Recently, the National Lung Screening Trial demonstrated that three annual low-dose

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1 Dign Interv Rdiol DOI /dir Turkish Society of Rdiology 2015 CHEST IMAGING ORIGINAL ARTICLE Impct of rdition dose nd itertive reconstruction on pulmonry nodule mesurements t chest CT: phntom study Hyungjin Kim Chng Min Prk Hee-Dong Che Sng Min Lee Jin Mo Goo PURPOSE We imed to identify the impct of rdition dose nd itertive reconstruction (IR) on mesurement of pulmonry nodules by chest computed tomogrphy (CT). METHODS CT scns were performed on chest phntom contining vrious nodules (dimeters of 3, 5, 8, 10 nd 12 mm; +100, -630 nd -800 HU for ech dimeter) t 80, 100, 120 kvp nd 10, 20, 50, 100 mas ( totl of 12 rdition dose settings). Ech CT ws reconstructed using filtered bck projection, idose 4, nd itertive model reconstruction (IMR). Therefter, two rdiologists mesured the dimeter nd ttenution of the nodules. Noise, contrst-to-noise rtio nd signl-to-noise rtio of CT imges were lso obtined. Influence of rdition dose nd reconstruction lgorithm on mesurement error nd objective imge qulity metrics ws nlyzed using generlized estimting equtions. RESULTS The 80 kvp, 10 mas CT scn ws not fesible for the mesurement of 3 mm sized simulted groundglss nodule (GGN); otherwise, dimeter mesurement error ws not significntly influenced by rdition dose (P > 0.05). IR did not hve significnt impct on dimeter mesurement error for simulted solid nodules (P > 0.05). However, for simulted GGNs, IMR ws ssocited with significntly decresed reltive dimeter mesurement error (P < 0.001). Attenution mesurement error ws not significntly influenced by either rdition dose or reconstruction lgorithm (P > 0.05). Objective imge qulity ws significntly better with IMR (P < 0.05). CONCLUSION Nodule mesurements were not ffected by rdition dose except for 3 mm simulted GGN on 80 kvp, 10 mas dose setting. However, for GGNs, IMR my help reduce dimeter mesurement error while improving imge qulity. From the Deprtment of Rdiology (H.K., C.M.P. cmprk@rdiol.snu.c.kr, H.D.C., S.M.L., J.M.G.), College of Medicine, nd Institute of Rdition Medicine, Medicl Reserch Center, Seoul Ntionl University, Seoul, Kore; Aerospce Medicl Group (H.K.), Air Force Eduction nd Trining Commnd, Jinju, Kore; Cncer Reserch Institute (C.M.P., J.M.G.), Seoul Ntionl University, Seoul, Kore. Received 19 December 2014; revision requested 1 Februry 2015; finl revision received 19 Mrch 2015; ccepted 14 April Published online 31 August 2015 DOI /dir This is preprint version of the rticle; the finl version will pper in the November-December 2015 issue of the Dignostic nd Interventionl Rdiology. Recently, the Ntionl Lung Screening Tril demonstrted tht three nnul low-dose computed tomogrphy (CT) screenings (cumultive verge effective dose, 4.5 msv) resulted in 20% reltive mortlity reduction of lung cncer in comprison with chest rdiogrphs for individuls t high risk of lung cncer (1, 2). Despite the gret dvntge of low-dose CT screenings, one of the biggest considertions must be rdition exposure. Currently, there re severl techniques known to reduce rdition exposure from chest CT (3, 4). Modifiction of the tube current is the simplest method of rdition dose reduction nd hs been minsty of chest CT imging for rdition dose reduction (5). As lowering rdition dose is often ccompnied by incresed noise in CT imges reconstructed with the conventionl filtered bck projection (FBP) lgorithm (6), noise-reducing itertive reconstruction (IR) lgorithms hve lso become vilble. At present, ll mjor CT vendors hve their own unique IR techniques (6). A novel IR lgorithm, itertive model reconstruction (IMR) (Philips Helthcre), ws developed recently nd this knowledge-bsed IR incorportes system optics s well s dt sttistics nd imge sttistics. For clinicl ppliction of these IR lgorithms in conjunction with reduced rdition dose, the fesibility of lesion chrcteriztion nd rdiologic mesurements re fundmentl prerequisites. Nodule mesurements should be performed eqully well without significnt vribility between low-dose IR-pplied CT imges nd stndrd-dose CT reconstructed with FBP. This is of gret significnce since the mngement of smll incidentlly-detected pulmonry nodules, especilly ground-glss nodules (GGNs), differs bsed on nodule size

2 nd their chnges over follow-up exmintions (7). Mnul mesurements of nodule dimeter on chest CT of vrious rdition doses from stndrd to ultr-low doses hve been studied previously; however, the effect of IR lgorithms were not considered in those investigtions (8, 9). In ddition, considering the fuzzy, ill-defined border of GGNs nd the fct tht GGNs re usully followed-up with low-dose CT, dvntge of IR for the mesurement of GGNs is clerly expected. Nevertheless, IR hs not been highlighted for evluting GGNs to dte. In this study, we hypothesized tht the ccurcy of mnul nodule mesurement would be potentilly ffected by vrious rdition dose settings nd reconstruction lgorithms such s idose 4 (Philips Helthcre) nd IMR. We suspected tht the mesurement of GGNs would be prticulrly influenced by the vribles. Therefore, we performed modeling nlysis using n nthropomorphic chest phntom with simulted nodules. Methods The present study ws exempt from Institutionl Review Bord pprovl of Seoul Ntionl University Hospitl s no niml or humn dt were cquired or used. Phntom To obtin CT scn imges of vrious rdition doses, we performed phntom study using n nthropomorphic mle chest phntom (multipurpose chest phntom N1 Lungmn, Kyoto Kgku) with simulted pulmonry nodules (10 13). The nthropomorphic chest phntom consisted of simulted pulmonry vessels, hert, trche, chest wll, diphrgm, nd bdomen block. The phntom ws mde of polyurethne (soft tissue) nd epoxy resin (synthetic bone). The phntom mesured cm in dimension with chest girth of 94 cm. Simulted pulmonry nodules of vrious dimeters nd ttenutions (dimeter 3, 5, 8, 10 nd 12 mm; ttenution +100, -630 nd -800 HU for ech dimeter) were mnully ffixed to the simulted pulmonry vessels. Nodules with +100 HU simulted solid nodules nd nodules with -630 nd -800 HU simulted GGNs. CT cquisition All CT scns were performed with 256-section ict scnner (Philips Helthcre). The phntom ws scnned with voltge of 80, 100, nd 120 kvp nd tube current-time product of 10, 20, 50, nd 100 mas. Thus, totl of 12 rdition dose settings were used in this study (Tble 1). Other cquisition prmeters were s follows: detector collimtion, mm; gntry rottion time, 0.4 s; pitch, 0.915; FOV, 350 mm nd mtrix size, pixels. All CT imges were reconstructed with slice thickness of 1 mm nd n increment of 0.9 mm. The phntom ws scnned once t ech dose setting nd ll CT scns were obtined sequentilly on the sme dy without chnging the positions of either the phntom or the nodules within it. Itertive reconstruction techniques (idose 4 nd IMR) A series of 12 CT scns t vrious rdition dose settings were reconstructed with FBP, idose 4 (level 4) nd IMR (level 1) lgorithms. IR levels for idose 4 nd IMR were chosen empiriclly fter preliminry review of CT imges t ech IR level to find single IR level with optimum imge qulity. Thus, totl of 36 CT dtsets were prepred (Fig. 1). A Y-Shrp (YA) filter ws used for FBP nd idose 4 nd shrp plus filter, s possible YA-equivlent, ws used for IMR, since YA could not be pplied directly to IMR. idose 4 is hybrid itertive reconstruction lgorithm nd incorportes sttistics-model bsed de-noising into rw nd imge dt spce (14). IMR is novel knowledge-bsed itertive reconstruction lgorithm nd is n optimiztion process tht incorportes knowledge of dt sttistics, imge sttistics, nd system models (15). The notble feture of IMR is tht the chrcteristics of the CT system such s detector smpling, ngulr smpling, nd system geometries re tken into ccount in the optimiztion process (15). Considertion of the system properties llow for design of the cost function, llowing IMR to effectively control imge noise while mximizing sptil resolution t rdition doses tht re significntly lower thn those trditionlly used with FBP reconstruction (15). Rdition dose ssessment For rdition dose ssessment, the volume CT dose index (CTDI vol ) nd doselength product (DLP) were recorded t ech kvp nd mas. CTDI vol nd DLP were cquired from the dose informtion provided by the CT scnner. Estimted effective dose ws clculted from the DLP using conversion fctor of ccording to the Interntionl Commission on Rdiologicl Protection publiction 103 recommendtions (16). Dose reduction in percentges ws clculted compred with the rdition dose of 120 kvp nd 100 mas CT scn (Tble 1). Mesurement of nodule dimeter nd ttenution Two rdiologists (H.K. nd H.D.C., with four nd three yers of experience in chest Min points Simulted pulmonry nodule dimeter mesurement error is not significntly ffected by the rdition dose. Itertive reconstruction lgorithms do not hve significnt impct on dimeter mesurement error for simulted solid nodules. Itertive model reconstruction (IMR) cn help reduce the mesurement error of ground-glss nodules. IMR provides better imge qulity in terms of imge noise, contrst-to-noise rtio nd signl-tonoise rtio. Figure 1. A -800 HU, 12 mm nodule scnned t vrious rdition dose protocols nd itertive reconstruction lgorithms. Noise is remrkbly reduced in IMR-pplied imges, leding to improved nodule mrgin delinetion nd decresed reltive dimeter mesurement error by the rdiologists. FBP, filtered bck projection; IR, itertive reconstruction; IMR, itertive model reconstruction. Kim et l.

3 CT, respectively), who were blinded to the size nd ttenution of simulted nodules, independently performed mesurements of mximum dimeter nd internl ttenution of the nodules t picture rchiving nd communiction system (PACS) of our hospitl (Mroview, Infinitt). Mximum dimeter ws mesured mnully using n electronic cliper in the fixed lung window setting (window width, 1600 HU; window level, -600 HU) nd internl ttenution ws mesured by plcing circulr region of interest (ROI) within ech phntom nodule. To void misregistrtion due to smll nodule size, ttenution mesurements were performed only for 8, 10, nd 12 mm nodules. The res of ROI were 21, 32, nd 44 mm 2, respectively. Mgnifiction of CT imges using the zoom function of PACS ws llowed for the mesurements. Objective imge qulity ssessment To ssess the imge qulity of CT scns, the stndrd devitions (SD) of ttenution in the two different simulted lung fields (left posterolterl lung field ner the chest wll nd right nteromedil lung field ner the medistinum t the level of the hert) nd in the ir outside the chest wll (pproximtely 3 cm wy from the middle nterior chest wll t the level of the hert) were mesured. As the chest phntom did not hve true lung prenchym, the simulted lung fields were ctully ir in the phntom. These three SD vlues were verged to clculte the noise of ech CT scn. The re of ROI ws 198 mm 2. In ddition, contrst-to-noise rtio (CNR) ws clculted by ech reder using the following eqution: CNR= (Attenution of the nodule - Attenution of the bckground lung field) / SD of the bckground lung field. Signl-to-noise rtio (SNR) ws lso clculted by ech reder using the following eqution: SNR = Attenution of the nodule / SD of the nodule. The nodule of -800 HU nd 12 mm ws chosen for CNR nd SNR nlyses, s this simulted nodule ws of the lowest lesion-to-bckground contrst nd CNR nd SNR re importnt metrics especilly for evlution of low contrst lesions. Simulted vessels were crefully voided from the ROIs of the bckground lung field. Sttisticl nlysis A series of generlized estimting equtions (GEE) models with n exchngeble correltion structure were performed to test the ssocitions between nodule size, nodule type, rdition dose, nd reconstruction lgorithm on chnges in the reltive mesurement error of the simulted nodules. This pproch tkes into ccount c Tble 1. Descriptive sttistics for rdition dose protocols clustered dt of 15 nodule dtsets imged t multiple rdition dose settings nd IR lgorithms. The GEE model ws run with the reltive mesurement error of dimeter s n dependent vrible nd nod- Tube voltge Tube current- CTDI vol DLP ED Dose (kvp) time product (mas) (mgy) (mgy cm) (msv) reduction b (%) Conversion fctor of ws used for the estimtion of ED (16). b Dose reduction of ech CT scn ws clculted compred to 120 kvp nd 100 mas cquisition. CTDIvol, volume CT dose index; DLP, dose-length product; ED, effective dose. Figure 2. d. Men reltive dimeter mesurement error ws significntly lrger in smll nodules (3 nd 5 mm) thn in medium sized nodules (8, 10, nd 12 mm) (). Men reltive mesurement error ws lso significntly lrger in simulted GGNs (-630, -800 HU) thn in solid (+100 HU) nodules (b). IMR ws ssocited with significnt decrese in mesurement error in GGNs (c). Men reltive ttenution mesurement error ws significntly lrger in simulted solid nodules (+100 HU) thn in GGNs (-630, -800 HU) (d). FBP, filtered bck projection; GGN, ground-glss nodule; HU, Hounsfield unit; IMR, itertive model reconstruction. b d Impct of rdition dose nd itertive reconstruction on pulmonry nodule mesurement

4 ule size, nodule type, rdition dose, nd reconstruction lgorithm s independent vribles. CNR nd SNR were not included in the GEE models s they were consequences of rdition dose nd reconstruction lgorithms, not fundmentl fctors. For reltive ttenution mesurement error, the sme independent vribles were used except for nodule size, s nodules of similr dimeter (8, 10, nd 12 mm) were mesured. The initil GEE models were run with min effects terms with entry of interction terms itertively. Then, the finl GEE model ws run with sttisticlly significnt min effects terms nd interction terms. Nodule size ws clssified into two groups of smll (3 nd 5 mm) nd medium (8, 10, nd 12 mm) sizes. Nodule type ws lso ctegorized into two groups of solid nodules (+100 HU) nd GGNs (-630 nd -800 HU). For rdition dose, CTDI vol ws used. Reconstruction lgorithms included FBP, idose 4, nd IMR. The dependent vrible of reltive mesurement error ws clculted s follows: (Mesured nodule dimeter or ttenution - Reference nodule dimeter or ttenution) / Reference nodule dimeter or ttenution. Dt of both reders were used in the nlyses. For objective imge qulity ssessment, GEE modeling ws lso performed s described bove with noise, CNR, nd SNR s dependent vribles, nd rdition dose nd reconstruction lgorithm s independent vribles. Dt of both reders were used in the nlyses. Interobserver greement of the mesured vlues ws evluted using the Blnd-Altmn plot nd Lin s concordnce Tble 2. Interobserver mesurement vribility correltion coefficient (r c ). Comprisons were performed pirwise on reconstruction lgorithm-to-reconstruction lgorithm bsis. For the Blnd-Altmn plot, reltive differences in mesurements were clculted s the difference between the two mesurements divided by the men. Then, interobserver vribility ws defined s 95% confidence intervl (CI) of the reltive differences (17). For Lin s concordnce correltion coefficient, poor greement ws defined s r c < 0.90, wheres higher r c vlues represented moderte (0.90 r c < 0.95), good (0.95 r c < 0.99), or excellent (r c > 0.99) greement (18, 19). All sttisticl nlyses were performed using SAS version 9.2 (SAS Institute Inc.) nd MedClc version (MedClc Softwre). A P vlue <0.05 ws considered to indicte sttisticl significnce. Results Reder 1 reported tht the dimeter mesurement of the -800 HU, 3 mm nodule ws not vilble on the 80 kvp, 10 mas scn due to n ill-defined nodule mrgin regrdless of the reconstruction lgorithm. Reder 1 lso reported tht the mrgin of the -630 HU, 3 mm nodule on the 80 kvp, 10 mas scn reconstructed using IMR ws not distinguishble from the bckground. Therefore, these four mesurements by reder 1 were not included in sttisticl nlyses. Detiled dt regrding the men nd CI of reltive dimeter mesurement error ccording to nodule size, nodule type, rdition dose, nd reconstruction lgorithm re listed in supplementl Tbles 1 nd 2. Mesurement FBP idose 4 IMR Dimeter Interobserver vribility -24.2, , , Attenution Interobserver vribility -10.9, , , Noise Interobserver vribility -5.1, , , CNR Interobserver vribility -16.8, , , SNR Interobserver vribility -13.5, , , The results of Blnd-Altmn nlyses re displyed in 95% confidence intervl of the reltive differences in percentge., concordnce correltion coefficient; FBP, filtered bck projection; IMR, itertive model reconstruction; CNR, contrst-tonoise rtio; SNR, signl-to-noise rtio. In the initil GEE models, rdition dose showed no significnt ssocition with reltive dimeter mesurement error (P > 0.05), nd thus it ws excluded from the model. Among the multiple interction terms, the interction between nodule type nd reconstruction lgorithm showed sttisticl significnce (P = 0.042), nd thus it ws included in the model. The finl GEE model reveled tht the nodule type of GGNs (-630 nd -800 HU; β= 0.09, P = 0.018) nd smll nodule size (3 nd 5 mm; β= 0.18, P < 0.001) were ssocited with incresed reltive dimeter mesurement error (Fig. 2, 2b). For solid nodules (+100 HU), IMR ws ssocited with decresed reltive dimeter mesurement error compred with idose 4 (β= -0.01, P = 0.047). However, for idose 4 compred with FBP or IMR compred with FBP, the ssocition between reltive dimeter mesurement error nd reconstruction lgorithm ws not significnt (idose 4 vs. FBP, P = 0.249; IMR vs. FBP, P = 0.739). For GGNs (-630 nd -800 HU), IMR ws ssocited with decresed reltive dimeter mesurement error compred with FBP (β= -0.02, P < 0.001) nd compred with idose 4 (β= -0.02, P < 0.001) (Fig. 2c); however, idose 4 ws not significntly different compred with FBP (P = 0.375). P vlues of GEE models re listed in detil in supplementl Tble 3. Detiled dt regrding the men nd CI of reltive ttenution mesurement error ccording to nodule type, rdition dose, nd reconstruction lgorithm re listed in supplementl Tble 4. Rdition dose nd reconstruction lgorithm did not show ny significnt ssocition with chnges in reltive ttenution mesurement error (ll P > 0.05). There were no significnt interctions mong vribles (ll P > 0.05). Therefore, the GEE model ws run with the independent vrible of nodule type. GGNs (-630 nd -800 HU; β= -0.19, P < 0.001) were ssocited with decresed reltive ttenution mesurement error (Fig. 2d). P vlues of GEE models re listed in detil in supplementl Tble 5. As for imge noise, CNR, nd SNR, the initil GEE model reveled tht the rdition dose by reconstruction lgorithm interction ws significnt (ll P < 0.001). Thus, the finl GEE model ws run with rdition dose, reconstruction lgorithm, nd rdition dose by reconstruction lgorithm interction. An increse in rdition dose ws significntly ssocited with decrese in imge noise t ll rdition dose settings (refer- Kim et l.

5 ence dose, 0.2 mgy) for ll three reconstruction lgorithms, except for 0.41 over 0.20 mgy t IMR (P = 0.054) (Fig. 3). The reduction in imge noise ccording to reconstruction lgorithm ws significnt t ll rdition dose settings (P < for idose 4 vs. FBP, IMR vs. FBP, nd IMR vs. idose 4 ). An increse in rdition dose ws lso significntly ssocited with n increse in CNR t ll rdition dose settings (reference dose, 0.2 mgy) for ll three reconstruction lgorithms, except for 0.41 over 0.20 mgy t IMR (β= -0.82, P < 0.001) (Fig. 3b). The increse in CNR ccording to reconstruction lgorithm ws significnt t ll rdition dose settings (P < for idose 4 vs. FBP, IMR vs. FBP, nd IMR vs. idose 4 ). Likewise, n increse in rdition dose ws significntly ssocited with n increse in SNR t ll rdition dose settings (reference dose, 0.2 mgy) of ll three reconstruction lgorithms except for 0.81 over 0.20 mgy t IMR (P = 0.589) (Fig. 3c). The increse in SNR ccording to reconstruction lgorithm (idose 4 vs. FBP, IMR vs. FBP, nd IMR vs. idose 4 ) ws significnt t ll rdition dose settings (ll P < 0.001). The results of Blnd-Altmn nlysis nd concordnce correltion coefficients re listed in Tble 2. Interobserver greement for mesuring dimeter, ttenution, noise, CNR, nd SNR ws good to excellent (ll r c > 0.97) except for the SNR mesurement t IMR (r c = 0.92). Discussion We found tht the nodule dimeter mesurement error ws not significntly influenced by rdition dose except for the 3 mm simulted GGN on 80 kvp, 10 mas dose setting. For simulted solid nodules, IR lgorithms did not hve significnt impct on dimeter mesurement error compred with FBP. However, for simulted GGNs, IMR ws shown to be significntly ssocited with decresed reltive nodule dimeter mesurement error. Finlly, IMR ws shown to hve significntly better imge qulity in terms of imge noise, CNR, nd SNR. There hve been severl studies which hve delt with multiple rdition dose settings nd tumor mesurements (8, 9). Hein et l. (9) performed two CT scns for ech ptient t different rdition doses (120 kv, 5 mas nd 120 kv, 75 mas), nd concluded tht the men reltive differences did not significntly differ between mesurements from 120 kv, 5 mas CT nd those from 120 kv, 75 mas CT (9). On the contrry, Christe et l. (8) reported contrdictory results showing tht the mnul dimeter mesurement exhibits significnt differences with lower tube current-time levels of 100 mas or less. However, ll CT scns in their study were performed using 120 kvp, 300 mas nd were rtificilly reconstructed with noise superimposing softwre to simulte multiple rdition dose levels. In ddition, the included nodules were of very smll size. The men nodule dimeter ws 2.11 mm nd rnged from mm (8). In our study, the nodule dimeter mesurement ws not ffected by rdition dose settings. Our finding is meningful in tht dimeter mesurement is fesible even when rdition dose is substntilly reduced. Seril follow-up CT scns re required for cncer ptients undergoing chemotherpy to evlute tumor response nd to decide whether to continue or discontinue the chemotherpy. It is lso required for ptients with indeterminte nodules so s to decide whether or not to conservtively follow-up these ptients. These ptients re expected to benefit from ultr-low dose CT without losing mesurement ccurcy. Nevertheless, we do not believe tht n 80 kvp, 10 mas scn (CTDI vol 0.20 mgy, the lowest dose in this study protocol) is the suitble CT protocol for either initil screening or follow-up. As stted in the study results, reder 1 reported tht the dimeter mesurement of the -800 HU, 3 mm nodule ws not vilble on this rdition dose due to the severely blurred nodule mrgin. Reder 1 lso reported tht the mrgin of the -630 HU, 3 mm nodule on the 80 kvp, 10 mas scn reconstructed using IMR ws not distinguishble from the bckground. Considering the observed loss of detectbility, the 80 kvp, 10 mas scn my not be fesible for the evlution of smll GGNs. Studies regrding semiutomtic volumetric nlysis of lung nodules showed tht nodule volumes mesured with IR were comprble to those with stndrd FBP (11, 18, 20). Although mnul mesurements cnnot be directly compred with semiutomtic computer-ided volumetry, these studies imply tht the nodule mrgin chrcteristics on CT scns reconstructed using n IR lgorithm re t the lest not deteriorted. Our study demonstrted tht the humn delinetion of the nodule mrgin ws not significntly influenced by the reconstruction lgorithm used. Rther, the mesurement ccurcy of GGNs in IMR-pplied CT scns improved significntly, compred with tht of FBP- or idose 4 -pplied CT scns. As GGNs re low contrst lesions, improvement in lesion mrgin delinetion on CT scns reconstructed with IMR my help rdiologists to detect nd follow-up GGNs in more reproducible mnner. In future, in vivo mesurement vribility studies re wrrnted to vlidte our findings. Regrding the incresed dimeter mesurement error of smll nodules, our re- b c Figure 3. c. Imge noise in IMR ws constntly lower thn the noise in other reconstruction lgorithms t ll rdition dose settings (). Contrst-to-noise rtio (CNR, b) nd signl-to-noise rtio (SNR, c) in IMR were constntly higher thn those in other reconstruction lgorithms. FBP, filtered bck projection; IMR, itertive model reconstruction. Impct of rdition dose nd itertive reconstruction on pulmonry nodule mesurement

6 sults re consistent with previous reports (21). Oxnrd et l. (21) reveled tht the reltive mesurement chnge (percent increse or percent decrese) ws found to be significntly lrger for smller tumors. Considering tht the vribility rnge of 2 cm nodule ws cm nd tht of 4 cm nodule ws cm in tht study (21), the mesurement vribility would be much higher for 3 mm nd 5 mm nodules, which in turn would increse the reltive mesurement error. As for mesurement ccurcy relted to the nodule type, it is plusible tht GGNs re ssocited with incresed dimeter mesurement error, given tht the simulted GGNs hve fr lower lesion-to-bckground contrst thn simulted solid nodules. In the clinicl setting, some GGNs even show the fde-out pttern of their nodule mrgin which would ggrvte the mesurement ccurcy nd reproducibility. As IR lgorithms hve cler merits of reducing imge noise nd rtifcts in lowdose CT scns, mny reserchers re now pying close ttention to the clinicl usefulness of IR. To dte, mny studies hve focused on imge qulity ssessment nd dose reduction in regrds to IR s these re the most importnt issues. Our study lso showed the improved imge qulity of IR-pplied CT scns from the spect of imge noise, CNR, nd SNR. In ddition, t ll rdition dose settings, IMR significntly improved imge noise, CNR, nd SNR compred to FBP nd idose 4. In ddition, the overll mgnitude of improvement in CNR nd SNR from switching reconstruction lgorithm (FBP to IMR) t ech dose level ws much higher thn tht cused by rdition dose increment t ech dose level when compred with the lowest rdition dose (FBP), s displyed on Fig. 3b, 3c. This fct would prtilly explin our study result tht only IMR, not the rdition dose, ws ssocited with the improvement in mesurement ccurcy of simulted GGNs. Thus fr, the reported chieved rdition dose reductions with IR hve vried widely from 23% to 76%, with preserved imge qulity (22). Ktsur et l. (23) even reported tht IR (model-bsed itertive reconstruction) enbled nerly 80% reduction in rdition dose t chest CT from low dose level to n ultr-low dose level, without ffecting nodule detectbility. In our study, we showed tht tumor mesurements were fesible in further reduced dose settings of pproximtely 0.2 msv (80 kvp, 20 mas). Issues regrding lesion detection nd chrcteriztion still remin for this dose setting with IMR ppliction. In our study, severl potentil limittions merit considertion. First, the results obtined from phntom study cnnot be directly pplied to ptients. This is prtly becuse simulted nodules used in the phntom study might be overly simplistic s the simulted nodules were completely sphericl in shpe with homogeneous rdiodensity. Also, noise cn be rtificilly low with IR in homogeneous phntom since IR cn reduce noise more prominently in homogeneous tissue thn in inhomogeneous tissue (6). Furthermore, the lck of true lung prenchym in the chest phntom my hve contributed to incresed mesurement reproducibility nd CNR. Second, the number of nodules in our study ws reltively smll nd thus further prospective studies with lrger number of pulmonry nodules re wrrnted. Third, our results regrding IR lgorithm re vendor specific. Other newly developed IR lgorithms from mjor vendors should be studied s well. Fourth, we did not del with nodule detectbility ccording to dose reduction in the current study nd this issue should be investigted in subsequent in vivo studies. Fifth, the imge filters used for ech reconstruction lgorithm were different (Y-Shrp for FBP nd idose 4 ; shrp plus filter for IMR) nd their equivlence or potentil impct on imge qulity ssessment ws not tested. Those filters re used for lung imging nd were chosen empiriclly fter the preliminry review of imges. Sixth, we did not evlute the interobserver vribility of dimeter mesurement ccording to nodule size s this issue ws beyond the primry purpose of our study. However, we dmit tht the lck of thorough investigtion of mesurement vribility would be limittion of our study s it is n importnt performnce metric. In conclusion, our study demonstrted tht nodule dimeter mesurement error ws not significntly influenced by rdition dose except for 3 mm simulted GGN on 80 kvp, 10 mas dose setting. IR lgorithms did not hve significnt impct on dimeter mesurement error compred with FBP for simulted solid nodules. However, for simulted GGNs, IMR ws shown to be ssocited with decresed reltive nodule dimeter mesurement error, while significntly improving imge noise, CNR, nd SNR. Acknowledgements We cknowledge Youngmi Chun nd Je Young Cho for their help in imge cquisition. We would like to express specil thnks to the Medicl Reserch Collborting Center in Seoul Ntionl University Hospitl for help on sttisticl nlyses. This study ws supported by the Reserch Grnt of the Koren Foundtion for Cncer Reserch (grnt number: CB ). The funding source hd no involvement in the study design; in the collection, nlysis nd interprettion of dt; in the writing of the report; nd in the decision to submit the pper for publiction. Conflict of interest disclosure The uthors declred no conflicts of interest. References 1. Bch PB, Mirkin JN, Oliver TK, et l. Benefits nd hrms of CT screening for lung cncer: systemtic review. JAMA 2012; 307: [CrossRef] 2. Aberle DR, Adms AM, Berg CD, et l. Reduced lung-cncer mortlity with low-dose computed tomogrphic screening. N Engl J Med 2011; 365: [CrossRef] 3. McCollough CH, Chen GH, Klender W, et l. Achieving routine submillisievert CT scnning: report from the summit on mngement of rdition dose in CT. Rdiology 2012; 264: [CrossRef] 4. 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Liner nd volume mesurements of pulmonry nodules t different CT dose levels - intrscn nd interscn nlysis. Rofo 2009; 181: [CrossRef] 10. Coenen A, Hond O, vn der Jgt EJ, Tomiym N. Computer-ssisted solid lung nodule 3D volumetry on CT: influence of scn mode nd itertive reconstruction: CT phntom study. Jpn J Rdiol 2013; 31: [CrossRef] 11. Willemink MJ, Leiner T, Budde RP, et l. Systemtic error in lung nodule volumetry: effect of itertive reconstruction versus filtered bck projection t different CT prmeters. AJR Am J Roentgenol 2012; 199: [CrossRef] 12. Xie X, Zho Y, Snijder RA, et l. Sensitivity nd ccurcy of volumetry of pulmonry nodules on low-dose 16- nd 64-row multi-detector CT: n nthropomorphic phntom study. Eur Rdiol 2013; 23: [CrossRef] Kim et l.

7 13. Kim H, Prk CM, Lee SM, Lee HJ, Goo JM. A comprison of two commercil volumetry softwre progrms in the nlysis of pulmonry groundglss nodules: segmenttion cpbility nd mesurement ccurcy. Koren J Rdiol 2013; 14: [CrossRef] 14. Funm Y, Tguchi K, Utsunomiy D, et l. Combintion of low-tube-voltge technique with hybrid itertive reconstruction (idose) lgorithm t coronry computed tomogrphic ngiogrphy. J Comput Assist Tomogr 2011; 35: [CrossRef] 15. Meht D, Thompson R, Morton T, Dhnntwri A, Shefer E. Itertive model reconstruction: simultneously lowered computed tomogrphy rdition dose nd improved imge qulity. Med Phys Int 2013; 1: Dek PD, Sml Y, Klender WA. Multisection CT protocols: sex- nd ge-specific conversion fctors used to determine effective dose from dose-length product. Rdiology 2010; 257: [CrossRef] 17. Blnd JM, Altmn DG. Mesuring greement in method comprison studies. Stt Methods Med Res 1999; 8: [CrossRef] 18. Willemink MJ, Borstlp J, Tkx RA, et l. The effects of computed tomogrphy with itertive reconstruction on solid pulmonry nodule volume quntifiction. PLoS One 2013; 8:e [CrossRef] 19. Lin LI. A concordnce correltion coefficient to evlute reproducibility. Biometrics 1989; 45: [CrossRef] 20. Xu Y, He W, Chen H, Hu Z, Li J, Zhng T. Impct of the dptive sttisticl itertive reconstruction technique on imge qulity in ultr-low-dose CT. Clin Rdiol 2013; 68: [CrossRef] 21. Oxnrd GR, Zho B, Sim CS, et l. Vribility of lung tumor mesurements on repet computed tomogrphy scns tken within 15 minutes. J Clin Oncol 2011; 29: [CrossRef] 22. Willemink MJ, Leiner T, de Jong PA, et l. Itertive reconstruction techniques for computed tomogrphy prt 2: initil results in dose reduction nd imge qulity. Eur Rdiol 2013; 23: [CrossRef] 23. Ktsur M, Mtsud I, Akhne M, et l. Model-bsed itertive reconstruction technique for ultrlow-dose chest CT: comprison of pulmonry nodule detectbility with the dptive sttisticl itertive reconstruction technique. Invest Rdiol 2013; 48: [CrossRef] Impct of rdition dose nd itertive reconstruction on pulmonry nodule mesurement

8 Supplementl Tble 1. Reltive dimeter mesurement error ccording to the nodule size, vrious rdition dose protocols, nd IR lgorithms Smll (3, 5 mm) Medium (8, 10, 12 mm) CTDI vol FBP idose 4 IMR FBP idose 4 IMR (mgy) Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , 0.05 Dt re presented s men±stndrd devition. IR, itertive reconstruction; CTDIvol, volume CT dose index; FBP, filtered bck projection; IMR, itertive model reconstruction; CI, confidence intervl. Supplementl Tble 2. Reltive dimeter mesurement error ccording to the nodule type, vrious rdition dose protocols, nd IR lgorithms Simulted solid nodule (+100 HU) Simulted GGN (-630, -800 HU) CTDI vol FBP idose 4 IMR FBP idose 4 IMR (mgy) Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI ± , ± , ± , ± , ± , ± , ± , ± , ± ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , 0.18 Dt re presented s men±stndrd devition. IR, itertive reconstruction; HU, Hounsfield unit; GGN, ground-glss nodule; CTDIvol, volume CT dose index; FBP, filtered bck projection; IMR, itertive model reconstruction; CI, confidence intervl. Kim et l.

9 Supplementl Tble 3. Generlized estimting equtions model for the reltive dimeter mesurement error Model number Independent vrible P Comprison detil Initil model 1 Nodule size Nodule type Rdition dose Reconstruction lgorithm Rdition dose* Reconstruction lgorithm Nodule size Nodule type Rdition dose Reconstruction lgorithm Rdition dose*nodule size Nodule size Nodule type Rdition dose Reconstruction lgorithm Rdition dose*nodule type Nodule size Nodule type Rdition dose Reconstruction lgorithm Reconstruction lgorithm* Nodule size Nodule size Nodule type Rdition dose Reconstruction lgorithm Reconstruction lgorithm* Nodule type Nodule size Nodule type Rdition dose Reconstruction lgorithm Nodule size*nodule type Finl model 1 Nodule size <0.001 Nodule type Reconstruction lgorithm nd Reconstruction lgorithm* Nodule type idose 4 compred to FBP; simulted solid nodule IMR compred to FBP; simulted solid nodule IMR compred to idose 4 ; simulted solid nodule idose 4 compred to FBP; simulted GGN <0.001 IMR compred to FBP; simulted GGN P < FBP, filtered bck projection; IMR, itertive model reconstruction; GGN, ground-glss nodule. <0.001 IMR compred to idose 4 ; simulted GGN Impct of rdition dose nd itertive reconstruction on pulmonry nodule mesurement

10 Supplementl Tble 4. Reltive ttenution mesurement error ccording to nodule type, vrious rdition dose protocols, nd IR lgorithms Simulted solid nodule (+100 HU) Simulted GGN (-630, -800 HU) CTDI vol FBP idose 4 IMR FBP idose 4 IMR (mgy) Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI Men 95% CI ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , ± , 0.03 Dt re presented s men±stndrd devition. IR, itertive reconstruction; HU, Hounsfield unit; GGN, ground-glss nodule; CTDIvol, volume CT dose index; FBP, filtered bck projection; IMR, itertive model reconstruction; CI, confidence intervl. Supplementl Tble 5. Generlized estimting equtions model for the reltive ttenution mesurement error Model number Independent vrible P Initil model 1 Nodule type Rdition dose Reconstruction lgorithm Rdition dose*reconstruction lgorithm Nodule type Rdition dose Reconstruction lgorithm Rdition dose*nodule type Nodule type Rdition dose Reconstruction lgorithm Reconstruction lgorithm *Nodule type Nodule type Rdition dose Reconstruction lgorithm Finl model 1 Nodule type <0.001 P < Kim et l.