Faculty Profiles - Koji Nishiguchi

Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases

Goto, K; Koyanagi, Y; Akiyama, M; Murakami, Y; Fukushima, M; Fujiwara, K; Iijima, H; Yamaguchi, M; Endo, M; Hashimoto, K; Ishizu, M; Hirakata, T; Mizobuchi, K; Takayama, M; Ota, J; Sajiki, A; Kominami, T; Ushida, H; Fujita, K; Kaneko, H; Ueno, S; Hayashi, T; Terao, C; Hotta, Y; Murakami, A; Kuniyoshi, K; Kusaka, S; Wada, Y; Abe, T; Nakazawa, T; Ikeda, Y; Momozawa, Y; Sonoda, KH; Nishiguchi, KM

JOURNAL OF MEDICAL GENETICS 2024.3

Language：English Publisher：Journal of Medical Genetics

Background As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)-related genes in a large number of Japanese patients with RP by applying the standardised variant interpretation guidelines for Japanese patients with IRD (J-IRD-VI guidelines) built upon the American College of Medical Genetics and Genomics and the Association for Molecular Pathology rules, and assess the contribution of these genes in RP–allied diseases. Methods We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, newly analysed), including Usher syndrome, Leber congenital amaurosis and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines. Results A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 patients with RP. This led to a genetic diagnostic rate in 38.6% of patients with RP, with EYS accounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for patients with CRD was 28.2%, with RP-related genes significantly contributing over other allied diseases. Conclusion A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the population-specific genetic findings for Japanese patients with IRD; these findings serve as a foundation for the clinical application of gene-specific therapies.

DOI： 10.1136/jmg-2023-109750

Genetic and Clinical Features of ABCA4-Associated Retinopathy in a Japanese Nationwide Cohort

Kei Mizobuchi, Takaaki Hayashi, Koji Tanaka, Kazuki Kuniyoshi, Yusuke Murakami, Natsuko Nakamura, Kaoruko Torii, Atsushi Mizota, Daiki Sakai, Akiko Maeda, Taro Kominami, Shinji Ueno, Shunji Kusaka, Koji M Nishiguchi, Yasuhiro Ikeda, Mineo Kondo, Kazushige Tsunoda, Yoshihiro Hotta, Tadashi Nakano

American Journal of Ophthalmology Vol. 264 page： 36 - 43 2024.3

Secondary Angle Closure Caused by Anterior Displacement of Capsular Tension Ring and Intraocular Lens Due to Aqueous Misdirection

Goto, K; Tomita, R; Hiraiwa, J; Kawabe, M; Nishiguchi, KM; Yuki, K

CUREUS JOURNAL OF MEDICAL SCIENCE Vol. 16 ( 3 ) page： e55716 2024.3

特集先端医療を先取りしよう-日本にはない海外の医療企画にあたって

西口康二

臨床眼科 Vol. 78 ( 2 ) page： 159 - 159 2024.2

Accuracy of pattern deviation in estimating the glaucomatous damage in the central 10° visual field in eyes with glaucoma and cataract

Tomita, R; Asaoka, R; Hirasawa, K; Fujino, Y; Nakakura, S; Murata, H; Omura, T; Shoji, N; Obana, A; Nishiguchi, KM; Tanito, M

BRITISH JOURNAL OF OPHTHALMOLOGY Vol. 108 ( 1 ) page： 78 - 83 2024.1

Language：English Publisher：British Journal of Ophthalmology

Background/aims The accuracy of pattern deviation (PD) in estimating the damage to the glaucomatous visual field (VF) in the central 10° in eyes with glaucoma and cataract is unclear. Methods This retrospective study includes 63 eyes of 52 glaucoma patients who successfully underwent cataract surgery or cataract surgery plus iStent implantation. Using the Humphrey Field Analyser 10-2 test, VF was measured within 6 months preoperatively and postoperatively (VF pre and VF post, respectively). The mean total deviation values in VF post (mTD post) indicates glaucomatous damage without cataract and the difference between this value and mean PD values in VF pre (mPD pre) was evaluated (ϵmPD). The effect of cataract was then evaluated as the difference between mTD post and mTD pre ( "mTD), while the effects of mTD post and "mTD on ϵmPD were also assessed. In addition, based on preoperative visual acuity (VA pre) and VF pre, the optimal model for predicting mTD post was identified. The error of this method (ϵOptimalModel) was estimated as the difference against mTD post, which was compared with ϵmPD. Results Compared with mTD pre, there was a significant improvement in mTD post (p=0.028). A significant difference was observed between mPD pre and mTD post (p<0.001). Further, ϵmPD significantly increased with the increase of mTD post or "mTD (p<0.001 and p=0.0444, respectively). The absolute ϵOptimalModel was significantly smaller than the absolute ϵmPD (p<0.001). Conclusions This study warns clinicians that PD of the central 10° VF might underestimate the glaucomatous VF damage with the progression of glaucoma and overestimate it as a cataract progresses.

DOI： 10.1136/bjo-2022-322274

Identification of OPTN p.(Asn51Thr): A novel pathogenic variant in primary open-angle glaucoma

Yukihiro Shiga, Kazuki Hashimoto, Kosuke Fujita, Shigeto Maekawa, Kota Sato, Shintaroh Kubo, Kazuhide Kawase, Kana Tokumo, Yoshiaki Kiuchi, Sotaro Mori, Makoto Nakamura, Takeshi Iwata, Koji M. Nishiguchi, Toru Nakazawa

Genetics in Medicine Open Vol. 2 page： 100839 - 100839 2024

The dawn of retinal gene therapy ～What is the problem?～

Nishiguchi Koji

JAPANESE ORTHOPTIC JOURNAL Vol. 54 ( 0 ) page： 1 - 6 2024

Language：Japanese Publisher：JAPANESE ASSOCIATION OF CERTIFIED ORTHOPTISTS

More than 15 years after the first successful gene therapy for severe congenital retinal dystrophies was reported in 2008, the therapy was approved as LuxturnaTM by the Japanese government in 2023. This marked the beginning of the era of genomic medicine in the field of ophthalmology. While this therapy has made it possible to significantly improve retinal sensitivity, there are still some issues to be addressed, such as the lack of improvement in visual acuity and the development of postoperative chorioretinal atrophy. In order to provide gene-specific treatment for genetic diseases under the Japanese national insurance, it is necessary to establish a system that allows nation-wide implementation of genetic testing. This paper discusses various issues related to retinal gene therapy in Japan.

DOI： 10.4263/jorthoptic.54t001

CiNii Research

Disease-specific variant interpretation highlighted the genetic findings in 2325 Japanese patients with retinitis pigmentosa and allied diseases

Kensuke Goto, Yoshito Koyanagi, Masato Akiyama, Yusuke Murakami, Masatoshi Fukushima, Kohta Fujiwara, Hanae Iijima, Mitsuyo Yamaguchi, Mikiko Endo, Kazuki Hashimoto, Masataka Ishizu, Toshiaki Hirakata, Kei Mizobuchi, Masakazu Takayama, Junya Ota, Ai Fujita Sajiki, Taro Kominami, Hiroaki Ushida, Kosuke Fujita, Hiroki Kaneko, Shinji Ueno, Takaaki Hayashi, Chikashi Terao, Yoshihiro Hotta, Akira Murakami, Kazuki Kuniyoshi, Shunji Kusaka, Yuko Wada, Toshiaki Abe, Toru Nakazawa, Yasuhiro Ikeda, Yukihide Momozawa, Koh-Hei Sonoda, Koji M. Nishiguchi

2023.11

Publisher：Cold Spring Harbor Laboratory

Abstract

Background

As gene-specific therapy for inherited retinal dystrophy (IRD) advances, unified variant interpretation across institutes is becoming increasingly important. This study aims to update the genetic findings of 86 retinitis pigmentosa (RP)–related genes in a large number of Japanese RP patients by applying the standardized variant interpretation guidelines for Japanese IRD patients (J-IRD-VI guidelines) built upon ACMG/AMP rules and assess the contribution of these genes in RP-allied diseases.

Methods

We assessed 2325 probands with RP (n=2155, including n=1204 sequenced previously with the same sequencing panel) and allied diseases (n=170, all newly analyzed), including Usher syndrome, Leber congenital amaurosis, and cone-rod dystrophy (CRD). Target sequencing using a panel of 86 genes was performed. The variants were interpreted according to the J-IRD-VI guidelines.

Results

A total of 3564 variants were detected, of which 524 variants were interpreted as pathogenic or likely pathogenic. Among these 524 variants, 280 (53.4%) had been either undetected or interpreted as variants of unknown significance or benign variants in our earlier study of 1204 RP patients. This led to a genetic diagnostic rate in 38.6% of RP patients, withEYSaccounting for 46.7% of the genetically solved patients, showing a 9% increase in diagnostic rate from our earlier study. The genetic diagnostic rate for CRD patients was 28.2%, with RP-related genes significantly contributing over other allied diseases.

Conclusion

A large-scale genetic analysis using the J-IRD-VI guidelines highlighted the unique genetic findings for Japanese IRD patients; these findings serve as a foundation for the clinical application of gene-specific therapies.

DOI： 10.1101/2023.11.09.23297953

Abilities of circumpapillary retinal nerve fiber layer thickness and vascular density to discriminate stages in primary open-angle glaucoma. International journal

Katsuya Yamaguchi, Ryo Tomita, Yoshito Koyanagi, Kazuhide Kawase, Ryo Asaoka, Hiroko Terasaki, Takeshi Iwase, Koji M Nishiguchi

Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie Vol. 262 ( 4 ) page： 1221 - 1229 2023.11

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To clarify the abilities of circumpapillary retinal nerve fiber layer thickness (cpRNFLT) obtained by optical coherence tomography (OCT) and circumpapillary vessel density (cpVD) measured by OCT-angiography to distinguish different stages in primary open-angle glaucoma determined by 24-2 or 30-2 static visual field (VF) testing. METHODS: This retrospective study includes 25 healthy normal eyes of 25 subjects and 87 primary open-angle glaucoma eyes of 87 patients. Areas under the receiver operating characteristic curves (AUROC) were evaluated for determining glaucoma stages using cpRNFLT and cpVD. The absolute errors of the estimated mean total deviation (mTD) using optimal models with cpRNFLT and cpVD were also compared. RESULTS: The AUROCs for discriminating glaucomatous eyes from normal eyes was significantly higher for cpRNFLT than the respective AUROCs for cpVD (0.969 [95% CI 0.939 to 0.998] vs. 0.872 [95% CI 0.806 to 0.938], p = 0.006), whereas cpVD had significantly higher AUROC for discriminating severe glaucoma eyes from moderate glaucoma eyes than cpRNFLT (0.771 [95% CI 0.655 to 0.886] vs. 0.578 [95% CI 0.420 to 0.736], p = 0.022). The mean absolute error in estimating mTD using both cpRNFLT and cpVD was significantly less than the error using cpRNFLT alone (4.56 ± 3.76 dB vs. 5.39 ± 4.00 dB, p = 0.027). CONCLUSION: Our results suggest that cpVD is better for follow-ups after moderate stage. The combination of cpRNFLT and cpVD may improve VF estimation compared to cpRNFLT alone.

DOI： 10.1007/s00417-023-06302-y

Retinal ferroptosis as a critical mechanism for the induction of retinochoroiditis during ocular toxoplasmosis

Yamada, K; Tazaki, A; Ushio-Watanabe, N; Usui, Y; Takeda, A; Matsunaga, M; Suzumura, A; Shimizu, H; Zheng, H; Ariefta, NR; Yamamoto, M; Hara, H; Goto, H; Sonoda, KH; Nishiguchi, KM; Kato, M; Nishikawa, Y; Toyokuni, S; Kaneko, H

REDOX BIOLOGY Vol. 67 page： 102890 2023.11

Language：English Publisher：Redox Biology

Toxoplasmosis is a major infectious disease, affecting approximately one-third of the world's population; its main clinical manifestation, ocular toxoplasmosis (OT), is a severe sight-threatening disease. Nevertheless, the diagnosis of OT is based on clinical findings, which needs improvement, even with biochemical tests, such as polymerase chain reaction and antibody detections. Furthermore, the efficacy of OT-targeted treatment is limited; thus, additional measures for diagnosis and treatments are needed. Here, we for the first time report a significantly reduced iron concentration in the vitreous humor (VH) of human patients infected with OT. To obtain further insights into molecular mechanisms, we established a mouse model of T. gondii infection, in which intravitreally injected tracer 57Fe, was accumulated in the neurosensory retina. T. gondii-infected eyes showed increased lipid peroxidation, reduction of glutathione peroxidase-4 expression and mitochondrial deformity in the photoreceptor as cristae loss. These findings strongly suggest the involvement of ferroptotic process in the photoreceptor of OT. In addition, deferiprone, an FDA-approved iron chelator, reduced the iron uptake but also ameliorated toxoplasma-induced retinochoroiditis by reducing retinal inflammation. In conclusion, the iron levels in the VH could serve as diagnostic markers and iron chelators as potential treatments for OT.

DOI： 10.1016/j.redox.2023.102890

Ornithine aminotransferase(OAT)遺伝子の複合ヘテロ接合性変異による脳回状脈絡網膜萎縮症の男児例

中野裕太, 安田小百合, 溝渕圭, 池田麻衣子, 濱島崇, 上野真治, 西口康二, 林孝彰

日本眼科学会雑誌 Vol. 127 ( 11 ) page： 1069 - 1080 2023.11

Language：Japanese Publisher：(公財)日本眼科学会

目的:脳回状脈絡網膜萎縮症(GACR)は,本邦ではまれな常染色体潜性遺伝(劣性遺伝)の先天性代謝異常症で,ビタミンB6(VitB6)依存性オルニチンアミノ基転移酵素活性の低下による高オルニチン血症を特徴とし,進行性の脈絡網膜変性を来す.今回,GACR症例を報告するとともに,過去の日本人GACR報告例の遺伝学的解析結果と比較検討した.症例:3歳,男児.外斜視の精査を目的に紹介受診となった.以前より夜盲を呈していたが,明らかな眼底異常はなく経過観察となった.6歳時の眼底検査で両眼の耳側網膜周辺部に特徴的な脳回状の網脈絡膜萎縮がみられた.全視野刺激網膜電図の杆体系・錐体系反応はいずれも消失していた.高オルニチン血症を認め,GACRが疑われたため,VitB6投与を開始したが,血中オルニチン値は低下しなかった.低蛋白質食治療を併用したところ血中オルニチン値は低下した.最終的に必須アミノ酸を補った蛋白質制限とVitB6投与によって血中オルニチン値の低下が維持された.全エクソーム解析を行い,ornithine aminotransferase(OAT)遺伝子に複合ヘテロ接合性変異(p.Arg271Lysとp.Arg426Ter)が検出された.8歳時の眼底検査で網脈絡膜萎縮は明らかに拡大していた.結論:低蛋白質食治療とVitB6投与の併用によって血中オルニチン値の低下が維持されたが,網脈絡膜萎縮は進行性に拡大した.本症例も含め,過去の日本人GACR症例(13例)のOAT遺伝子変異をまとめた結果,p.Arg426Terが高頻度変異(27%,7/26アレル)であることが見出された.(著者抄録)

今月の表紙中心性漿液性脈絡網膜症のEn face画像

稲垣恵子, 西口康二

臨床眼科 Vol. 77 ( 10 ) page： 1234 - 1234 2023.10

Association Between Torque Teno Virus and Systemic Immunodeficiency in Patients With Uveitis With a Suspected Infectious Etiology. Reviewed International journal

Ai Fujita Sajiki, Yoshito Koyanagi, Hiroaki Ushida, Kenichi Kawano, Kosuke Fujita, Daishi Okuda, Mitsuki Kawabe, Kazuhisa Yamada, Ayana Suzumura, Shu Kachi, Hiroki Kaneko, Hiroyuki Komatsu, Yoshihiko Usui, Hiroshi Goto, Koji M Nishiguchi

American journal of ophthalmology Vol. 254 page： 80 - 86 2023.10

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To determine the correlation between the presence of torque teno virus (TTV) in the aqueous humor of patients with uveitis and clinical information, including immunodeficiency history. DESIGN: Multicenter, retrospective, cross-sectional study. METHODS: Fifty-eight patients with uveitis with a suspected infectious etiology and 24 controls with cataract or age-related macular degeneration were included. We used quantitative polymerase chain reaction to test all subjects for TTV and multiplex polymerase chain reaction to test uveitis subjects for common ocular pathogens. When possible, both serum and aqueous humor samples were tested. Ocular TTV positivity was compared with age, sex, and a history of systemic immunodeficiency with logistic analysis. RESULTS: Ocular TTV positivity was found in 23%, 11%, and 0% of patients with herpetic uveitis, nonherpetic uveitis, and controls, respectively. Among patients with herpes infection, positivity for ocular TTV was found in 43%, 8%, 14%, and 50% of patients with cytomegalovirus retinitis, iridocyclitis, acute retinal necrosis, and Epstein-Barr virus-positive uveitis, respectively. Patients with cytomegalovirus retinitis showed a significantly higher rate of ocular TTV infection than controls (P = .008). Serum analysis revealed TTV positivity in 90% of patients with uveitis and in 100% of controls. Age- and gender-adjusted logistic analysis revealed a correlation between ocular TTV positivity and systemic immunodeficiency (P = .01), but no correlations between ocular TTV and age, gender, or viral pathogenic type. CONCLUSIONS: These findings suggest that positivity for ocular TTV was correlated with a clinical history of systemic immunodeficiency.

DOI： 10.1016/j.ajo.2023.06.012

Pathogenic variants of MFRP and PRSS56 genes are major causes of nanophthalmos in Japanese patients

Ota, J; Inooka, T; Okado, S; Maeda, N; Koyanagi, Y; Kominami, T; Nishiguchi, KM; Ueno, S

OPHTHALMIC GENETICS Vol. 44 ( 5 ) page： 423 - 429 2023.9

Language：English Publisher：Ophthalmic Genetics

Background: Nanophthalmos (NNO) is a rare condition with significantly shorter axial length than normal. Several genes are known to cause NNO, among them the MFRP and PRSS56 genes have been reported to cause majority of NNOs. The purpose of this study was to determine the genetic basis of Japanese patients with NNO. Materials and Methods: We studied seven patients with NNO. Whole exome sequencing (WES) and Sanger sequencing were performed to determine the variants causing the NNO. We also reviewed the medical charts of the patients to determine the phenotype of these seven patients. Results: WES revealed that four patients from three families carried homozygous frameshift variants of the PRSS56 gene (c.1066dupC). Two novel variants of the MFRP gene were detected in the other two patients: one proband had a homozygous missense variant (c.1486 G>A) and the other had a compound heterozygous variant (c.1486 G>A and c.662_663insT). The axial length of the eight eyes with the PRSS56 variant was 15.69 ± 0.48 mm (mean ± SD) and that for the 4 eyes with the MFRP variant was 15.63 ± 0.69 mm. Three of the six cases with the PRSS56 or MFRP variant had the uveal effusion syndrome. Conclusions: NNOs in Japanese patients are caused by variants of the PRSS56 and MFRP genes as in other ethnic populations. In addition, two new variants of the MFRP gene were found in our cohort. The phenotypes and anomalies in Japanese patients with NNO were similar to those reported for other ethnic populations.

DOI： 10.1080/13816810.2023.2208220

Predictive factors for outcomes of half-dose photodynamic therapy combined with aflibercept for pachychoroid neovasculopathy

Takeuchi, J; Ota, H; Nakano, Y; Horiguchi, E; Taki, Y; Ito, Y; Terasaki, H; Nishiguchi, KM; Kataoka, K

GRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY Vol. 261 ( 8 ) page： 2235 - 2243 2023.8

Language：English Publisher：Graefe's Archive for Clinical and Experimental Ophthalmology

Purpose: To assess the effects of half-dose photodynamic therapy (PDT) combined with an intravitreous aflibercept (IVA) injection for pachychoroid neovasculopathy (PNV) and its predictive factors. Methods: Clinical information of 43 patients (43 eyes) with PNV obtained before and 6 months after treatment with half-dose PDT combined with IVA was retrospectively analyzed. Patients were categorized into the sufficient (25 eyes, 58.1%) or insufficient (18 eyes, 41.9%) group based on resolution or persistence/recurrence of subretinal fluid (SRF), respectively, and clinical data were compared. Macular neovascularization (MNV) change was studied in 30 cases with available pre- and post-treatment optical coherence tomography angiography images. Results: The sufficient group included younger patients with better baseline best-corrected visual acuity (BCVA), more treatment-naïve eyes, and smaller MNV lesions at baseline than the insufficient group (all, P < 0.047). Complete SRF resolution was 81.8% in treatment-naïve eyes and only 33.3% in previously treated eyes. MNV expanded after half-dose PDT was combined with IVA regardless of the treatment outcome (P = 0.003). Conclusion: Half-dose PDT combined with IVA was effective for PNV treatment, especially for younger patients with good baseline BCVA, treatment-naïve eyes, and small MNV sizes at baseline. MNV expanded after treatment regardless of the treatment outcomes.

DOI： 10.1007/s00417-023-06030-3

Genetic characteristics of retinitis pigmentosa and allied diseases in 2063 Japanese patients

Nishiguchi, KM; Koyanagi, Y; Akiyama, M; Murakami, Y; Iijima, H; Endo, M; Ueno, S; Hayashi, T; Hotta, Y; Murakami, A; Wada, Y; Abe, T; Nakazawa, T; Ikeda, Y; Sonoda, KH; Goto, K

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE Vol. 64 ( 8 ) 2023.6

遺伝性網膜ジストロフィにおける遺伝学的検査のガイドライン

池田康博, 堀田喜裕, 近藤寛之, 西口康二, 前田亜希子, 藤波芳, 大石明生, 三宅正裕, 秋山雅人, 厚生労働科学研究費補助金難治性疾患政策研究事業網膜脈絡膜・視神経萎縮症に関する調査研究班遺伝性網膜ジストロフィにおける遺伝学的検査のガイドライン作成ワーキンググループ

日本眼科学会雑誌 Vol. 127 ( 6 ) page： 628 - 632 2023.6

Assessment of factors affecting flicker ERGs recorded with RETeval from data obtained from health checkup screening. International journal

Taiga Inooka, Taro Kominami, Shunsuke Yasuda, Yoshito Koyanagi, Junya Ota, Satoshi Okado, Ryo Tomita, Yasuki Ito, Takeshi Iwase, Hiroko Terasaki, Koji M Nishiguchi, Shinji Ueno

PloS one Vol. 18 ( 4 ) page： e0284686 2023.4

Language：English Publishing type：Research paper (scientific journal)

PURPOSE: To determine the factors significantly associated with the amplitudes and implicit times of the flicker electroretinograms (ERGs) recorded with the RETeval system by analyzing the comprehensive data obtained during a health checkup screening. METHODS: Flicker ERGs were recorded with the RETeval system from 373 individuals who had a normal fundus and optical coherence tomography images. The sex, age, anthropometric, ophthalmologic, and hematologic data were collected from all participants who were 40- to 89-years-of-age. Univariable and multivariable linear mixed effects regression analyses were performed to identify factors that were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. RESULTS: Univariable linear mixed effects regression analysis showed significant correlations between the implicit times and the best-corrected visual acuity, the age, the axial length, the blood sugar level, and the blood urea nitrogen level. Analyses by multivariable linear mixed effects regression identified that the axial length (β = 0.28), the age (β = 0.24), and the blood sugar level (β = 0.092) were three independent factors that were significantly correlated with the implicit times of the RETeval flicker ERGs. Univariable linear mixed effects regression analysis also showed significant correlations between the amplitudes of the RETeval flicker ERGs and the age, the platelet count, and the creatinine level. Multivariable linear mixed effects regression models identified the age (β = -0.092), the platelet count (β = 0.099), and the creatinine level (β = -0.12) as three independent factors that were significantly correlated with the amplitudes of the RETeval flicker ERGs. However, the smoking habits, body mass index, and the blood pressure were not significantly correlated with either the implicit times or amplitudes of the RETeval flicker ERGs. CONCLUSIONS: Our results indicate that the age and some ophthalmologic and hematologic findings but not the anthropometric findings were significantly associated with the implicit times and amplitudes of the RETeval flicker ERGs. Thus, clinicians should remember these factors when analyzing the RETeval flicker ERGs.

DOI： 10.1371/journal.pone.0284686