RESUMO
Increasing evidence suggests that kynurenine pathway (KP) dyshomeostasis may promote disease progression in dementia. Studies in Alzheimer's disease (AD) patients confirm KP dyshomeostasis in plasma and cerebrospinal fluid (CSF) which correlates with amyloid-ß and tau pathology. Herein, we performed the first comprehensive study assessing baseline levels of KP metabolites in participants enrolling in the Australian Imaging Biomarkers Flagship Study of Aging. Our purpose was to test the hypothesis that changes in KP metabolites may be biomarkers of dementia processes that are largely silent. We used a cross-sectional analytical approach to assess non-progressors (N = 73); cognitively normal (CN) or mild cognitive impairment (MCI) participants at baseline and throughout the study, and progressors (N = 166); CN or MCI at baseline but progressing to either MCI or AD during the study. Significant KP changes in progressors included increased 3-hydroxyanthranilic acid (3-HAA) and 3-hydroxyanthranilic acid/anthranilic acid (3-HAA/AA) ratio, the latter having the largest effect on the odds of an individual being a progressor (OR 35.3; 95% CI between 14 and 104). 3-HAA levels were hence surprisingly bi-phasic, high in progressors but low in non-progressors or participants who had already transitioned to MCI or dementia. This is a new, unexpected and interesting result, as most studies of the KP in neurodegenerative disease show reduced 3-HAA/AA ratio after diagnosis. The neuroprotective metabolite picolinic acid was also significantly decreased while the neurotoxic metabolite 3-hydroxykynurenine increased in progressors. These results were significant even after adjustment for confounders. Considering the magnitude of the OR to predict change in cognition, it is important that these findings are replicated in other populations. Independent validation of our findings may confirm the utility of 3-HAA/AA ratio to predict change in cognition leading to dementia in clinical settings.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doenças Neurodegenerativas , Ácido 3-Hidroxiantranílico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Austrália , Biomarcadores , Disfunção Cognitiva/líquido cefalorraquidiano , Estudos Transversais , Progressão da Doença , Humanos , Cinurenina , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: The Australian Imaging and Biomarker Lifestyle (AIBL) study of aging is designed to aid the discovery of biomarkers. The current study aimed to discover differentially expressed plasma proteins that could yield a blood-based screening tool for Alzheimer's disease. METHODS: The concentration of proteins in plasma covers a vast range of 12 orders of magnitude. Therefore, to search for medium to low abundant biomarkers and elucidate mechanisms of AD, we immuno-depleted the most abundant plasma proteins and pre-fractionated the remaining proteins by HPLC, prior to two-dimensional gel electrophoresis. The relative levels of approximately 3400 protein species resolved on the 2D gels were compared using in-gel differential analysis with spectrally resolved fluorescent protein detection dyes (Zdyes™). Here we report on analysis of pooled plasma samples from an initial screen of a sex-matched cohort of 72 probable AD patients and 72 healthy controls from the baseline time point of AIBL. RESULTS: We report significant changes in variants of apolipoprotein E, haptoglobin, α1 anti-trypsin, inter-α trypsin inhibitor, histidine-rich glycoprotein, and a protein of unknown identity. α1 anti-trypsin and α1 anti-chymotrypsin demonstrated plasma concentrations that were dependent on APOE ε4 allele dose. Our analysis also identified an association with the level of Vitamin D binding protein fragments and complement factor I with sex. We then conducted a preliminary validation study, on unique individual samples compared to the discovery cohort, using a targeted LC-MS/MS assay on a subset of discovered biomarkers. We found that targets that displayed a high degree of isoform specific changes in the 2D gels were not changed in the targeted MS assay which reports on the total level of the biomarker. CONCLUSIONS: This demonstrates that further development of mass spectrometry assays is needed to capture the isoform complexity that exists in theses biological samples. However, this study indicates that a peripheral protein signature has potential to aid in the characterization of AD.
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BACKGROUND: To enhance the accuracy of clinical diagnosis for Alzheimer's disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. OBJECTIVE: Assessing levels of Aß-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers to predict PET Aß-amyloid (32 Aß-amyloid-and 45 Aß-amyloid+), as well as concordance between CSF biomarker levels and PET Aß-amyloid imaging. METHODS: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. RESULTS: Across all three platforms, the T-tau/Aß42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ=â0.69-0.8) as compared with Aß42 alone (ρ=â0.66-0.75). Differences in CSF biomarker levels between the PET Aß-amyloid-and Aß-amyloid+ groups were strongest for the Aß42/Aß40 and T-tau/Aß42 ratios (pâ<â0.0001); however, comparison of predictive models for PET Aß-amyloid showed no difference between Aß42 alone and the T-tau/Aß42 ratio. CONCLUSION: This study confirms strong concordance between CSF biomarkers and PET Aß-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Biomarcadores/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/patologia , Feminino , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Fragmentos de Peptídeos/líquido cefalorraquidiano , Tomografia por Emissão de Pósitrons , Curva ROC , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Cerebrospinal fluid (CSF) biomarkers, although of established utility in the diagnostic evaluation of Alzheimer's disease (AD), are known to be sensitive to variation based on pre-analytical sample processing. We assessed whether gravity droplet collection versus syringe aspiration was another factor influencing CSF biomarker analyte concentrations and reproducibility. METHODS: Standardized lumbar puncture using small calibre atraumatic spinal needles and CSF collection using gravity fed collection followed by syringe aspirated extraction was performed in a sample of elderly individuals participating in a large long-term observational research trial. Analyte assay concentrations were compared. RESULTS: For the 44 total paired samples of gravity collection and aspiration, reproducibility was high for biomarker CSF analyte assay concentrations (concordance correlation [95%CI]: beta-amyloid1-42 (Aß42) 0.83 [0.71 - 0.90]), t-tau 0.99 [0.98 - 0.99], and phosphorylated tau (p-tau) 0.82 [95 % CI 0.71 - 0.89]) and Bonferroni corrected paired sample t-tests showed no significant differences (group means (SD): Aß42 366.5 (86.8) vs 354.3 (82.6), p = 0.10; t-tau 83.9 (46.6) vs 84.7 (47.4) p = 0.49; p-tau 43.5 (22.8) vs 40.0 (17.7), p = 0.05). The mean duration of collection was 10.9 minutes for gravity collection and <1 minute for aspiration. CONCLUSIONS: Our results demonstrate that aspiration of CSF is comparable to gravity droplet collection for AD biomarker analyses but could considerably accelerate throughput and improve the procedural tolerability for assessment of CSF biomarkers.
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Doença de Alzheimer/líquido cefalorraquidiano , Disfunção Cognitiva/líquido cefalorraquidiano , Paracentese/métodos , Punção Espinal/métodos , Idoso , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Apolipoproteína E4/genética , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/genética , Estudos de Coortes , Feminino , Gravitação , Humanos , Masculino , Entrevista Psiquiátrica Padronizada , Paracentese/instrumentação , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fosforilação , Psicometria , Reprodutibilidade dos Testes , Punção Espinal/instrumentação , Fatores de Tempo , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: The cerebrospinal fluid (CSF) amyloid-ß (Aß)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE: The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aß imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aß amyloid ligands. METHODS: Aß pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹8F-flutemetamol, or ¹8F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aß(1-42) >544âng/L, T-tau <407âng/L, and P-tau181P <78âng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (nâ=â97), and compared with the presence of PET demonstrated AD pathology. RESULTS: CSF Aß(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aß(1-42) provided greater accuracy, predicting MCI/AD with Aß pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aß(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS: CSF Aß(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aß imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
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Doença de Alzheimer , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Estilo de Vida , Fragmentos de Peptídeos/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Compostos de Anilina/metabolismo , Austrália , Benzotiazóis/metabolismo , Etilenoglicóis/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Entrevista Psiquiátrica Padronizada , Tomografia por Emissão de Pósitrons , Curva ROC , Tiazóis/metabolismo , Proteínas tau/líquido cefalorraquidianoRESUMO
Biomarkers enabling the preclinical identification of Alzheimer's disease (AD) remain one of the major unmet challenges in the field. The blood cellular fractions offer a viable alternative to current cerebrospinal fluid and neuroimaging modalities. The current study aimed to replicate our earlier reports of altered binding within the AD-affected blood cellular fraction to copper-loaded immobilized metal affinity capture (IMAC) arrays. IMAC and anti-amyloid-ß (Aß) antibody arrays coupled with mass spectrometry were used to analyze blood samples collected from 218 participants from within the AIBL Study of Aging. Peripheral Aß was fragile and prone to degradation in the AIBL samples, even when stored at -80°C. IMAC analysis of the AIBL samples lead to the isolation and identification of alpha-defensins 1 and 2 at elevated levels in the AD periphery, validating earlier findings. Alpha-defensins 1 and 2 were elevated in AD patients indicating that an inflammatory phenotype is present in the AD periphery; however, peripheral Aß levels are required to supplement their prognostic power.
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Doença de Alzheimer/sangue , alfa-Defensinas/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Testes Neuropsicológicos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Estatísticas não ParamétricasRESUMO
BACKGROUND: A practical biomarker is required to facilitate the preclinical diagnosis of Alzheimer's disease (AD). METHODS: Plasma amyloid beta (Aß)1-40, Aß1-42, Aßn-40, and Aßn-42 peptides were measured at baseline and after 18 months in 771 participants from the Australian Imaging Biomarkers and Lifestyle (AIBL) study of aging. Aß peptide levels were compared with clinical pathology, neuroimaging and neuropsychological measurements. RESULTS: Although inflammatory and renal function covariates influenced plasma Aß levels significantly, a decrease in Aß1-42/Aß1-40 was observed in patients with AD, and was also inversely correlated with neocortical amyloid burden. During the 18 months, plasma Aß1-42 decreased in subjects with mild cognitive impairment (MCI) and in those transitioning from healthy to MCI. CONCLUSION: Our findings are consistent with a number of published plasma Aß studies and, although the prognostic value of individual measures in any given subject is limited, the diagnostic contribution of plasma Aß may demonstrate utility when combined with a panel of peripheral biomarkers.
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Envelhecimento/sangue , Doença de Alzheimer/sangue , Peptídeos beta-Amiloides/sangue , Fragmentos de Peptídeos/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Apolipoproteína E4/genética , Distribuição de Qui-Quadrado , Disfunção Cognitiva/sangue , Disfunção Cognitiva/diagnóstico por imagem , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Several studies have reported that peripheral levels of copper and ceruloplasmin (CP) can differentiate patients with Alzheimer's disease (AD) from non-AD cases. The aim of this study was to determine the diagnostic value of serum copper, CP, and non-CP copper levels in a large cohort of AD subjects. METHODS: Serum copper and CP concentrations were measured at baseline and at 18-months in participants from the Australian Imaging Biomarkers and Lifestyle Study of Ageing. Cross-sectional and longitudinal analyses were conducted using both univariate and multivariate testing adjusting for age, gender, total protein, and ApoE ε4 genotype status. RESULTS: There was no significant difference in levels of serum copper or CP between the AD and healthy control groups, however, we identified a near-significant decrease in non-CP copper in the mild cognitive impairment and AD groups at baseline (p = 0.02) that was significant at 18-months (p = 0.003). CONCLUSION: Our results suggest that there may be decreased non-CP copper levels in mild cognitive impairment and AD, which is consistent with diminished copper-dependent biochemical activities described in AD.
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Doença de Alzheimer/sangue , Ceruloplasmina/metabolismo , Cobre/sangue , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Transtornos Cognitivos/sangue , Transtornos Cognitivos/diagnóstico por imagem , Feminino , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , TiazóisRESUMO
There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate.
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Envelhecimento/sangue , Doença de Alzheimer/sangue , Disfunção Cognitiva/sangue , Ácido Fólico/sangue , Homocisteína/sangue , Vitamina B 12/sangue , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Doença de Alzheimer/patologia , Análise de Variância , Austrália , Encéfalo/patologia , Disfunção Cognitiva/patologia , Estudos de Coortes , Feminino , Ácido Fólico/administração & dosagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação PsiquiátricaRESUMO
OBJECTIVE: Refractive errors such as myopia and hypermetropia are among the leading causes of visual impairment worldwide. Several genetic loci have been associated with myopia but none to date have been reported for hypermetropia. We investigated the hepatocyte growth factor (HGF) as a candidate gene influencing these 2 refractive error states. DESIGN: Case-control study. PARTICIPANTS: A total of 551 individuals (193 males, 358 females; mean age, 55.41+/-12.65 years) including 117 individuals with high myopia
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Fator de Crescimento de Hepatócito/genética , Hiperopia/genética , Miopia/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Primers do DNA/química , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da PolimeraseRESUMO
PURPOSE: Transforming growth beta-induced factor (TGIF) has been identified as a candidate gene for high myopia through genetic linkage studies and through its role in ocular growth in animal studies. However, the association of single nucleotide polymorphisms (SNPs), based solely on myopia refraction, has so far been inconclusive. This is the first study conducted to investigate the association of TGIF with refraction and ocular biometric measurements. METHODS: Twelve tag SNPs (tSNPs) encompassing the TGIF gene and 2 kb upstream of its promoter region were used to evaluate the association between TGIF variants with both ocular biometric measures and refraction. A total of 257 cases of myopia (spherical equivalent [SE] worse than -0.50 D) and 294 control subjects (no myopia) were genotyped. Genotype frequencies were analyzed by chi(2) test and one-way ANOVA. RESULTS: Two tSNPs showed significant association with biometric measures, with the SNP rs8082866 being associated with both axial length (P = 0.013) and corneal curvature (P = 0.007) and the SNP rs2020436 being associated with corneal curvature (P = 0.022). However, these associations became nonsignificant after multiple testing (Bonferroni correction). CONCLUSIONS: Findings of this study suggest that the TGIF gene is unlikely to play a major role in either ocular biometric measures or refraction in a Caucasian population. Future studies should focus on other genes in the MYP2 linkage region or other linked regions to identify myopia-causing genes.
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Proteínas de Homeodomínio/genética , Miopia/genética , Polimorfismo de Nucleotídeo Único/genética , Proteínas Repressoras/genética , Biometria , Estudos de Casos e Controles , Córnea/patologia , Olho/patologia , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Miopia/classificação , Miopia/patologia , Refração OcularRESUMO
PURPOSE: Myopia (short sightedness) is a complex trait influenced by as yet unidentified genetic factors. To date, there have been four myopia susceptibility loci (MYP7 to -10) identified in twin studies, but these are yet to be independently verified. In an independent yet ethnically and phenotypically similar twin cohort, linkage to these chromosomal regions was sought. METHODS: Participants were 223 dizygotic twin pairs from the Australian Twin Registry who were assessed for evidence of linkage, by using polymorphic microsatellite markers spanning MYP7-10. Data were analyzed by using Haseman-Elston regression analysis. RESULTS: No evidence of linkage of myopia or its underlying biological components such as eye length to the MYP7-10 regions was found in this twin cohort. CONCLUSIONS: This is the first study to assess for linkage in a secondary myopia twin cohort and highlights the problems associated with applying linkage results from complex traits to the other populations.
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Doenças em Gêmeos/genética , Ligação Genética/genética , Predisposição Genética para Doença , Miopia/genética , Gêmeos Dizigóticos/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Austrália , Mapeamento Cromossômico , Feminino , Genótipo , Humanos , Masculino , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Sistema de RegistrosRESUMO
PURPOSE: Myopia is a common disorder with a large public health impact. Although 12 myopia loci have been reported and heterogeneity for high myopia loci have been demonstrated, replication of high-myopia loci with a common myopia phenotype has not been successful. This study reports the successful replication of MYP12 in three large, multigenerational families with autosomal dominant (AD) common myopia (spherical equivalent [SphE] = -0.50 D). METHODS: These families contained 49 participants (35 affected). The average spherical equivalent was -2.76 D (range, -0.50 to -10.25 D), average axial length was 24.52 mm (range, 23.05-27.11 mm), and average keratometry was 43.21 D (range, 39.12-47.31 D). Only five individuals in the three families presented with myopia of SphE = -6.00 D. Glaucoma, keratoconus, lenticonus, and dislocated lens were not present in any study participants. A genomewide scan was performed using a mapping set with 400 markers at approximately 10 cM coverage. Merlin software was used for multipoint linkage analysis based on an AD model with a penetrance of 0.9 and disease allele frequency of 0.013. RESULTS: Significant linkage with a multipoint parametric LOD score of 3.428 (P = 0.000035) and a multipoint nonparametric (Kong and Cox) LOD score of 2.37 (empiric P < 0.001) was obtained on 2q37.1, with a 1-LOD support interval that overlapped the previously reported MYP12 locus for high myopia. CONCLUSIONS: This study provided evidence that some high-myopia loci may contribute to all degrees of myopia and indicated the likely location of a myopia gene for the low/moderate as well as the high form of myopia.
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Mapeamento Cromossômico , Cromossomos Humanos Par 2/genética , Ligação Genética , Miopia/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Criança , Feminino , Frequência do Gene , Genótipo , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
PURPOSE: Proband-reported family histories are widely used in epidemiological and genetic studies. The accuracy of these reports may have significant effects on the intended outcome, particularly in genetic studies. This study aims to determine the accuracy of proband-reported family history of myopia and to assess whether demographic or clinical factors are predictive of an accurate history. METHODS: In 2004 to 2005, the study recruited 120 myopic probands (< or = -0.50 D spherical equivalent in both eyes) aged 18 to 72 years and 358 nuclear family members residing within Victoria, Australia as part of the Genes in Myopia (GEM) family study. Data collection used an examiner-administered questionnaire with an ocular examination. Proband-reported family history of myopia was evaluated for agreement with ophthalmic examination results of family members. RESULTS: The statistical measures of accuracy used in this report were sensitivity, specificity, positive predictive value, and negative predictive value. Sensitivity varied from 85 to 98%, specificity from 84 to 96%, positive predictive value from 83 to 97%, and negative predictive value from 84 to 97%. Following multivariate analysis, an evaluation of demographic and clinical factors indicated that the highest predictive accuracy was obtained from proband reporting of their children [odds ratio (OR), 0.38; 95% confidence interval (CI), 0.15 to 0.94] whereas the most inaccurate reporting of a proband was when there was less-severe maternal myopia (per 0.50 D less myopic) (OR, 1.23; 95% CI, 1.06 to 1.43) or for increase in total education of the proband (per 1 year increase) (OR, 1.22; 95% CI, 1.04 to 1.42). CONCLUSIONS: Several variables influence the accuracy of obtaining a family history of myopia. A questionnaire-based approach alone will introduce some error into the study and this should be taken into account when designing and undertaking family-based epidemiological or genetic studies of myopia.