Lisa A. Jones

Corneal reshaping and myopia progression

Background/aims: Anecdotal evidence indicates that corneal reshaping contact lenses may slow myopia progression in children. The purpose of this investigation is to determine whether corneal reshaping contact lenses slow eye growth. Methods: Forty subjects were fitted with corneal reshaping contact lenses. All subjects were 8 to 11 years and had between −0.75 D and −4.00 D myopia with less than 1.00 D astigmatism. Subjects were age-matched to a soft contact lens wearer from another myopia control study. A-scan ultrasound was performed at baseline and annually for 2 years. Results: Twenty-eight of 40 (70%) subjects wore corneal reshaping contact lenses for 2 years. The refractive error and axial length were similar between the two groups at baseline. The corneal reshaping group had an annual rate of change in axial lengths that was significantly less than the soft contact lens wearers (mean difference in annual change = 0.16 mm, p = 0.0004). Vitreous chamber depth experienced similar changes (mean difference in annual change = 0.10 mm, p = 0.006). Conclusion: Results confirm previous reports of slowed eye growth following corneal reshaping contact lens wear.

Ocular component data in schoolchildren as a function of age and gender.

Purpose. To describe the refractive error and ocular components of a large group of school-aged children as a function of age and gender. Methods. In this report, we describe the refractive error and ocular components of 2583 school-aged children (49.3% girls, overall mean [±SD] age 10.0 ± 2.3). Measurement methods included cycloplegic autorefraction, autokeratometry, videophakometry, and A-scan ultrasonography. For statistical comparisons across gender and age, a critical point of &agr; = 0.005 was used to assess significance because of the large sample size and the large number of comparisons made. Results. Of these 2583 children, 10.1% were myopic (−0.75 D or more myopia in both meridians), and 8.6% were hyperopic (+1.25 D or more hyperopia in both meridians). As would be expected, there was a significant effect of age on refractive error (spherical equivalent, p < 0.0001), toward less hyperopia/more myopia. There was no significant difference in the average refractive error between girls and boys (p = 0.0192). Girls had steeper corneas than boys (0.74 D steeper in the vertical meridian and 0.63 D steeper in the horizontal meridian, p < 0.0001). There were no significant differences in corneal power with age (p = 0.16). Both older age and male gender were significantly associated with deeper anterior chambers (p < 0.0001 for both). The crystalline lens showed significant thinning with age (p < 0.0001), however, there was no significant difference in the lens thickness between girls and boys (p = 0.66). Both Gullstrand lens power and calculated lens power showed significant effects of age and gender (p < 0.0001 for both). Girls, on average, had Gullstrand lens powers that were 0.28 D steeper and calculated lens powers that were 0.80 D more powerful than boys. Axial length also showed significant effects of age and gender (p < 0.0001 for both). Girls’ eyes were, on average, 0.32 mm shorter than those of boys. Conclusions. These cross-sectional data show a general pattern of ocular growth, no change in corneal power, and crystalline lens thinning and flattening between the ages of 6 and 14 years. Girls tended to have steeper corneas, stronger crystalline lenses, and shorter eyes compared with boys.

Genome-Wide Association Study of Major Recurrent Depression in the U.K. Population

OBJECTIVE Studies of major depression in twins and families have shown moderate to high heritability, but extensive molecular studies have failed to identify susceptibility genes convincingly. To detect genetic variants contributing to major depression, the authors performed a genome-wide association study using 1,636 cases of depression ascertained in the U.K. and 1,594 comparison subjects screened negative for psychiatric disorders. METHOD Cases were collected from 1) a case-control study of recurrent depression (the Depression Case Control [DeCC] study; N=1346), 2) an affected sibling pair linkage study of recurrent depression (probands from the Depression Network [DeNT] study; N=332), and 3) a pharmacogenetic study (the Genome-Based Therapeutic Drugs for Depression [GENDEP] study; N=88). Depression cases and comparison subjects were genotyped at Centre National de Génotypage on the Illumina Human610-Quad BeadChip. After applying stringent quality control criteria for missing genotypes, departure from Hardy-Weinberg equilibrium, and low minor allele frequency, the authors tested for association to depression using logistic regression, correcting for population ancestry. RESULTS Single nucleotide polymorphisms (SNPs) in BICC1 achieved suggestive evidence for association, which strengthened after imputation of ungenotyped markers, and in analysis of female depression cases. A meta-analysis of U.K. data with previously published results from studies in Munich and Lausanne showed some evidence for association near neuroligin 1 (NLGN1) on chromosome 3, but did not support findings at BICC1. CONCLUSIONS This study identifies several signals for association worthy of further investigation but, as in previous genome-wide studies, suggests that individual gene contributions to depression are likely to have only minor effects, and very large pooled analyses will be required to identify them.

Genome wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC

The Schizophrenia Psychiatric Genome-Wide Association Study Consortium (PGC) highlighted 81 single-nucleotide polymorphisms (SNPs) with moderate evidence for association to schizophrenia. After follow-up in independent samples, seven loci attained genome-wide significance (GWS), but multi-locus tests suggested some SNPs that did not do so represented true associations. We tested 78 of the 81 SNPs in 2640 individuals with a clinical diagnosis of schizophrenia attending a clozapine clinic (CLOZUK), 2504 cases with a research diagnosis of bipolar disorder, and 2878 controls. In CLOZUK, we obtained significant replication to the PGC-associated allele for no fewer than 37 (47%) of the SNPs, including many prior GWS major histocompatibility complex (MHC) SNPs as well as 3/6 non-MHC SNPs for which we had data that were reported as GWS by the PGC. After combining the new schizophrenia data with those of the PGC, variants at three loci (ITIH3/4, CACNA1C and SDCCAG8) that had not previously been GWS in schizophrenia attained that level of support. In bipolar disorder, we also obtained significant evidence for association for 21% of the alleles that had been associated with schizophrenia in the PGC. Our study independently confirms association to three loci previously reported to be GWS in schizophrenia, and identifies the first GWS evidence in schizophrenia for a further three loci. Given the number of independent replications and the power of our sample, we estimate 98% (confidence interval (CI) 78–100%) of the original set of 78 SNPs represent true associations. We also provide strong evidence for overlap in genetic risk between schizophrenia and bipolar disorder.

Overnight orthokeratology: preliminary results of the Lenses and Overnight Orthokeratology (LOOK) study.

Background. The Lenses and Overnight Orthokeratology (LOOK) study is a pilot study designed to learn the procedures of orthokeratology lens fitting in preparation for a planned larger clinical trial and to obtain data with which to calculate a sample size for that larger study. Data are presented for the first 3 months of the LOOK study. Methods. Sixty subjects were enrolled in this multicenter pilot study to evaluate the success and safety of treatment with overnight orthokeratology contact lenses. Refractive error, corneal topography, and biomicroscopic data were collected to determine the amount of refractive error change achieved, corneal changes, and a safety profile of overnight wear of reverse geometry rigid gas permeable lenses for orthokeratology. Results. Of the 60 subjects enrolled, 46 completed the 1-month visit, and 31 completed the 3-month visit. The mean change in spherical equivalent manifest refraction from baseline to the morning 3-month visit was 2.08 ± 1.11 D in the right eye and 2.16 ± 1.05 D in the left eye. At the 3-month morning visit, 74% of right eyes and 61% of left eyes had 20/20 unaided visual acuity. No corneal infiltrates or ulcers were noted in any subjects. Observations of fluorescein staining of the cornea, imprinting, and microcysts were noted in some patients at the 3-month visit. Conclusions. The preliminary results of the LOOK study indicate that improvement in unaided visual acuity can be attained for at least 6 h after lens removal. The short-term safety and efficacy of the procedure appear to be favorable; however, future studies are needed to determine the long-term outcomes of treatment.

Replication of bipolar disorder susceptibility alleles and identification of two novel genome-wide significant associations in a new bipolar disorder case-control sample.

We have conducted a genotyping study using a custom Illumina Infinium HD genotyping array, the ImmunoChip, in a new UK sample of 1218 bipolar disorder (BD) cases and 2913 controls that have not been used in any studies previously reported independently or in meta-analyses. The ImmunoChip was designed before the publication of the Psychiatric Genome-Wide Association Study Consortium Bipolar Disorder Working Group (PGC-BD) meta-analysis data. As such 3106 single-nucleotide polymorphisms (SNPs) with a P-value <1 × 10−3 from the BD meta-analysis by Ferreira et al. were genotyped. We report support for two of the three most strongly associated chromosomal regions in the Ferreira study, CACNA1C (rs1006737, P=4.09 × 10−4) and 15q14 (rs2172835, P=0.043) but not ANK3 (rs10994336, P=0.912). We have combined our ImmunoChip data (569 quasi-independent SNPs from the 3016 SNPs genotyped) with the recently published PGC-BD meta-analysis data, using either the PGC-BD combined discovery and replication data where available or just the discovery data where the SNP was not typed in a replication sample in PGC-BD. Our data provide support for two regions, at ODZ4 and CACNA1C, with prior evidence for genome-wide significant (GWS) association in PGC-BD meta-analysis. In addition, the combined analysis shows two novel GWS associations. First, rs7296288 (P=8.97 × 10−9, odds ratio (OR)=0.9), an intergenic polymorphism on chromosome 12 located between RHEBL1 and DHH. Second, rs3818253 (P=3.88 × 10−8, OR=1.16), an intronic SNP on chromosome 20q11.2 in the gene TRPC4AP, which lies in a high linkage disequilibrium region along with the genes GSS and MYH7B.

Clinical differences between bipolar and unipolar depression

It is commonly -- but wrongly -- assumed that there are no important differences between the clinical presentations of major depressive disorder and bipolar depression. Here we compare clinical course variables and depressive symptom profiles in a large sample of individuals with major depressive disorder (n=593) and bipolar disorder (n=443). Clinical characteristics associated with a bipolar course included the presence of psychosis, diurnal mood variation and hypersomnia during depressive episodes, and a greater number of shorter depressive episodes. Such features should alert a clinician to a possible bipolar course. This is important because optimal management is not the same for bipolar and unipolar depression.

Genetic utility of broadly defined bipolar schizoaffective disorder as a diagnostic concept

Background Psychiatric phenotypes are currently defined according to sets of descriptive criteria. Although many of these phenotypes are heritable, it would be useful to know whether any of the various diagnostic categories in current use identify cases that are particularly helpful for biological–genetic research. Aims To use genome-wide genetic association data to explore the relative genetic utility of seven different descriptive operational diagnostic categories relevant to bipolar illness within a large UK case–control bipolar disorder sample. Method We analysed our previously published Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder genome-wide association data-set, comprising 1868 individuals with bipolar disorder and 2938 controls genotyped for 276 122 single nucleotide polymorphisms (SNPs) that met stringent criteria for genotype quality. For each SNP we performed a test of association (bipolar disorder group v. control group) and used the number of associated independent SNPs statistically significant at P<0.00001 as a metric for the overall genetic signal in the sample. We next compared this metric with that obtained using each of seven diagnostic subsets of the group with bipolar disorder: Research Diagnostic Criteria (RDC): bipolar I disorder; manic disorder; bipolar II disorder; schizoaffective disorder, bipolar type; DSM–IV: bipolar I disorder; bipolar II disorder; schizoaffective disorder, bipolar type. Results The RDC schizoaffective disorder, bipolar type (v. controls) stood out from the other diagnostic subsets as having a significant excess of independent association signals (P<0.003) compared with that expected in samples of the same size selected randomly from the total bipolar disorder group data-set. The strongest association in this subset of participants with bipolar disorder was at rs4818065 (P = 2.42×10–7). Biological systems implicated included gamma amniobutyric acid (GABA)A receptors. Genes having at least one associated polymorphism at P<10–4 included B3GALTS, A2BP1, GABRB1, AUTS2, BSN, PTPRG, GIRK2 and CDH12. Conclusions Our findings show that individuals with broadly defined bipolar schizoaffective features have either a particularly strong genetic contribution or that, as a group, are genetically more homogeneous than the other phenotypes tested. The results point to the importance of using diagnostic approaches that recognise this group of individuals. Our approach can be applied to similar data-sets for other psychiatric and non-psychiatric phenotypes.

Normal eye growth in emmetropic schoolchildren.

Purpose. The purpose of this report is to describe the normal growth pattern of the optical components of the eye in a cohort of emmetropic, school-aged children. Methods. Emmetropia was defined as refractive error (measured by cycloplegic autorefraction) in the vertical and horizontal meridians of the right eye between +1.00 D and −0.25 D at all the visits. This definition resulted in a sample of 194 children enrolled in the Orinda Longitudinal Study of Myopia (OLSM) between ages 6 and 14 years with at least 2 years of follow-up evaluation (across three annual visits) between 1989 and 2000. The optical components measured included corneal power, anterior chamber depth, crystalline lens thickness, Gullstrand lens power, calculated lens power, crystalline lens index, vitreous chamber depth, and axial length. Results. Corneal power and anterior chamber depth were best modeled as quadratic functions of ln (age). The model involving the square of the inverse of age best described calculated lens power and crystalline lens index. The relationship between age and crystalline lens thickness was best described using a linear function of age with a point of inflection. A linear function of ln (age) with a point of inflection best described the relationship between age and axial length, Gullstrand lens power, and vitreous chamber depth. For five of the eight components (crystalline lens thickness, Gullstrand lens power, calculated lens power, corneal power, and crystalline lens index), the line modeling the data was negative in overall direction, indicating that the component value decreased with age. The upward trend of the line modeling axial length, anterior chamber depth, and vitreous chamber depth reflected the continued growth of the eye from age 6 years to age 15 years. Conclusions. A picture of normal eye growth in emmetropes from ages 6 to 15 years is provided based on a combination of cross-sectional and longitudinal data. Axial elongation, crystalline lens flattening and thinning, and decrease in lens power are its hallmarks.

The Children's Overnight Orthokeratology Investigation (COOKI) Pilot Study

Purpose. Innovations in contact lens materials and designs allow patients to wear contact lenses during sleep to flatten the cornea and temporarily to reduce myopic refractive error and improve unaided visual acuity. We conducted the Children’s Overnight Orthokeratology Investigation (COOKI) pilot study, a case series, to describe the refractive error and visual changes, as well as the slitlamp observations associated with overnight orthokeratology in children, over a period of 6 months. Methods. Twenty-nine 8- to 11-year-old children with myopia between −0.75 and −5.00 D and <−1.50 D corneal toricity were fitted with corneal refractive therapy contact lenses (Paragon Vision Sciences, Mesa, AZ). They were examined within 1 hour of awakening and about 6 hours later at 1 day, 1 week, 2 weeks, 1 month, 3 months, and 6 months after the first night of contact lens wear. At each visit, the logarithm of the minimum angle of resolution (logMAR) visual acuity, manifest refraction, slitlamp examination, and corneal topography were performed. Results. Twenty-three subjects completed the 6-month study. Three subjects decided not to wear contact lenses, two did not achieve acceptable fits, and one moved from the area. At the 6-month afternoon visit, the mean ± SD uncorrected high-contrast visual acuity was +0.08 ± 0.15 logMAR (Snellen equivalent, 20/24), and the mean ± SD spherical equivalent refraction was −0.16 ± 0.66 D. The corneas of three-fifths of the subjects showed mild staining at the morning visit, and one-third of the patients showed mild corneal staining at the afternoon visit. The most common type of stain was central punctate staining. No subjects experienced lasting adverse visual effects from cornea-reshaping contact lens wear during the study period. Conclusions. Overnight cornea-reshaping contact lenses are efficacious for young myopic patients, and no children experienced a serious adverse event during the study.