Early reviews identified over 20 risk factors associated with Alzheimer's disease (AD) including age, familial inheritance, exposure to aluminium, traumatic brain injury (TBI), and associated ...co-morbidities such as vascular disease and infection. In the light of recent evidence, this review reconsiders these risk factors, identifies those currently regarded as important, and discusses various hypotheses to explain how they may cause AD. Rare forms of early-onset familial AD (EO-FAD) are strongly linked to causal gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (LO-SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) and many other genes, vascular disease, TBI and risk factors associated with diet, the immune system, mitochondrial function, metal exposure, and infection are all implicated. These risk factors may act collectively to cause AD pathology: 1) by promoting the liberation of oxygen free radicals with age, 2) via environmental stress acting on regulatory genes early and later in life ('dual hit' hypothesis), or 3) by increasing the cumulative 'allostatic load' on the body over a lifetime. As a consequence, life-style changes which reduce the impact of these factors may be necessary to lower the risk of AD.
Purpose
The Bonferroni correction adjusts probability (p) values because of the increased risk of a type I error when making multiple statistical tests. The routine use of this test has been ...criticised as deleterious to sound statistical judgment, testing the wrong hypothesis, and reducing the chance of a type I error but at the expense of a type II error; yet it remains popular in ophthalmic research. The purpose of this article was to survey the use of the Bonferroni correction in research articles published in three optometric journals, viz. Ophthalmic & Physiological Optics, Optometry & Vision Science, and Clinical & Experimental Optometry, and to provide advice to authors contemplating multiple testing.
Recent findings
Some authors ignored the problem of multiple testing while others used the method uncritically with no rationale or discussion. A variety of methods of correcting p values were employed, the Bonferroni method being the single most popular. Bonferroni was used in a variety of circumstances, most commonly to correct the experiment‐wise error rate when using multiple ‘t’ tests or as a post‐hoc procedure to correct the family‐wise error rate following analysis of variance (anova). Some studies quoted adjusted p values incorrectly or gave an erroneous rationale.
Summary
Whether or not to use the Bonferroni correction depends on the circumstances of the study. It should not be used routinely and should be considered if: (1) a single test of the ‘universal null hypothesis’ (Ho) that all tests are not significant is required, (2) it is imperative to avoid a type I error, and (3) a large number of tests are carried out without preplanned hypotheses.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
A hypothesis is proposed to explain the pathogenesis of neurodegenerative disease and the diversity of its phenotypes. The hypothesis is based on seven main propositions: 1) neurodegenerative disease ...is associated with multiple risk factors, 2) age is the most important of the risk factors, 3) aging differentially affects neuroanatomical pathways, 4) degeneration of these pathways results in the formation of pathogenic proteins, 5) pathogenic proteins spread along anatomical pathways, 6) the phenotypes of familial and sporadic forms of disease are similar and 7) neurodegenerative disease is characterised by heterogeneity, overlapping phenotypes, and multiple pathology. It is hypothesised that most cases of neurodegenerative disease are multifactorial in which interactions between external environmental and internal genetic risk factors act cumulatively over a lifetime to determine the 'allostatic load' of an individual. The allostatic load determines the rate of neural aging and results in the differential breakdown of neuro-anatomical pathways influenced by their relative use or disuse during life. The consequence is the formation of one or more pathogenic proteins, some of which may exhibit 'prion-like' behaviour and propagate through the brain from initial sites of formation along neuro-anatomical pathways to affect connected brain regions. Variations in the pathological proteins formed and their anatomical spread are ultimately responsible for the clinical and pathological diversity of disease phenotypes. Minimising the factors which contribute to the allostatic load over a lifetime and maximising cognitive and physical exercise may be necessary to reduce the incidence of neurodegenerative disease.
Purpose
Measurements obtained from the right and left eye of a subject are often correlated whereas many statistical tests assume observations in a sample are independent. Hence, data collected from ...both eyes cannot be combined without taking this correlation into account. Current practice is reviewed with reference to articles published in three optometry journals, viz., Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), Clinical and Experimental Optometry (CEO) during the period 2009–2012.
Recent findings
Of the 230 articles reviewed, 148/230 (64%) obtained data from one eye and 82/230 (36%) from both eyes. Of the 148 one‐eye articles, the right eye, left eye, a randomly selected eye, the better eye, the worse or diseased eye, or the dominant eye were all used as selection criteria. Of the 82 two‐eye articles, the analysis utilized data from: (1) one eye only rejecting data from the adjacent eye, (2) both eyes separately, (3) both eyes taking into account the correlation between eyes, or (4) both eyes using one eye as a treated or diseased eye, the other acting as a control. In a proportion of studies, data were combined from both eyes without correction.
Summary
It is suggested that: (1) investigators should consider whether it is advantageous to collect data from both eyes, (2) if one eye is studied and both are eligible, then it should be chosen at random, and (3) two‐eye data can be analysed incorporating eyes as a ‘within subjects’ factor.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Traumatic brain injury (TBI) and its associated concussion are major causes of disability and death. All ages can be affected but children, young adults and the elderly are particularly susceptible. ...A decline in mortality has resulted in many more individuals living with a disability caused by TBI including those affecting vision. This review describes: (1) the major clinical and pathological features of TBI; (2) the visual signs and symptoms associated with the disorder; and (3) discusses the assessment of quality of life and visual rehabilitation of the patient. Defects in primary vision such as visual acuity and visual fields, eye movement including vergence, saccadic and smooth pursuit movements, and in more complex aspects of vision involving visual perception, motion vision ('akinopsia'), and visuo-spatial function have all been reported in TBI. Eye movement dysfunction may be an early sign of TBI. Hence, TBI can result in a variety of visual problems, many patients exhibiting multiple visual defects in combination with a decline in overall health. Patients with chronic dysfunction following TBI may require occupational, vestibular, cognitive and other forms of physical therapy. Such patients may also benefit from visual rehabilitation, including reading-related oculomotor training and the prescribing of spectacles with a variety of tints and prism combinations.
Purpose
To survey the use of Pearson's correlation coefficient (r) and related statistical methods in the ophthalmic literature, to consider the limitations of r, and to suggest suitable alternative ...methods of analysis.
Recent findings
Searching Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), and Clinical and Experimental Optometry (CXO) online archives using correlation and Pearson's r as search terms resulted in 4057 and 281 hits respectively. Coefficient of determination, r square, or r squared received fewer hits (65, 8, and 22 hits respectively). The assumption that r follows a bivariate normal distribution was rarely encountered (3 hits) although several studies applied Spearman's rank correlation (70 hits). The intra‐class correlation coefficient (ICC) was widely used (178 hits), but fewer hits were recorded for partial correlation (43 hits) and multiple correlation (13) hits. There was little evidence that the problem of sample size was addressed in correlation studies.
Summary
Investigators should be alert to whether: (1) the relationship between two variables could be non‐linear, (2) the data are bivariate normal, (3) r accounts for a significant proportion of the variance in Y, (4) outliers are present, the data are clustered, or have a restricted range, (5) the sample size is appropriate, and (6) a significant correlation indicates causality. In addition, the number of significant digits used to express r and the problems of multiple testing should be addressed. The problems and limitations of r suggest a more cautious approach regarding its use and the application of alternative methods where appropriate.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Objective:
To describe a distinctive seizure semiology that closely associates with voltage‐gated potassium channel (VGKC)‐complex/Lgi1 antibodies and commonly precedes the onset of limbic ...encephalitis (LE).
Methods:
Twenty‐nine patients were identified by the authors (n = 15) or referring clinicians (n = 14). The temporal progression of clinical features and serum sodium, brain magnetic resonance imaging (MRI), positron emission tomography/single photon emission computed tomography, and VGKC‐complex antibodies was studied.
Results:
Videos and still images showed a distinctive adult‐onset, frequent, brief dystonic seizure semiology that predominantly affected the arm and ipsilateral face. We have termed these faciobrachial dystonic seizures (FBDS). All patients tested during their illness had antibodies to VGKC complexes; the specific antigenic target was Lgi1 in 89%. Whereas 3 patients never developed LE, 20 of the remaining 26 (77%) experienced FBDS prior to the development of the amnesia and confusion that characterize LE. During the prodrome of FBDS alone, patients had normal sodium and brain MRIs, but electroencephalography demonstrated ictal epileptiform activity in 7 patients (24%). Following development of LE, the patients often developed other seizure semiologies, including typical mesial temporal lobe seizures. At this stage, investigations commonly showed hyponatremia and MRI hippocampal high T2 signal; functional brain imaging showed evidence of basal ganglia involvement in 5/8. Antiepileptic drugs (AEDs) were generally ineffective and in 41% were associated with cutaneous reactions that were often severe. By contrast, immunotherapies produced a clear, and often dramatic, reduction in FBDS frequency.
Interpretation:
Recognition of FBDS should prompt testing for VGKC‐complex/Lgi1 antibodies. AEDs often produce adverse effects; treatment with immunotherapies may prevent the development of LE with its potential for cerebral atrophy and cognitive impairment. ANN NEUROL 2010;
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose
A common experimental design in ophthalmic research is the repeated‐measures design in which at least one variable is a within‐subject factor. This design is vulnerable to lack of ...‘sphericity’ which assumes that the variances of the differences among all possible pairs of within‐subject means are equal. Traditionally, this design has been analysed using a repeated‐measures analysis of variance (RM‐anova) but increasingly more complex methods such as multivariate anova (manova) and mixed model analysis (MMA) are being used. This article surveys current practice in the analysis of designs incorporating different factors in research articles published in three optometric journals, namely Ophthalmic and Physiological Optics (OPO), Optometry and Vision Science (OVS), and Clinical and Experimental Optometry (CXO), and provides advice to authors regarding the analysis of repeated‐measures designs.
Recent findings
Of the total sample of articles, 66% used a repeated‐measures design. Of those articles using a repeated‐measures design, 59% and 8% analysed the data using RM‐anova or manova respectively and 33% used MMA. The use of MMA relative to RM‐anova has increased significantly since 2009/10. A further search using terms to select those papers testing and correcting for sphericity (‘Mauchly's test’, ‘Greenhouse‐Geisser’, ‘Huynh and Feld’) identified 66 articles, 62% of which were published from 2012 to the present.
Summary
If the design is balanced without missing data then manova should be used rather than RM‐anova as it gives better protection against lack of sphericity. If the design is unbalanced or with missing data then MMA is the method of choice. However, MMA is a more complex analysis and can be difficult to set up and run, and care should be taken first, to define appropriate models to be tested and second, to ensure that sample sizes are adequate.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
The 'amyloid cascade hypothesis' (ACH) is the most influential model of the pathogenesis of Alzheimer's disease (AD). The hypothesis proposes that the deposition of β-amyloid (Aβ) is the initial ...pathological event in AD, leading to the formation of extracellular senile plaques (SP), tau-immunoreactive neurofibrillary tangles (NFT), neuronal loss, and ultimately, clinical dementia. Ever since the formulation of the ACH, however, there have been questions regarding whether it completely describes AD pathogenesis. This review critically examines various aspects of the ACH including its origin and development, the role of amyloid precursor protein (APP), whether SP and NFT are related to the development of clinical dementia, whether Aβ and tau are 'reactive' proteins, and whether there is a pathogenic relationship between SP and NFT. The results of transgenic experiments and treatments for AD designed on the basis of the ACH are also reviewed. It was concluded: (1) Aβ and tau could be the products rather than the cause of neurodegeneration in AD, (2) it is doubtful whether there is a direct causal link between Aβ and tau, and (3) SP and NFT may not be directly related to the development of dementia, (4) transgenic models involving APP alone do not completely replicate AD pathology, and (5) treatments based on the ACH have been unsuccessful. Hence, a modification of the ACH is proposed which may provide a more complete explanation of the pathogenesis of AD.
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