is tested, and concrete operations are as follows:
1. the preparation of slide:The slide and cover glass of preparation flowing water after 24h in acid solution, taking-up is placed in first to rush Wash, then rinsed 3-4 times with ddH20, be then immersed in 95% alcohol 2h, also need to make anti-flake processing after slide is dry, by what is cleaned Slide is put into 30s in the 3- of Fresh aminopropyls-triethoxysilane (APES) working solution, uses pure acetone after taking-up again Solution or ddH20 wash away uncombined APES, are fitted into standby in box after drying.
2. section:The sample of all surgery excisions is fixed with 10% neutral formalin, then after FFPE Serial section, slice thickness is 4 μm, and every serial section three carries out conventional H E dyeing observation pathomorphisms, immuning tissue Learn dyeing observation Ki-67, EGFR, P53, CEA expression;Roasting piece 6-8h under the conditions of 60 DEG C of electrically heated drying cabinet constant temperature can be used.
3. dewaxing:First with dimethylbenzene in dewaxing 3 times, each 15min at 60 DEG C;Gradient alcohol dehydration is used again, is followed successively by Absolute alcohol 2 times, 95% alcohol 2 times, 80% alcohol 1 time, 70% alcohol 1 time, are 5min every time;Running water developing sheet is used again DdH20 rinses 5min after quarter;0.01M PBS are rinsed 3 times, each 3min.
4. configuring 3% hydrogen peroxide blocks endogenous peroxydase, 10min is maintained at room temperature, then is rinsed 3 times with PBS, Each 3-5min.
5. antigen retrieval:It is 6.0 citrate buffer solution that first the section handled by above-mentioned steps, which is placed on, and fills PH In beaker, then beaker be put into high steam pot in, boil to pressure cooker jet and maintain 10min;Make after then taking out section It naturally cools to room temperature, first with distilled water flushing 2 times, then is rinsed 3 times with PBS, each 3min.
6. closing:Excess surface moisture is cleaned, 2h is incubated at room temperature after the closing of 4% sheep blood serum is added dropwise, non-specific dye is reduced Color.
7. primary antibody:Sheep blood serum is got rid of, ready first antibody is added dropwise, incubation at room temperature 1h is after 4 DEG C after each antibody dilution It is lower to stay overnight;0.01M PBS are added dropwise and are used as negative control;0.01M PBS are rinsed 3 times, each 3min.
8. remove surface moisture, the reagent l in kit is added dropwise, 37 DEG C of incubation 20min, 0.01M PBS rinse 3 times, often Secondary 3min;2,37 DEG C of incubation 30min of reagent in kit are added dropwise;0.01M PBS are rinsed 3 times, each 3min.
9. getting rid of PBS liquid, the section after above-mentioned processing is immersed to 5min in the DAB nitrite ions of Fresh, while Micro- Microscopic observation colour developing degree, stained positive often shows as brown color or sepia, will then be cut after positive reaction colour developing substantially Piece under flowing water in rinsing, and timely terminating reaction, general developing time is 5 minutes or so.
11. haematoxylin is redyed flowing water after 30s-2min and rinsed, then is broken up with l% hydrochloric acid-alcohol, ammoniacal liquor returns blue or running water Indigo plant is returned, running water is rinsed.
12. gradient alcohol dehydration:It is dehydrated successively using 70% alcohol, 80% alcohol, 95% alcohol, absolute alcohol, every time It is 5min;Xylene soak 2 times, each 8min.
13. using neutral gum fat mounting, then diagosis under microscope, coloration result is recorded.
The unified standard of the relevant strong and weak classification of Ki-67 expression is there is no at present.In Research Literature and Clinicopathologic Work generally Ki-67 label indexs are represented using rough percentage, i.e., randomly choosing 10 under 40 × 10 times of mirrors, in every slide regards Open country, the ratio for calculating the average shared visual field of 10 visual field positive cells estimates Ki-67LI roughly, and nuclei dyeing is brown color Or the cell of sepia is then positive cell.As shown in figure 1, using image measurement software I mage Pro Plus in the present embodiment 6.0, which carry out the picture after being detected to ki-67 SABCs, carries out quantitative measurment.Figure 1A represents grey black in the karyon of proliferative cell Grain is ki-67 positive expression;Figure 1B represents different according to gray value during quantitative detection, software automatic identification gray area Gray value is simultaneously measured.
3rd, CT image scans and three-dimensional reconstruction post processing
It is commonly unenhanced to the leading routine of lung, then thin layer volume helical scanning is carried out to focus.Shield after advising the deep air-breathing of patient Firmly, scanned by apertura thoracis superior to base of lung portion.
The condition of scanning:
120~140kV of voltage
200~400mA of electric current
Rebuild thickness 0.625mm
Matrix 512 × 512
Algorithm:Bone algorithm is axially rebuild, filtered back projection (filtered back projection, FBP) and double lungs are most Low coverage method.
The CT of all cases is diagnosed and post-processed by two image doctor's read tablets for having 8 years and 12 years respectively, works as tubercle More than one aspect can be diagnosed as GGO.HRCT images are stored in hospital DICM (digital imaging and Communications in medicine) in computer system for inquiring about and study.
The related parameter of 5 GGO Three-dimension Reconstruction Models is have chosen in the present embodiment as variable:Average diameter, cumulative volume (Total volume, TV), maximum CT values (MAX), mean CT-number (AVG) and CT Distribution values standard deviation (STD).
Three-dimensional reconstruction processing:Using ADW3.1 work stations (Advantage Workstation 4.3;GE Healthcare), reconstruction software (Lung VCAR are utilized;GE Healthcare) three-dimensional reconstruction is carried out, main method is using appearance (volume rendering, VR) is rebuild in product display.In VR image reconstructions, software after tubercle is clicked on not automatic according to CT value differences Detect and delimit interest region (region of interest, ROI), i.e. GGO tubercles and surrounding adjacent structure, including in tubercle The blood vessel and bronchiole in portion;The structure for being not belonging to tubercle to perinodal by cutting technique again is different according to each several part CT value differences Surface trimming is carried out after discrimination;After three dimensional volumetric image is shown, contrast, brightness are suitably adjusted, image is reached optimum visual Effect;Then can be used rotation technique from 720 ° of full angles tubercle three-dimensional configuration, internal blood vessel or bronchiole structure and Situations such as with the relation of edge pleura;It is last automatic arranged side by side to the three-dimensional diameters of GGO, the accurate measurement of TV, MAX, AVG and STD progress Go out.Fig. 2 shows the three-dimensional reconstruction processing and parameter measurement of lung ground glass tubercle (ground-glass opacity, GGO), Fig. 2A Represent typical GGO (arrow) on high-resolution ct (HRCT);Fig. 2 B represent the GGO models after the reconstruction that software is automatically generated with And automatic measurement relevant parameter;Fig. 2 C represent the parameter list amplification in 2B, including three-dimensional diameter, volume (TV), maximum CT values (MAX), mean CT-number (AVG) and CT Distribution values standard deviation (STD).
4th, statistical analysis
All data are recorded as mean+SD.Using Levene inspection variable homogeneities of variance, as a result remove All variables are heterogeneity of variance beyond ki-67LI, as shown in table 2.Therefore use Kruskal- for the variable of heterogeneity of variance Wallis examines to calculate whether variable between each group has significant difference, and the ki-67LI of homogeneity of variance then uses single factor test variance (ANOVA) is analyzed to analyze group difference.In addition, Pair test two-by-two between group with LSD inspections to carry out ki-67LI, is used Tamhane ' s T2 carry out Pair test between being carried out two-by-two to tubercle diameter, TV, MAX, AVG, STD and ki-67LI predicted value.With by Examination person's performance curve (Receiver operating curve, ROC) is analyzed to detect each variable for differentiating different diseases Manage the sensitivity and specificity of the GGO focuses of type.Simultaneously ten foldings intersection is tested for Spearman correlation analysis and multiple regression analysis Demonstrate,prove to set up ki-67LI forecast model.Software used by statistical analysis is SPSS 22.0, and P < 0.05 have statistics meaning for difference Justice.
Table 2 is examined with Levene and carries out variable homogeneity test of variance result
Note:
Variable includes GGO tubercles diameter, cumulative volume, maximum CT values, mean CT-number, CT Distribution values standard deviation, Ki-67 expression Index and Ki-67 expression index predicted values;
p(Sig.)<0.05 represents variable heterogeneity of variance, need to be examined with Tamhane ' s T2, p (Sig.)>0.05 expression Homogeneity of variance, need to be examined (LSD) with least significant difference;
Two, results
1st, Features and Tissue pathological diagnosis
GGO three-dimensional reconstruction CT parameters are by the poster processing soft automatic measurement, and the parameter of each pathology compares as shown in figure 3, Fig. 3 The comparison of each parameter between expression non-infiltration gland cancer (PIA), micro- adenocarcinoma infiltrating (MIA) and adenocarcinoma infiltrating (IAC).Ki-67 Expression positive cell shows as the brown granular in the nucleus of excessive proliferated cell, and relevant statistics, which are shown in, is still shown in Table 1.
2nd, each parameter ROC curve discriminatory analysis of different pathological types
Tubercle diameter, TV, MAX, AVG, STD and ki-67LI are obtained for being reflected between PIA and MIA groups by ROC curve analysis Other TG-AUC (AUC) divides 0.801,0.822,0.890,0.857,0.901 and 0.907 respectively, for MIA and IAC groups Between the AUC that differentiates be respectively 0.812,0.793,0.749,0.731,0.684,0.901;Point on each independent variable curve is simultaneously Choose maximum True Positive Rate (i.e. sensitivity) and minimum false positive rate (i.e. 1- specificity) just can obtain each variable between group Discrimination threshold, be typically near the curve upper left corner that [37].Therefore gained diameter, TV, MAX, AVG, STD and ki- 67LI is respectively 10.55mm, 217mm for best discriminant technique threshold value between PIA and MIA groups3,-126.5HU,-615.5HU,135.5 With 4.38%, and it is respectively 21.8mm for best discriminant technique threshold value between MIA and IAC groups, 1708.5mm3,189HU,-464HU, 169.4 and 9.88%, as shown in figure 4, Fig. 4 represents lung ground glass tubercle (GGO) diameter, volume (TV), maximum CT values (MAX), Receiver operating curve (ROC) analysis of mean CT-number (AVG) and CT Distribution values standard deviation (STD).According to song Area (AUC) under line is it can be seen that ki-67LI has than other the every more preferable sensitivitys of three dimensional CT parameter and specificity.It is every Parameter is for difference is more efficient between difference ratio MIA and IAC groups between discriminating PIA and MIA groups.
3rd, the correlation between three dimensional CT parameter and ki-67LI
Pass through Spearman correlation analysis, GGO diameters (p<0.001)、TV(p<0.001)、MAX(p<0.001),AVG (p<0.001) with STD (p<0.001) there is conspicuousness related between ki-67Li, each auto-correlation coefficient is respectively 0.575, 0.559,0.605,0.585and 0.639, as shown in figure 5, Fig. 5 is the diameter of lung ground glass tubercle (GGO), volume (TV), most Big CT values (MAX), mean CT-number (AVG) and CT Distribution values standard deviation (STD) Spearman correlation analysis between ki-67Li Scatter diagram (r is coefficient correlation);Each parameter is with ki-67Li into conspicuousness positive correlation;Fig. 5 (S) demonstrate GGO have it is heterogeneous Property, be not in that STD parabolic declines when more than 50% with increasing for property composition really.
In addition, by multiple linear regression analysis come the phase between further quantitative search three dimensional CT parameter and ki-67Li Guan Xing, and 160 GGO cases are divided into 10 groups by ten folding cross validations of progress (10-fold cross-validation), It is test group (testing sets) to define 1 group successively, and 9 groups are training group (training sets) to carry out recurrence mould in addition Type is built, and then substitutes into detection checking with test group.10 multiple regression equations on ki-67LI are finally obtained, and are calculated The mean absolute error (Mean absolute error, MAE) of each equation, average relative error (Mean relative Error, MRE) and root-mean-square error (Root mean square error, RMSE) evaluate the recurrence efficiency of respective equation.
N represents test group case load i.e. 10 in above-mentioned formula,Represent ki-67Li predicted value, y1Represent ki-67 LI's Actual value.
3160 GGO case three dimensional CT parameters of table are handed over ten foldings of ki-67 expression index (LI) multiple linear regression model Fork checking
Note:R represents multiple correlation coefficient, R2The coefficient of determination is represented, MAE represents mean absolute error, and MRE represents average phase To error, RMSE represents root mean square error;
R and R2Represent the compatible degree of regression model;
MAE, MRE and RMSE represent the prediction precision of regression model, and three is more low, and then forecast of regression model is more accurate.
In final 10 regression equations, relatively show that the 5th prescription journey has of a relatively high prediction accurate by cross validation True rate, regression equation is as follows:
Ki-67 LI=0.022*STD+0.001*TV+2.137 (4)
The 160 case three dimensional CT parameters for including research are all substituted into and obtain overall ki-67LI predicted values, PIA, MIA Ki-67 LI predicted value averages with IAC be respectively 4.27 ± 0.76 (range, 2.67~6.05%), 6.50 ± 1.69 (range, 3.00~11.74%) and 8.81 ± 3.73 (range, 3.75~16.65%), and have conspicuousness poor between group two-by-two Different (ANOVA P<0.001,LSD PIA vs.MIA P<0.001, MIA vs.IAC P=0.014, PIA vs.IAC P< 0.001) it grinds glass as shown in fig. 6, Fig. 6 Fig. 6 is ki-67 expression index (LI) actual value and predicted value in different pathological types lung Glass tubercle (GGO) includes the box traction substation ratio between non-infiltration gland cancer (PIA), micro- infiltration gland cancer (MIA) and adenocarcinoma infiltrating (IAC) Compared with.As a result ki-67 LI actual values are shown and have significant difference between predicted value group.Analyzed additionally by ROC curve, I Compare the AUC of ki-67 LI predicted values and actual value, although the AUC (PIA/MIA of ki-67 LI predicted values:0.893; MIA/IAC:0.841) AUC (PIA/MIA without actual value:0.907;MIA/IAC:0.901) it is high, but also than iconography parameter For the degree of accuracy height differentiated between different pathological types GGO groups, it is as shown in fig. 7, Fig. 7 ROC curve com-parison and analysis ki-67 LI Actual value and predicted value judge the sensitivity and specificity of different pathological types lung ground glass tubercle (GGO) for discriminating.
It is of the invention initiative will be measured related in the GGO Three-dimension Reconstruction Models of accuracy with preferable objectivity CT parameters are associated with lung carcinoma cell ki-67 expression index (Labeling index, LI) in Pathologic specimen, pass through both research Quantization correlation set up with three-dimensional reconstruction parameter prediction KI-67 LI multivariate regression models so as to preoperative GGO disease The antidiastole of rationality matter provides more accurate quantifiable assessment, judges to provide a preferable median for doctor.Will compare It is in the past simple more accurate come subjective judgement by Features.
The specific embodiment of the present invention is described in detail above, but it is intended only as example, and the present invention is not limited It is formed on particular embodiments described above.To those skilled in the art, it is any to the equivalent modifications that carry out of the present invention and Substitute also all among scope of the invention.Therefore, the impartial conversion made without departing from the spirit and scope of the invention and Modification, all should be contained within the scope of the invention.

Claims (5)

1. a kind of method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index, it is characterised in that including following step Suddenly:
Step (1):Case is screened, standard compliant patient is obtained;
Step (2):The described patient's KI-67 expression index of detection;
Step (3):CT image scans and three-dimensional reconstruction are carried out to described patient lungs, each CT supplemental characteristics and graphics is obtained Picture;
Step (4):Statistical procedures analysis and cross validation are carried out to described CT supplemental characteristics and KI-67 expression index, and Set up KI-67 forecast model.
2. the method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index according to claim 1, its feature It is that described patient is to meet following standard:
(1) preoperative row CT examination and GGO patient is diagnosed as first;
(2) it is postoperative to have clear and definite pathological diagnosis result;
(3) diameter is less than 3cm pure GGO and Combination GGO.
3. the method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index according to claim 1, its feature It is that the detection of KI-67 expression index uses SABC two step method.
4. the method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index according to claim 1, its feature It is that described CT supplemental characteristics are average diameter, cumulative volume, maximum CT values, mean CT-number and CT Distribution value standard deviations.
5. the method for building up of the preoperative forecast model of lung carcinoma cell KI-67 expression index according to claim 1, its feature It is that the step (5) is further comprising the steps of:
Step (5.1):Using Levene inspection CT supplemental characteristics and KI-67 expression index homogeneities of variance;
Step (5.2):For the CT supplemental characteristics of heterogeneity of variance parameter between each group is calculated with Kruskal-Wallis inspections Whether data have significant difference;
Step (5.3):KI-67 expression index for homogeneity of variance then analyzes group difference with single factor test variance, and uses LSD examines between group to carry out kI-67 Pair test two-by-two;
Step (5.4):Matched between being carried out with Tamhane ' s T2 to CT supplemental characteristics and ki-67 expression index predicted value two-by-two Examine;
Step (5.5):Detect each CT supplemental characteristics and ki-67 expression index for mirror with Receiver operating curve's analysis The sensitivity and specificity of the GGO focuses of other different pathological types;
Step (5.6):KI-67 tables are set up using Spearman correlation analysis and multiple regression analysis and ten folding cross validations Up to the forecast model of index.
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