We read with great interest the recent paper by Zhang and Ying exploring statistical approaches in published ophthalmic clinical science papers.1 We very much agree with the main conclusion drawn by the authors that collaborative efforts should be made in the vision research community to improve statistical practise for ocular data. In this vein, however, we were disappointed not to see reference to the Statistics Notes Series that has been published in this very journal. These have been written with a view to tackling some of the more prevalent statistical issues within ophthalmology and we would encourage readers to make use of these.2- 12. Within the UK this view that there needs to be greater collaboration in the vision research community has led to the formation of the Ophthalmology Research Section of the NIHR Statistics group which is championing cross- professional collaboration and active discussion in relation to statistical issues. It is always important when reviewing misuse of statistics in biomedical research to distinguish between misuse that leads to distorted or incorrect results and those methods which do not fully use data to maximum potential given that this loss of information might be viewed as unethical. In this regard we find the results from Zhang et al pleasing in that the proportion of papers which analysed at the level of the individual because of the nature of the observation rose from 15.2 % in 1995 to 50 % in 2017. A finding which is...
We read with great interest the recent paper by Zhang and Ying exploring statistical approaches in published ophthalmic clinical science papers.1 We very much agree with the main conclusion drawn by the authors that collaborative efforts should be made in the vision research community to improve statistical practise for ocular data. In this vein, however, we were disappointed not to see reference to the Statistics Notes Series that has been published in this very journal. These have been written with a view to tackling some of the more prevalent statistical issues within ophthalmology and we would encourage readers to make use of these.2- 12. Within the UK this view that there needs to be greater collaboration in the vision research community has led to the formation of the Ophthalmology Research Section of the NIHR Statistics group which is championing cross- professional collaboration and active discussion in relation to statistical issues. It is always important when reviewing misuse of statistics in biomedical research to distinguish between misuse that leads to distorted or incorrect results and those methods which do not fully use data to maximum potential given that this loss of information might be viewed as unethical. In this regard we find the results from Zhang et al pleasing in that the proportion of papers which analysed at the level of the individual because of the nature of the observation rose from 15.2 % in 1995 to 50 % in 2017. A finding which is statistically significant (P< 0.001, two-tailed Chi-square test). This is pertinent in that historically single person-level responses were often created by ophthalmologists (taking the worse eye only for example or combining information from each eye) prior to the development of the more advanced techniques that make better use of the data (by using data from both eyes instead of one) such as generalised estimating equations. A review by Gange et al has shown that point estimates and tests of significance that used this simple person-level approach are similar to those obtained from the more complex methods and concluded that there would therefore be unlikely benefit from a reanalysis with more sophisticated methods 13 . Misuse of statistics in medical research is unethical and this is a message that has been strongly advocated by Professor Doug Altman since 1980. 14 Professor Altman died in June of 2018 and his loss is hugely felt by the applied statistics community. Let us make 2019 a year of improved statistics throughout all research in vision and eyes.
1 Zhang HG, Ying GS. Statistical approaches in published ophthalmic clinical science papers: a comparison to statistical practice two decades ago. Br J Ophthalmol. 2018 Sep;102(9):1188-1191.
2 Stephenson J, Bunce C, Doré CJ, Freemantle N; Ophthalmic Statistics Group. Ophthalmic statistics note 11: logistic regression. Br J Ophthalmol. 2016 Dec;100(12):1594-1595.
3 Bunce C, Stephenson J, Doré CJ, Freemantle N; Ophthalmic Statistics Group.Ophthalmic statistics note 10: data transformations.Br J Ophthalmol. 2016 Dec;100(12):1591-1593.
4 Skene SS, Bunce C, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 9: parametric versus non-parametric methods for data analysis. Br J Ophthalmol. 2016 Jul;100(7):877-878.
5 Bunce C, Quartilho A, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 8: missing data--exploring the unknown. Br J Ophthalmol. 2016 Mar;100(3):291-4.
6 Cipriani V, Quartilho A, Bunce C, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 7: multiple hypothesis testing—to adjust or not to adjust. Br J Ophthalmol. 2015 Sep;99(9):1155-7.
7 Cook JA, Bunce C, Doré CJ, Freemantle N; Ophthalmic Statistics Group. Ophthalmic statistics note 6: effect sizes matter. Br J Ophthalmol. 2015 May;99(5):580-1.
8 Saunders LJ, Zhu H, Bunce C, Doré CJ, Freemantle N, Crabb DP; Ophthalmic Statistics Group. Ophthalmic statistics note 5: diagnostic tests—sensitivity and specificity. Br J Ophthalmol. 2015 Sep;99(9):1168-70.
9 Nash R, Bunce C, Freemantle N, Doré CJ, Rogers CA; Ophthalmic Statistics Group.
Ophthalmic Statistics Note 4: analysing data from randomised controlled trials with baseline and follow-up measurements. Br J Ophthalmol. 2014 Nov;98(11):1467-9.
10 Ophthalmic statistics note: the perils of dichotomising continuous variables. Cumberland PM, Czanner G, Bunce C, Doré CJ, Freemantle N, García-Fiñana M; Ophthalmic Statistics Group.Br J Ophthalmol. 2014 Jun;98(6):841-3.
11 Bunce C, Patel KV, Xing W, Freemantle N, Doré CJ; Ophthalmic Statistics Group. Ophthalmic statistics note 2: absence of evidence is not evidence of absence. Br J Ophthalmol. 2014 May;98(5):703-5.
12 Bunce C, Patel KV, Xing W, Freemantle N, Doré CJ; Ophthalmic Statistics Group Ophthalmic statistics note 1: unit of analysis. Br J Ophthalmol. 2014 Mar;98(3):408-12.
13 Gange SJ, Linton KL, Scott AJ, DeMets DL, Klein R. A comparison of methods for correlated ordinal measures with ophthalmic applications. Stat Med. 1995 Sep 30;14(18):1961-74
14 Altman DG. Statistics and ethics in medical research. Misuse of statistics is unethical. Br Med J. 1980 Nov 1;281(6249):1182-4.
We read the recent article in the journal by Monfermé and coauthors (1) on phenotypic associations of TYR R402Q compound heterozygosity with keen interest. Given our own and others previous findings (2-4) that the R402Q-S192Y haplotype seemed to have a stronger biological effect, we were surprised that a triallelic effect was not supported in the clinical discussion by Monfermé et al. When we examined these results more closely, we noted that their sample included 52 S192Y variant allele carriers out of the entire collection of 69 patients, of whom 31 (44.9%) carried the R402Q-S192Y double variant haplotype. In our own collections from the Australian general population (BNMS and BLTS, Duffy et al., in submission), only 6% of R402Q carriers also carried S192Y in cis. When we examined the European 1000 Genomes subsamples, there too only 7% of R402Q haplotypes had the 192Y rather than 192S wild type allele. So, even though Monfermé et al could not detect a statistically significant additive effect on OCA trait severity due to the S192Y polymorphism within their sample, it is clear that the S192 variant allele is markedly overrepresented compared to the general population, suggesting that it must have some relationship to albinism. This genetic association of the TYR R402Q-S192Y double variant haplotype with OCA1 is now clearly causative (2, 3), and explains some of the missing heritability that has previously been seen in OCA patients (4).
We read the recent article in the journal by Monfermé and coauthors (1) on phenotypic associations of TYR R402Q compound heterozygosity with keen interest. Given our own and others previous findings (2-4) that the R402Q-S192Y haplotype seemed to have a stronger biological effect, we were surprised that a triallelic effect was not supported in the clinical discussion by Monfermé et al. When we examined these results more closely, we noted that their sample included 52 S192Y variant allele carriers out of the entire collection of 69 patients, of whom 31 (44.9%) carried the R402Q-S192Y double variant haplotype. In our own collections from the Australian general population (BNMS and BLTS, Duffy et al., in submission), only 6% of R402Q carriers also carried S192Y in cis. When we examined the European 1000 Genomes subsamples, there too only 7% of R402Q haplotypes had the 192Y rather than 192S wild type allele. So, even though Monfermé et al could not detect a statistically significant additive effect on OCA trait severity due to the S192Y polymorphism within their sample, it is clear that the S192 variant allele is markedly overrepresented compared to the general population, suggesting that it must have some relationship to albinism. This genetic association of the TYR R402Q-S192Y double variant haplotype with OCA1 is now clearly causative (2, 3), and explains some of the missing heritability that has previously been seen in OCA patients (4).
1 Dermatology Research Centre, The University of Queensland, The University of Queensland Diamantina Institute, Brisbane, Qld, Australia; 2 QIMR Berghofer Medical Research Institute, Brisbane, Australia
References
1. Monferme S, Lasseaux E, Duncombe-Poulet C, et al. Mild form of oculocutaneous albinism type 1: phenotypic analysis of compound heterozygous patients with the R402Q variant of the TYR gene. Br J Ophthalmol 2018 doi: 10.1136/bjophthalmol-2018-312729
2. Jagirdar K, Smit DJ, Ainger SA, et al. Molecular analysis of common polymorphisms within the human Tyrosinase locus and genetic association with pigmentation traits. Pigment cell & melanoma research 2014;27(4):552-64. doi: 10.1111/pcmr.12253
3. Norman CS, O'Gorman L, Gibson J, et al. Identification of a functionally significant tri-allelic genotype in the Tyrosinase gene (TYR) causing hypomorphic oculocutaneous albinism (OCA1B). Sci Rep 2017;7(1):4415. doi: 10.1038/s41598-017-04401-5
4. Gronskov K, Jespersgaard C, Bruun GH, et al. A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1. Sci Rep 2019;9(1):645. doi: 10.1038/s41598-018-37272-5
To the Editor,
Intravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12...
To the Editor,
Intravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12-month period, and there is no explanation for this omission in the text.
We also detected some methodological issues that depart from international recommendations.3,4 On replicating the meta-analysis using the data provided by Low et al1 in the STATA statistical package, we did not find the same results as those reported. In Figure 2, the mean difference (95% CI) given for months in the GEFAL study is 2.36 (-0.72 to 5.44), whereas we obtained a difference of 1.90 (95 CI%: -0.73 to 4.53). This modifies the magnitude of the overall measure (in our case, -0.25; 95% CI: -1.39 to 0.89), but not its direction or interpretation. We observed a similar finding for the 18-24 month period for the CATT study, as Figure 2B shows a difference of -1.00 (95% CI: -3.54 to 1.54), whereas we observed an overall difference of -0.51 (9 5CI% :-1.91 to 0.88).
Another aspect that caught our attention is that some of the meta-analysis subgroup analyses were underpowered (<50%), but this is not mentioned in the results or discussed as an important limitation. The authors also make no mention of publication bias, which is normally evaluated using a funnel plot or Egger’s plot, as per reporting guidelines.3,4 Finally, Low et al1 reported that they analyzed the quality of the individual studies included in their systematic review and show the corresponding results in Table 1. However, they did not report on any sensitivity analyses to identify lower-quality studies that should have possibly been excluded or studies that might have significantly affected results.
The authors clearly attempted to cover many aspects in their systematic review, from the effectiveness and harms to the cost and cost-effectiveness of three VGEF agents in three conditions: neovascular age-related macular degeneration, diabetic macular oedema (DME), and branch retinal vein occlusion. It is not our place to comment on the wisdom or not of analyzing so many aspects, but we would like to point out that just one study was analyzed to assess the evidence on the cost-effectiveness of bevacizumab versus aflibercept versus ranibizumab in DME. Despite the commendable efforts of the authors, they failed to report on some key methodological aspects from the PRISMA (Preferred Reported Items for Systematic Review and Meta-Analyses) checklist3 and the Cochrane Handbook for Systematic Reviews of Interventions.4
REFERENCES
1. Low A, Faridi A, Bhavsar KV, Cockerham GC, Freeman M, Fu R, et al. Comparative effectiveness and harms of intravitreal antivascular endothelial growth factor agents for three retinal conditions: a systematic review and meta-analysis. Br J Ophthalmol. 8 de noviembre de 2018;
2. Cai S, Bressler NM. Aflibercept, bevacizumab or ranibizumab for diabetic macular oedema: recent clinically relevant findings from DRCR.net Protocol T. Curr Opin Ophthalmol. noviembre de 2017;28(6):636-43.
3. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 21 de julio de 2009;339:b2535.
4. Higgins JP, Green, Sally. Cochrane Handbook for Systematic Reviews of Interventions [Internet]. The Cochrane Collaboration. Disponible en: https://handbook-5-1.cochrane.org/
Editor,
We read with great interest the article titled “Choroidal thickness and vascular density in macular telangiectasia type 2 using en face swept-source optical coherence tomography” by Wang et al.[1] This is an interesting study in which the authors performed multimodal imaging for the diagnosis of macular telangiectasia (MacTel) type 2 and reported similar choroidal thickness (CT) between MacTel type 2 and control eyes using swept-source optical coherence tomography (SS-OCT).[1]
There are a few concerns that we would like to highlight. Although the authors control for confounders like age and spherical equivalent, axial length is another important confounder that has not been evaluated in this prospectively conducted study. The subfoveal CT has been reported to decrease by up to 58µm per one mm increase in the axial length after adjusting for age and sex.[2] Ignoring the axial length in choroidal thickness analysis may have untoward consequences.
Although the number of cases was small (n=39 eyes), the stagewise distribution of CT may be of help. A recent study by Kumar et al. using SS-OCT reported different subfoveal CT in non-proliferative and proliferative stages of the disease, although the results were not statistically significant.[3] If a varied distribution is observed between different stages, this may support the role of the choroid in the pathophysiology of this disease.
Inter-ocular asymmetry does exist in CT[4] as well as in the pr...
Editor,
We read with great interest the article titled “Choroidal thickness and vascular density in macular telangiectasia type 2 using en face swept-source optical coherence tomography” by Wang et al.[1] This is an interesting study in which the authors performed multimodal imaging for the diagnosis of macular telangiectasia (MacTel) type 2 and reported similar choroidal thickness (CT) between MacTel type 2 and control eyes using swept-source optical coherence tomography (SS-OCT).[1]
There are a few concerns that we would like to highlight. Although the authors control for confounders like age and spherical equivalent, axial length is another important confounder that has not been evaluated in this prospectively conducted study. The subfoveal CT has been reported to decrease by up to 58µm per one mm increase in the axial length after adjusting for age and sex.[2] Ignoring the axial length in choroidal thickness analysis may have untoward consequences.
Although the number of cases was small (n=39 eyes), the stagewise distribution of CT may be of help. A recent study by Kumar et al. using SS-OCT reported different subfoveal CT in non-proliferative and proliferative stages of the disease, although the results were not statistically significant.[3] If a varied distribution is observed between different stages, this may support the role of the choroid in the pathophysiology of this disease.
Inter-ocular asymmetry does exist in CT[4] as well as in the presentation of MacTel.[3,5] Although a significant inter-ocular difference in subfoveal CT may not exist, the reported difference reaches up to 85µm with thicker choroid in the right eyes.[4] It may be useful to compare the right and left eyes separately. The authors used multilevel mixed effect linear regression as both eyes of the patients were included.[1] However, there may exist a difference in the stage of disease among the fellow eyes, and the fellow eyes may be studied separately.[3,5] The comparison of disease characteristics between the fellow eyes may, therefore, be important.
References
1 Wang JC, Laíns I, Oellers P, et al. Choroidal thickness and vascular density in macular telangiectasia type 2 using enface swept-source optical coherence tomography. Br J Ophthalmol Published Online First: 2 January 2019. doi:10.1136/bjophthalmol-2018-313414
2 Li XQ, Larsen M, Munch IC. Subfoveal choroidal thickness in relation to sex and axial length in 93 Danish university students. Invest Ophthalmol Vis Sci 2011;52:8438–41. doi:10.1167/iovs.11-8108
3 Kumar V, Kumawat D, Kumar P. Swept source optical coherence tomography analysis of choroidal thickness in macular telangiectasia type 2: a case-control study. Graefes Arch Clin Exp Ophthalmol Albrecht Von Graefes Arch Klin Exp Ophthalmol Published Online First: 17 December 2018. doi:10.1007/s00417-018-04215-9
4 Chen FK, Yeoh J, Rahman W, et al. Topographic variation and interocular symmetry of macular choroidal thickness using enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:975–85. doi:10.1167/iovs.11-8771
5 Bruè C, Tseng JJ, Barbazetto I, et al. PECULIAR MANIFESTATION OF MACULAR TELANGIECTASIA TYPE 2. Retin Cases Brief Rep 2011;5:309. doi:10.1097/ICB.0b013e3181f66b8c
We appreciate the valuable comments from Dr. Sato regarding our recently published article.1 Dr. Sato’s comments raise important points about definition of collateral vessels in eyes with branch retinal vein occlusion (BRVO).
As previously reported,2 collateral vessels develop from the pre-existing retinal capillary network to drain a blood flow from an obstructed vein into an adjacent area in eyes with BRVO. Therefore, in the current study, we defined collateral vessels as dilated and tortuous capillaries occurring in pre-existing capillary beds and linking the obstructed vessel with the nearest patent vessel. Thus, the adjacent vessels also seemed to be dilated and tortuous, which had been similarly observed in our previous study.3 We speculate that the pressure gradient between an obstructed vein and neighbouring unobstructed vessels causes collateral vessels formation. The collaterals detection rate in the current study was higher than in the previous study.3 This is because wider optical coherence tomography angiography (OCTA) images, the size of which was 6 ✕ 6 mm in area, were used in the current study.
Regarding the other comment about the location of collateral vessels, Freund et al4 reported that collateral vessels were observed in only deep retinal capillary layer. However, we confirmed that the collateral vessels were present in both the superficial and the deep capillary layers on B scan images of OCTA. Additionally, fluoresc...
We appreciate the valuable comments from Dr. Sato regarding our recently published article.1 Dr. Sato’s comments raise important points about definition of collateral vessels in eyes with branch retinal vein occlusion (BRVO).
As previously reported,2 collateral vessels develop from the pre-existing retinal capillary network to drain a blood flow from an obstructed vein into an adjacent area in eyes with BRVO. Therefore, in the current study, we defined collateral vessels as dilated and tortuous capillaries occurring in pre-existing capillary beds and linking the obstructed vessel with the nearest patent vessel. Thus, the adjacent vessels also seemed to be dilated and tortuous, which had been similarly observed in our previous study.3 We speculate that the pressure gradient between an obstructed vein and neighbouring unobstructed vessels causes collateral vessels formation. The collaterals detection rate in the current study was higher than in the previous study.3 This is because wider optical coherence tomography angiography (OCTA) images, the size of which was 6 ✕ 6 mm in area, were used in the current study.
Regarding the other comment about the location of collateral vessels, Freund et al4 reported that collateral vessels were observed in only deep retinal capillary layer. However, we confirmed that the collateral vessels were present in both the superficial and the deep capillary layers on B scan images of OCTA. Additionally, fluorescein angiography images, which usually provides the information about retinal superficial capillaries and less about deep capillaries,5 also demonstrated the presence of collateral vessels, which may support the presence in the superficial capillaries.
The authors would again like to thank Dr. Sato for his interest in our work and the Editor for the opportunity to clarify the interesting and important issues that he has raised.
References:
1. Suzuki N, Hirano Y, Tomiyasu T, et al. Collateral vessels on optical coherence tomography angiography in eyes with branch retinal vein occlusion. Br J Ophthalmol. (in press).
2. Klein R, Klein B, Henkind P, et al. Retinal collateral vessel formation. Invest Ophthalmol. 1971;10:471-80.
3. Suzuki N, Hirano Y, Yoshida M, et al. Microvascular abnormalities on optical coherence tomography angiography in macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2016;161:126-32.
4. Freund KB, Sarraf D, Leong BCS, et al. Association of optical coherence tomography angiography of collaterals in retinal vein occlusion with major venous outflow through the deep vascular complex. JAMA Ophthalmology. 2018;136:1262-70.
5. Mendis KR, Balaratnasingam C, Yu P, et al. Correlation of histologic and clinical images to determine the diagnostic value of fluorescein angiography for studying retinal capillary detail. Invest Ophthalmol Vis Sci. 2010;51:5864-9.
Dear Editors,
Thanks for your email and comments for John H Fingert et al.
In our work, we aim to characterize the genotype(s), phenotype(s) and age-related penetrance in a Chinese family with primary open-angle glaucoma (POAG). We recruited a four-generation Chinese family with 22 participants and identified a novel heterozygous MYOC gene mutation (exon3 c.1309T>C p.Y437H) only among seven POAG patients and one ocular hypertension (OHT) patient. Further, we summarized the exact phenotype characterization of MYOC Y437H mutation and calculated the age-related penetrance of this family. Hopefully, we can do a favor in establishing genotype–phenotype correlations, which play a significant role in predicting the range of phenotypic variation of a specific mutation, in managing the disease better and in genetic counselling.
To the best of our knowledge, this is the first report of Y437H mutation in Chinese.Thus, we titled our work as “A novel MYOC gene mutation in a Chinese family with primary open-angle glaucoma”, which we really mean is a novel mutation only in Chinese population. We are very sorry about the misunderstanding the inappropriate title of our article may cause. In “Molecular analysis” section, we have affirmed that the Y437H mutation has been reported and referred previous article titled” Identification of a gene that causes primary open angle glaucoma” and so on.
To avoid above misunderstanding ever happening, if it is possible we’d li...
Dear Editors,
Thanks for your email and comments for John H Fingert et al.
In our work, we aim to characterize the genotype(s), phenotype(s) and age-related penetrance in a Chinese family with primary open-angle glaucoma (POAG). We recruited a four-generation Chinese family with 22 participants and identified a novel heterozygous MYOC gene mutation (exon3 c.1309T>C p.Y437H) only among seven POAG patients and one ocular hypertension (OHT) patient. Further, we summarized the exact phenotype characterization of MYOC Y437H mutation and calculated the age-related penetrance of this family. Hopefully, we can do a favor in establishing genotype–phenotype correlations, which play a significant role in predicting the range of phenotypic variation of a specific mutation, in managing the disease better and in genetic counselling.
To the best of our knowledge, this is the first report of Y437H mutation in Chinese.Thus, we titled our work as “A novel MYOC gene mutation in a Chinese family with primary open-angle glaucoma”, which we really mean is a novel mutation only in Chinese population. We are very sorry about the misunderstanding the inappropriate title of our article may cause. In “Molecular analysis” section, we have affirmed that the Y437H mutation has been reported and referred previous article titled” Identification of a gene that causes primary open angle glaucoma” and so on.
To avoid above misunderstanding ever happening, if it is possible we’d like to change our title as “The clinical feature of myocilin Y437H mutation in a Chinese family with primary open-angle glaucoma”. If you have any queries, please don’t hesitate to contact us.
Yours sincerely,
Lei Lei
We thank Dr. Sarnicola and family for their interest in our work and at the same time we apologize for not mentioning their preliminary results published in 2010; in this regard, some issues need be clarified.
We used an acronym to shorten the text and facilitate the readers of our article by eliminating this way long descriptive wording of the procedure. This did not imply by any means an attempt at modifying the terminology of surgical techniques, which is usually a task of the ophthalmological community. In fact, a particular acronym becomes a standard only when it is cited as such by numerous papers in the literature. This is not seeming the case, for the acronym “AVB”, that has never been used after its initial introduction by Sarnicola et al., thus failing to achieve the purpose aimed at.
In addition, we had a reason to introduce a new acronym because of a substantial difference in the surgical technique: in fact, instead of creating a new corneal tunnel into the emphysematous tissue, we inject ophthalmic viscoelastic device (OVD) in the same track created for pneumatic dissection, thus increasing surgical reproducibility and safety.
The lack of previous data we indicated (“…little data are available on the success rate…type of cleavage obtained, visual results and complications of this approach”) was simply related to the new concept of performing the injection of the OVD in the same corneal path where the air had failed.
In our series visual...
We thank Dr. Sarnicola and family for their interest in our work and at the same time we apologize for not mentioning their preliminary results published in 2010; in this regard, some issues need be clarified.
We used an acronym to shorten the text and facilitate the readers of our article by eliminating this way long descriptive wording of the procedure. This did not imply by any means an attempt at modifying the terminology of surgical techniques, which is usually a task of the ophthalmological community. In fact, a particular acronym becomes a standard only when it is cited as such by numerous papers in the literature. This is not seeming the case, for the acronym “AVB”, that has never been used after its initial introduction by Sarnicola et al., thus failing to achieve the purpose aimed at.
In addition, we had a reason to introduce a new acronym because of a substantial difference in the surgical technique: in fact, instead of creating a new corneal tunnel into the emphysematous tissue, we inject ophthalmic viscoelastic device (OVD) in the same track created for pneumatic dissection, thus increasing surgical reproducibility and safety.
The lack of previous data we indicated (“…little data are available on the success rate…type of cleavage obtained, visual results and complications of this approach”) was simply related to the new concept of performing the injection of the OVD in the same corneal path where the air had failed.
In our series visual acuity was significantly better after big bubble-DALK than after viscobubble-DALK in the first postoperative months, suggesting a transient negative effect of the OVD; this is an original result never described in any of the papers cited by the Sarnicola et al. in addition, they classified as dDALK all those procedures with a successful pneumatic dissection, whereas we now know that most of big bubbles created with air injection are actually pre-descemetic. This has been demonstrated by several authors after the initial observation by Dua.1 This mistake due to the lack of knowledge of the true anatomy of the floor is combined with the procedural error of putting together all cases with a successful bubble creation, without distinction between those obtained with air injection and those obtained with OVD injection. Our original results show a significant difference in postoperative vision between these two subgroups and represents the main original contribution of the paper. Instead, the methodology used by the Sarnicola group leads to a completely false analysis of the results because it is based to the erroneous assumption that all successful bubbles are descemetic.
References:
1. Dua HS, Faraj LA, Said DG, et al. Human corneal anatomy redefined: a novel pre-
Descemet’s layer (Dua’s layer). Ophthalmology 2013;120:1778–85.
The British Journal of Ophthalmology article, “Novel MYOC gene mutation in a Chinese family with primary open angle glaucoma” by Lei and coworkers describes a Tyr437His mutation in the myocilin gene. Contrary to descriptions in the title, abstract, and text of this article, the Tyr437His mutation is not novel. We and others have previously reported the same Tyr437His mutation in several publications dating back to 1997 [1-5].
1 Stone EM, Fingert JH, Alward WLM, et al. Identification of a Gene That Causes Primary Open Angle Glaucoma. Science 1997;275:668–70.
2 Alward WL, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 1998;338:1022–7.
3 Wiggs JL, Allingham RR, Vollrath D, et al. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. Am J Hum Genet 1998;63:1549–52.
4 Fingert JH, Héon E, Liebmann JM, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999;8:899–905.
5 Fingert JH, Stone EM, Sheffield VC, et al. Myocilin glaucoma. Survey of Ophthalmology 2002;47:547–61.
We read the article published by Fieß, et al (1) with considerable interest and laud them on their study and the large cohort. Considerable work has been done earlier, which looks at factors associated with refractive errors, however few studies document association with birth weight. Keeping this in mind, we feel that there are a few points requiring further clarity in this article.
The authors mention their inability to control for factors such as paternal refractive error and family history. However, previous studies not only discuss the paternal refractive error and family history, but also expand the affecting factors to include the number of myopic parents. (2) In the study design described by Höhn et al. where comprehensive information on living conditions and birth weight was collected via computer-assisted telephone interviews, (3) information on number of myopic parents could also have been collected, and would have proven to be an important covariate in the analysis.
The authors also report that 8369 participants provided birth weight data, of which 45 were excluded due to unreliable self-reported data [<1000g (n=7) or >6000g (n=38)]. However, tables 2 and 3 report analysed results based on 8369 participants not 8324 (after exclusion of the 45). Even though 45 is an insignificant number, and does not affect the results as such, this aspect of the results needs further clarity.
We read the article published by Fieß, et al (1) with considerable interest and laud them on their study and the large cohort. Considerable work has been done earlier, which looks at factors associated with refractive errors, however few studies document association with birth weight. Keeping this in mind, we feel that there are a few points requiring further clarity in this article.
The authors mention their inability to control for factors such as paternal refractive error and family history. However, previous studies not only discuss the paternal refractive error and family history, but also expand the affecting factors to include the number of myopic parents. (2) In the study design described by Höhn et al. where comprehensive information on living conditions and birth weight was collected via computer-assisted telephone interviews, (3) information on number of myopic parents could also have been collected, and would have proven to be an important covariate in the analysis.
The authors also report that 8369 participants provided birth weight data, of which 45 were excluded due to unreliable self-reported data [<1000g (n=7) or >6000g (n=38)]. However, tables 2 and 3 report analysed results based on 8369 participants not 8324 (after exclusion of the 45). Even though 45 is an insignificant number, and does not affect the results as such, this aspect of the results needs further clarity.
Lastly, while the authors mention, further factors that affect BCVA and refractive errors such as amount of outdoor activity, near work in childhood and adolescence, prematurity (4,5) and gestational age, the non-inclusion of these possible confounders in their analysis makes it difficult to plan public health interventions based on these results. In the present form, the results of association of birth weight with myopic refractive error are significant but emphasise the need for further studies which control for gestational age, prematurity and other factors mentioned above, while studying the association, so that the effect can be isolated to birth weight. Public health interventions can then be planned accordingly.
We appreciate the opportunity to be able to discuss our views on the subject and the article in question.
References
1. Fieß A, Schuster AK, Nickels S, et al, Association of low birth weight with myopic refractive error and lower visual acuity in adulthood: results from the population-based Gutenberg Health Study (GHS), British Journal of Ophthalmology 2019;103:99-105.
2. Jones LA, Sinnott LT, Mutti DO, Mitchell GL, Moeschberger ML, Zadnik K. Parental history of myopia, sports and outdoor activities, and future myopia. Invest Ophthalmol Vis Sci. 2007;48(8):3524-32.
3. Höhn R, Kottler U, Peto T, et al. The ophthalmic branch of the Gutenberg Health Study: study design, cohort profile and self-reported diseases. PLoS One. 2015;10(3):e0120476. Published 2015 Mar 16. doi:10.1371/journal.pone.0120476
4. Cook A, White S, Batterbury M, et al. Ocular growth and refractive error development in premature infants without retinopathy of prematurity. Invest Ophthalmol Vis Sci. 2003;44:953–960.
5. Fieß A, Kölb-Keerl R, Knuf M, et al. Axial Length and Anterior Segment Alterations in Former Preterm Infants and Full-Term Neonates Analyzed With Scheimpflug Imaging. Cornea 2017;36:821–7.
We thank Dr. Tobon for his comments regarding our recently published article on refractive errors frequency in Colombia.1
Initially he referred to the exclusion of the participants with less than 20/40 of distance corrected vision. The explanation of the application of this criterium was that, since as it has been shown, reproducibility of manifest refraction is less in patients with bad distance corrected visual acuity, and in this study we needed to have a very reliable manifest refraction examination.2
However, we believe that Dr. Tobon highlights a very interesting point, which is worth analyzing in more detail. Ours and other studies that have analyzed the prevalence of refractive errors in a population have excluded eyes with other ocular conditions, including amblyopia. For example, in the study conducted in Mexico by Gomez-Salazar et al, which included a very large sample (more than 670,000 patients), they excluded patients with amblyopia.3 This made it impossible to analyze the frequency of amblyopia or anisometropia.
In our study we excluded those patients with less than 20/40 of distance corrected visual acuity in any eye. Unfortunately, we did not keep the information on those patients excluded, and therefore we cannot determine the exact number or diagnosis of those cases. For future studies we will record such information.
With regard to the second query of Dr. Tobon, we decided not to use cyclopegic refraction in this study, performed...
We thank Dr. Tobon for his comments regarding our recently published article on refractive errors frequency in Colombia.1
Initially he referred to the exclusion of the participants with less than 20/40 of distance corrected vision. The explanation of the application of this criterium was that, since as it has been shown, reproducibility of manifest refraction is less in patients with bad distance corrected visual acuity, and in this study we needed to have a very reliable manifest refraction examination.2
However, we believe that Dr. Tobon highlights a very interesting point, which is worth analyzing in more detail. Ours and other studies that have analyzed the prevalence of refractive errors in a population have excluded eyes with other ocular conditions, including amblyopia. For example, in the study conducted in Mexico by Gomez-Salazar et al, which included a very large sample (more than 670,000 patients), they excluded patients with amblyopia.3 This made it impossible to analyze the frequency of amblyopia or anisometropia.
In our study we excluded those patients with less than 20/40 of distance corrected visual acuity in any eye. Unfortunately, we did not keep the information on those patients excluded, and therefore we cannot determine the exact number or diagnosis of those cases. For future studies we will record such information.
With regard to the second query of Dr. Tobon, we decided not to use cyclopegic refraction in this study, performed around our country, because this additional intervention would have required more complex logistical necessities, ethical requirements. Since the participants would have been exposed to an additional risk,4 although small, it should have been expressly indicated in the informed consent, and accepted by the potential participants (or in the case of the children by the parents or guardians), issue that at a given moment could have decreased the confidence of the population and made it more difficult to recruit patients in certain areas of the country, distant from our usual care center, being us a group of researchers not known in those areas to which we move for the study. Instead, we decided to perform a sequential examination by experienced optometrists: first a non-cycloplegic retinoscopy, making it as static as possible by requesting the patients to keep the fixation in a distant object in order to relax the accommodation and secondly, we carried out a careful manifest refraction. The results of the latter were the one taken into account in the study. If there was a discrepancy between the retinoscopy and the manifest refraction, the optometrist rechecked the patient. As other experts have indicated (see the explanation by Marsh-Tootle and Frazier), this approach is valid, but as we recognized it, it could be considered a weakness of our study. It is correct that despite the meticulousness in performing these non-cycloplegic examinations, we could have overestimated the frequency of myopia and underestimated that of hyperopia, especially in patients with ages between 8 and 11 years.
REFERENCES
1. Galvis V, Tello A, Otero J, et al. Prevalence of refractive errors in Colombia: MIOPUR study. Br J Ophthalmol 2018;102:1320-3.
2. Leinonen J, Laakkonen E, Laatikainen L. Repeatability (test-retest variability) of refractive error measurement in clinical settings. Acta Ophthalmol Scand 2006;84:532-6.
3. Gomez-Salazar F, Campos-Romero A, Gomez-Campaña H, et al. Refractive errors among children, adolescents and adults attending eye clinics in Mexico. Int J Ophthalmol 2017;10:796-802.
4. Bhatia SS, Vidyashankar C, Sharma RK, et al. Systemic toxicity with cyclopentolate eye drops. Indian Pediatr 2000;37:329-31.
5. Marsh-Tootle WL, Frazier MG. Infants, toddlers and children. Borish's Clinical
Refraction. 2nd edn. Philadelphia: Buiterworth Heinemann Elsevier, 2006:1415–6.
We read with great interest the recent paper by Zhang and Ying exploring statistical approaches in published ophthalmic clinical science papers.1 We very much agree with the main conclusion drawn by the authors that collaborative efforts should be made in the vision research community to improve statistical practise for ocular data. In this vein, however, we were disappointed not to see reference to the Statistics Notes Series that has been published in this very journal. These have been written with a view to tackling some of the more prevalent statistical issues within ophthalmology and we would encourage readers to make use of these.2- 12. Within the UK this view that there needs to be greater collaboration in the vision research community has led to the formation of the Ophthalmology Research Section of the NIHR Statistics group which is championing cross- professional collaboration and active discussion in relation to statistical issues. It is always important when reviewing misuse of statistics in biomedical research to distinguish between misuse that leads to distorted or incorrect results and those methods which do not fully use data to maximum potential given that this loss of information might be viewed as unethical. In this regard we find the results from Zhang et al pleasing in that the proportion of papers which analysed at the level of the individual because of the nature of the observation rose from 15.2 % in 1995 to 50 % in 2017. A finding which is...
Show MoreTo the Editor:
We read the recent article in the journal by Monfermé and coauthors (1) on phenotypic associations of TYR R402Q compound heterozygosity with keen interest. Given our own and others previous findings (2-4) that the R402Q-S192Y haplotype seemed to have a stronger biological effect, we were surprised that a triallelic effect was not supported in the clinical discussion by Monfermé et al. When we examined these results more closely, we noted that their sample included 52 S192Y variant allele carriers out of the entire collection of 69 patients, of whom 31 (44.9%) carried the R402Q-S192Y double variant haplotype. In our own collections from the Australian general population (BNMS and BLTS, Duffy et al., in submission), only 6% of R402Q carriers also carried S192Y in cis. When we examined the European 1000 Genomes subsamples, there too only 7% of R402Q haplotypes had the 192Y rather than 192S wild type allele. So, even though Monfermé et al could not detect a statistically significant additive effect on OCA trait severity due to the S192Y polymorphism within their sample, it is clear that the S192 variant allele is markedly overrepresented compared to the general population, suggesting that it must have some relationship to albinism. This genetic association of the TYR R402Q-S192Y double variant haplotype with OCA1 is now clearly causative (2, 3), and explains some of the missing heritability that has previously been seen in OCA patients (4).
Yours,...
Show MoreTo the Editor,
Show MoreIntravitreal antivascular endothelial growth factor (VEGF) agents undeniably have many clinical applications and we read with great interest the recent meta-analysis published in your journal by Low et al1 comparing the effectiveness and harms of these agents in three retinal disorders.
We would first like to thank the authors for their exhaustive review and synthesis of the evidence in this area. The conclusions they reached served to confirm what many of us had already suspected.2 Nevertheless, the article features some important methodological flaws and inadequate reporting of data that we would like to highlight to ensure that readers are in a position to interpret the findings of the meta-analysis correctly.
In relation to reporting issues, we were surprised to see that Table 1, which is quite creative and unique in terms of systematic review tables, does not include a list of the studies analyzed for each section. The authors, for example, state that they included two clinical trials comparing aflibercept and ranibizumab, but they do not specify which ones. This detracts from the transparency of the study and makes it difficult to review the findings. We also noticed a lack of uniformity within the figures, as some of the studies are listed by author name and others by author name and year of publication. In addition, Figure 3 shows data from the 2011 study by Biswas P, Sengupta S, Choudhary R, et al for the 18-24–month but not the 12...
Editor,
Show MoreWe read with great interest the article titled “Choroidal thickness and vascular density in macular telangiectasia type 2 using en face swept-source optical coherence tomography” by Wang et al.[1] This is an interesting study in which the authors performed multimodal imaging for the diagnosis of macular telangiectasia (MacTel) type 2 and reported similar choroidal thickness (CT) between MacTel type 2 and control eyes using swept-source optical coherence tomography (SS-OCT).[1]
There are a few concerns that we would like to highlight. Although the authors control for confounders like age and spherical equivalent, axial length is another important confounder that has not been evaluated in this prospectively conducted study. The subfoveal CT has been reported to decrease by up to 58µm per one mm increase in the axial length after adjusting for age and sex.[2] Ignoring the axial length in choroidal thickness analysis may have untoward consequences.
Although the number of cases was small (n=39 eyes), the stagewise distribution of CT may be of help. A recent study by Kumar et al. using SS-OCT reported different subfoveal CT in non-proliferative and proliferative stages of the disease, although the results were not statistically significant.[3] If a varied distribution is observed between different stages, this may support the role of the choroid in the pathophysiology of this disease.
Inter-ocular asymmetry does exist in CT[4] as well as in the pr...
Dear Editor,
We appreciate the valuable comments from Dr. Sato regarding our recently published article.1 Dr. Sato’s comments raise important points about definition of collateral vessels in eyes with branch retinal vein occlusion (BRVO).
Show MoreAs previously reported,2 collateral vessels develop from the pre-existing retinal capillary network to drain a blood flow from an obstructed vein into an adjacent area in eyes with BRVO. Therefore, in the current study, we defined collateral vessels as dilated and tortuous capillaries occurring in pre-existing capillary beds and linking the obstructed vessel with the nearest patent vessel. Thus, the adjacent vessels also seemed to be dilated and tortuous, which had been similarly observed in our previous study.3 We speculate that the pressure gradient between an obstructed vein and neighbouring unobstructed vessels causes collateral vessels formation. The collaterals detection rate in the current study was higher than in the previous study.3 This is because wider optical coherence tomography angiography (OCTA) images, the size of which was 6 ✕ 6 mm in area, were used in the current study.
Regarding the other comment about the location of collateral vessels, Freund et al4 reported that collateral vessels were observed in only deep retinal capillary layer. However, we confirmed that the collateral vessels were present in both the superficial and the deep capillary layers on B scan images of OCTA. Additionally, fluoresc...
Dear Editors,
Show MoreThanks for your email and comments for John H Fingert et al.
In our work, we aim to characterize the genotype(s), phenotype(s) and age-related penetrance in a Chinese family with primary open-angle glaucoma (POAG). We recruited a four-generation Chinese family with 22 participants and identified a novel heterozygous MYOC gene mutation (exon3 c.1309T>C p.Y437H) only among seven POAG patients and one ocular hypertension (OHT) patient. Further, we summarized the exact phenotype characterization of MYOC Y437H mutation and calculated the age-related penetrance of this family. Hopefully, we can do a favor in establishing genotype–phenotype correlations, which play a significant role in predicting the range of phenotypic variation of a specific mutation, in managing the disease better and in genetic counselling.
To the best of our knowledge, this is the first report of Y437H mutation in Chinese.Thus, we titled our work as “A novel MYOC gene mutation in a Chinese family with primary open-angle glaucoma”, which we really mean is a novel mutation only in Chinese population. We are very sorry about the misunderstanding the inappropriate title of our article may cause. In “Molecular analysis” section, we have affirmed that the Y437H mutation has been reported and referred previous article titled” Identification of a gene that causes primary open angle glaucoma” and so on.
To avoid above misunderstanding ever happening, if it is possible we’d li...
We thank Dr. Sarnicola and family for their interest in our work and at the same time we apologize for not mentioning their preliminary results published in 2010; in this regard, some issues need be clarified.
Show MoreWe used an acronym to shorten the text and facilitate the readers of our article by eliminating this way long descriptive wording of the procedure. This did not imply by any means an attempt at modifying the terminology of surgical techniques, which is usually a task of the ophthalmological community. In fact, a particular acronym becomes a standard only when it is cited as such by numerous papers in the literature. This is not seeming the case, for the acronym “AVB”, that has never been used after its initial introduction by Sarnicola et al., thus failing to achieve the purpose aimed at.
In addition, we had a reason to introduce a new acronym because of a substantial difference in the surgical technique: in fact, instead of creating a new corneal tunnel into the emphysematous tissue, we inject ophthalmic viscoelastic device (OVD) in the same track created for pneumatic dissection, thus increasing surgical reproducibility and safety.
The lack of previous data we indicated (“…little data are available on the success rate…type of cleavage obtained, visual results and complications of this approach”) was simply related to the new concept of performing the injection of the OVD in the same corneal path where the air had failed.
In our series visual...
Dear Editors,
The British Journal of Ophthalmology article, “Novel MYOC gene mutation in a Chinese family with primary open angle glaucoma” by Lei and coworkers describes a Tyr437His mutation in the myocilin gene. Contrary to descriptions in the title, abstract, and text of this article, the Tyr437His mutation is not novel. We and others have previously reported the same Tyr437His mutation in several publications dating back to 1997 [1-5].
1 Stone EM, Fingert JH, Alward WLM, et al. Identification of a Gene That Causes Primary Open Angle Glaucoma. Science 1997;275:668–70.
2 Alward WL, Fingert JH, Coote MA, et al. Clinical features associated with mutations in the chromosome 1 open-angle glaucoma gene (GLC1A). N Engl J Med 1998;338:1022–7.
3 Wiggs JL, Allingham RR, Vollrath D, et al. Prevalence of mutations in TIGR/Myocilin in patients with adult and juvenile primary open-angle glaucoma. Am J Hum Genet 1998;63:1549–52.
4 Fingert JH, Héon E, Liebmann JM, et al. Analysis of myocilin mutations in 1703 glaucoma patients from five different populations. Hum Mol Genet 1999;8:899–905.
5 Fingert JH, Stone EM, Sheffield VC, et al. Myocilin glaucoma. Survey of Ophthalmology 2002;47:547–61.
Dear Editor,
We read the article published by Fieß, et al (1) with considerable interest and laud them on their study and the large cohort. Considerable work has been done earlier, which looks at factors associated with refractive errors, however few studies document association with birth weight. Keeping this in mind, we feel that there are a few points requiring further clarity in this article.
The authors mention their inability to control for factors such as paternal refractive error and family history. However, previous studies not only discuss the paternal refractive error and family history, but also expand the affecting factors to include the number of myopic parents. (2) In the study design described by Höhn et al. where comprehensive information on living conditions and birth weight was collected via computer-assisted telephone interviews, (3) information on number of myopic parents could also have been collected, and would have proven to be an important covariate in the analysis.
The authors also report that 8369 participants provided birth weight data, of which 45 were excluded due to unreliable self-reported data [<1000g (n=7) or >6000g (n=38)]. However, tables 2 and 3 report analysed results based on 8369 participants not 8324 (after exclusion of the 45). Even though 45 is an insignificant number, and does not affect the results as such, this aspect of the results needs further clarity.
Lastly, while the authors mention, furt...
Show MoreWe thank Dr. Tobon for his comments regarding our recently published article on refractive errors frequency in Colombia.1
Show MoreInitially he referred to the exclusion of the participants with less than 20/40 of distance corrected vision. The explanation of the application of this criterium was that, since as it has been shown, reproducibility of manifest refraction is less in patients with bad distance corrected visual acuity, and in this study we needed to have a very reliable manifest refraction examination.2
However, we believe that Dr. Tobon highlights a very interesting point, which is worth analyzing in more detail. Ours and other studies that have analyzed the prevalence of refractive errors in a population have excluded eyes with other ocular conditions, including amblyopia. For example, in the study conducted in Mexico by Gomez-Salazar et al, which included a very large sample (more than 670,000 patients), they excluded patients with amblyopia.3 This made it impossible to analyze the frequency of amblyopia or anisometropia.
In our study we excluded those patients with less than 20/40 of distance corrected visual acuity in any eye. Unfortunately, we did not keep the information on those patients excluded, and therefore we cannot determine the exact number or diagnosis of those cases. For future studies we will record such information.
With regard to the second query of Dr. Tobon, we decided not to use cyclopegic refraction in this study, performed...
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