Geographical variation in anophthalmia and microphthalmia in England, 1988-94   Commentary: Clustering of anophthalmia and microphthalmia is not supported by the data

Dolk, Helen; Busby, Araceli; Armstrong, Ben; Walls, P

doi:10.1136/bmj.317.7163.905

Cited by 89 publications

(9 citation statements)

References 19 publications

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“…This study simulated conditions that could reasonably occur in public health settings, which usually have a few thousand observations [ 15 – 17 ]. Additionally, with the move towards “big data” by government organizations [ 18 ] and industry, both the number of observations and the size of the areas being routinely studied could increase substantially.…”

Section: Resultsmentioning

confidence: 99%

Testing for clustering at many ranges inflates family-wise error rate (FWE)

Loop

McClure

2015

International Journal of Health Geographics

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BackgroundTesting for clustering at multiple ranges within a single dataset is a common practice in spatial epidemiology. It is not documented whether this approach has an impact on the type 1 error rate.MethodsWe estimated the family-wise error rate (FWE) for the difference in Ripley’s K functions test, when testing at an increasing number of ranges at an alpha-level of 0.05. Case and control locations were generated from a Cox process on a square area the size of the continental US (≈3,000,000 mi2). Two thousand Monte Carlo replicates were used to estimate the FWE with 95% confidence intervals when testing for clustering at one range, as well as 10, 50, and 100 equidistant ranges.ResultsThe estimated FWE and 95% confidence intervals when testing 10, 50, and 100 ranges were 0.22 (0.20 - 0.24), 0.34 (0.31 - 0.36), and 0.36 (0.34 - 0.38), respectively.ConclusionsTesting for clustering at multiple ranges within a single dataset inflated the FWE above the nominal level of 0.05. Investigators should construct simultaneous critical envelopes (available in spatstat package in R), or use a test statistic that integrates the test statistics from each range, as suggested by the creators of the difference in Ripley’s K functions test.

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Section: Resultsmentioning

confidence: 99%

Testing for clustering at many ranges inflates family-wise error rate (FWE)

Loop

McClure

2015

International Journal of Health Geographics

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“…Dolk et al [ 6 ] reported that prevalence of anophthalmia is extremely low, i.e. around 3/100,000 births.…”

Section: Discussionmentioning

confidence: 99%

“…Anophthalmia has also been related to environmental factors like maternal vitamin A deficiency, solvent use or exposure to X-rays, or to drugs like thalidomide, warfarin or alcohol [ 6 ]. We do not think any of these was the cause of anophthalmia, since the mother was not exposed to the referred risks and did not present clinical findings related to vitamin A deficiency along pregnancy, like blurred vision, nocturnal blindness or corneal ulcers [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Report of an unsual case of anophthalmia and craniofacial cleft in a newborn with Toxoplasma gondii congenital infection

et al. 2017

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BackgroundWe present one unusual case of anophthalmia and craniofacial cleft, probably due to congenital toxoplasmosis only.Case presentationA two-month-old male had a twin in utero who disappeared between the 7th and the 14th week of gestation. At birth, the baby presented anophthalmia and craniofacial cleft, and no sign compatible with genetic or exposition/deficiency problems, like the Wolf-Hirschhorn syndrome or maternal vitamin A deficiency. Congenital toxoplasmosis was confirmed by the presence of IgM abs and IgG neo-antibodies in western blot, as well as by real time PCR in blood. CMV infection was also discarded by PCR and IgM negative results. Structures suggestive of T. gondii pseudocysts were observed in a biopsy taken during the first functional/esthetic surgery.ConclusionsWe conclude that this is a rare case of anophthalmia combined with craniofacial cleft due to congenital toxoplasmosis, that must be considered by physicians. This has not been reported before.

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“…Nonconservative missense mutations in SUFU (orthologous to the gene mutated in the zebrafish dre mutants) have been observed in independently isolated medulloblastomas [73] and are therefore associated with cancer. Geographical clusters of children with eye malformations, born to unaffected parents, and the increased incidence of some cancers in certain areas suggest that environmental factors may be implicated in these diseases [74,75]. Might such factors play their role by affecting the penetrance of underlying mutations or deleterious polymorphisms in susceptible individuals through diversion of Hsp90 function?…”

Section: Discussionmentioning

confidence: 99%

Hsp90 Selectively Modulates Phenotype in Vertebrate Development

et al. 2007

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Compromised heat shock protein 90 (Hsp90) function reveals cryptic phenotypes in flies and plants. These observations were interpreted to suggest that this molecular stress-response chaperone has a capacity to buffer underlying genetic variation. Conversely, the protective role of Hsp90 could account for the variable penetrance or severity of some heritable developmental malformations in vertebrates. Using zebrafish as a model, we defined Hsp90 inhibitor levels that did not induce a heat shock response or perturb phenotype in wild-type strains. Under these conditions the severity of the recessive eye phenotype in sunrise, caused by a pax6b mutation, was increased, while in dreumes, caused by a sufu mutation, it was decreased. In another strain, a previously unobserved spectrum of severe structural eye malformations, reminiscent of anophthalmia, microphthalmia, and nanophthalmia complex in humans, was uncovered by this limited inhibition of Hsp90 function. Inbreeding of offspring from selected unaffected carrier parents led to significantly elevated malformation frequencies and revealed the oligogenic nature of this phenotype. Unlike in Drosophila, Hsp90 inhibition can decrease developmental stability in zebrafish, as indicated by increased asymmetric presentation of anophthalmia, microphthalmia, and nanophthalmia and sunrise phenotypes. Analysis of the sunrise pax6b mutation suggests a molecular mechanism for the buffering of mutations by Hsp90. The zebrafish studies imply that mild perturbation of Hsp90 function at critical developmental stages may underpin the variable penetrance and expressivity of many developmental anomalies where the interaction between genotype and environment plays a major role.

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Geographical variation in anophthalmia and microphthalmia in England, 1988-94 Commentary: Clustering of anophthalmia and microphthalmia is not supported by the data

Cited by 89 publications

References 19 publications

Testing for clustering at many ranges inflates family-wise error rate (FWE)

Testing for clustering at many ranges inflates family-wise error rate (FWE)

Report of an unsual case of anophthalmia and craniofacial cleft in a newborn with Toxoplasma gondii congenital infection

Hsp90 Selectively Modulates Phenotype in Vertebrate Development

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