Applying data science methodologies with artificial intelligence variant reinterpretation to map and estimate genetic disorder prevalence utilizing clinical data.

Data science methodologies can be utilized to ascertain and analyze clinical genetic data that is often unstructured and rarely used outside of patient encounters. Genetic variants from all genetic testing resulting to a large pediatric healthcare system for a 5-year period were obtained and reinterpreted utilizing the previously validated Franklin© Artificial Intelligence (AI). Using PowerBI©, the data were further matched to patients in the electronic healthcare record to associate with demographic data to generate a variant data table and mapped by ZIP codes. Three thousand and sixty-five variants were identified and 98% were matched to patients with geographic data. Franklin© changed the interpretation for 24% of variants. One hundred and fifty-six clinically actionable variant reinterpretations were made. A total of 739 Mendelian genetic disorders were identified with disorder prevalence estimation. Mapping of variants demonstrated hot-spots for pathogenic genetic variation such as PEX6-associated Zellweger Spectrum Disorder. Seven patients were identified with Bardet-Biedl syndrome and seven patients with Rett syndrome amenable to newly FDA-approved therapeutics. Utilizing readily available software we developed a database and Exploratory Data Analysis (EDA) methodology enabling us to systematically reinterpret variants, estimate variant prevalence, identify conditions amenable to new treatments, and localize geographies enriched for pathogenic variants.

Next generation phenotyping with quantitative narration for DEGCAGS syndrome.

The diagnosis of rare Mendelian disorders usually relies upon the interpretation of prose and is complicated by a lack of objective, reproducible phenotypic data. To address this limitation, we developed a next generation phenotyping workflow to phenotypically characterize developmental delay with gastrointestinal, cardiovascular, genitourinary, and skeletal abnormalities (DEGCAGS). We identified 15 people affected with DEGCAGS, including one novel patient identified at our hospital and 14 patients previously reported in the literature. Human Phenotype Ontology (HPO) terms were extracted from the patient chart and literature review. The HPO terms were sorted by count according to HPO hierarchy of terms. Phenotypes that cosegregate were identified utilizing a co-occurrence matrix. A quantitative narrative illustrated by violin plots was created for our patient from phenotypic data per each day of hospital admission. A total of 252 unique HPO terms were extracted from the patient record and literature review. The highest count of systemically sorted and unsorted terms and the most commonly co-occurring terms were described. A violin plot of phenotype occurrences demonstrated a progression of phenotypes over time. NGP offers a quantitative approach to phenotyping to generate phenotypic data in an objective and reproducible manner akin to NGS.

MeCP2 isoform e1 mutant mice recapitulate motor and metabolic phenotypes of Rett syndrome.

Mutations in the X-linked gene MECP2 cause the majority of Rett syndrome (RTT) cases. Two differentially spliced isoforms of exons 1 and 2 (MeCP2-e1 and MeCP2-e2) contribute to the diverse functions of MeCP2, but only mutations in exon 1, not exon 2, are observed in RTT. We previously described an isoform-specific MeCP2-e1-deficient male mouse model of a human RTT mutation that lacks MeCP2-e1 while preserving expression of MeCP2-e2. However, RTT patients are heterozygous females that exhibit delayed and progressive symptom onset beginning in late infancy, including neurologic as well as metabolic, immune, respiratory and gastrointestinal phenotypes. Consequently, we conducted a longitudinal assessment of symptom development in MeCP2-e1 mutant females and males. A delayed and progressive onset of motor impairments was observed in both female and male MeCP2-e1 mutant mice, including hind limb clasping and motor deficits in gait and balance. Because these motor impairments were significantly impacted by age-dependent increases in body weight, we also investigated metabolic phenotypes at an early stage of disease progression. Both male and female MeCP2-e1 mutants exhibited significantly increased body fat compared to sex-matched wild-type littermates prior to weight differences. Mecp2e1-/y males exhibited significant metabolic phenotypes of hypoactivity, decreased energy expenditure, increased respiratory exchange ratio, but decreased food intake compared to wild-type. Untargeted analysis of lipid metabolites demonstrated a distinguishable profile in MeCP2-e1 female mutant liver characterized by increased triglycerides. Together, these results demonstrate that MeCP2-e1 mutation in mice of both sexes recapitulates early and progressive metabolic and motor phenotypes of human RTT.

Early motor phenotype detection in a female mouse model of Rett syndrome is improved by cross-fostering.

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the gene encoding methyl CpG binding protein 2 (MeCP2) that occur sporadically in 1:10,000 female births. RTT is characterized by a period of largely normal development followed by regression in language and motor skills at 6-18 months of age. Mecp2 mutant mice recapitulate many of the clinical features of RTT, but the majority of behavioral assessments have been conducted in male Mecp2 hemizygous null mice as offspring of heterozygous dams. Given that RTT patients are predominantly female, we conducted a systematic analysis of developmental milestones, sensory abilities, and motor deficits, following the longitudinal decline of function from early postnatal to adult ages in female Mecp2 heterozygotes of the conventional Bird line (Mecp2tm1.1bird-/+), as compared to their female wildtype littermate controls. Further, we assessed the impact of postnatal maternal environment on developmental milestones and behavioral phenotypes. Cross-fostering to CD1 dams accelerated several developmental milestones independent of genotype, and induced earlier onset of weight gain in adult female Mecp2tm1.1bird-/+ mice. Cross-fostering improved the sensitivity of a number of motor behaviors that resulted in observable deficits in Mecp2tm1.1bird-/+ mice at much earlier (6-7 weeks) ages than were previously reported (6-9 months). Our findings indicate that female Mecp2tm1.1bird-/+ mice recapitulate many of the motor aspects of RTT syndrome earlier than previously appreciated. In addition, rearing conditions may impact the phenotypic severity and improve the ability to detect genotype differences in female Mecp2 mutant mice.

Transcultural adaptation of the Johns Hopkins Fall Risk Assessment Tool.

OBJECTIVE: to perform the transcultural adaptation and content validity analysis of the Johns Hopkins Fall Risk Assessment Tool to assess both fall risk and fall-related injury risk for hospitalized elderly in Brazil. METHOD: the transcultural adaptation consisted of translating the scale to Portuguese (Brazil), back-translating it into its language of origin, establishing a consensus version, and having an expert committee verify its transcultural equivalence. Content assessment was conducted by a committee of judges, ending with the calculation of the items and scales' content validity index. Nurses tested the tool. RESULTS: the scale's translated version went through two evaluation rounds by the judges, based on which, the items with unsatisfactory performance were changed. The content validity index for the items was ≥80.0% and the global index 97.1%. The experimental application showed the scale is user-friendly. CONCLUSION: the scale presents valid content for the assessment of fall risk and risk of fall-related injuries and is easy to use, with the potential to contribute to the proper identification of risks and the establishment of care actions.

Transcultural adaptation of the Johns Hopkins Fall Risk Assessment Tool / Adaptação transcultural da Johns Hopkins Fall Risk Assessment Tool para avaliação do risco de quedas / Adaptación transcultural de la Johns Hopkins Fall Risk Assessment Tool para evaluación del riesgo de caídas

ABSTRACT Objective: to perform the transcultural adaptation and content validity analysis of the Johns Hopkins Fall Risk Assessment Tool to assess both fall risk and fall-related injury risk for hospitalized elderly in Brazil. Method: the transcultural adaptation consisted of translating the scale to Portuguese (Brazil), back-translating it into its language of origin, establishing a consensus version, and having an expert committee verify its transcultural equivalence. Content assessment was conducted by a committee of judges, ending with the calculation of the items and scales' content validity index. Nurses tested the tool. Results: the scale's translated version went through two evaluation rounds by the judges, based on which, the items with unsatisfactory performance were changed. The content validity index for the items was ≥80.0% and the global index 97.1%. The experimental application showed the scale is user-friendly. Conclusion: the scale presents valid content for the assessment of fall risk and risk of fall-related injuries and is easy to use, with the potential to contribute to the proper identification of risks and the establishment of care actions.

RESUMO Objetivo: realizar a adaptação transcultural para uso no Brasil e a avaliação da validade de conteúdo da Johns Hopkins Fall Risk Assessment Tool para avaliação de risco de quedas e de danos por quedas em pacientes adultos hospitalizados. Método: adaptação transcultural consistiu na tradução da escala para a língua portuguesa (Brasil), retrotradução para a língua de origem, versão de consenso e análise da equivalência transcultural por um comitê de especialistas. A avaliação do conteúdo foi realizada por meio de um comitê de juízes, finalizando com o cálculo do índice de validade de conteúdo dos itens e da escala. Foi realizada a aplicação experimental do instrumento por enfermeiros. Resultados: a versão traduzida da escala passou por duas rodadas de avaliação pelos juízes, a partir das quais os itens com desempenho insatisfatório foram modificados. O índice de validade de conteúdo para itens foi ≥80,0% e o global foi 97,1%. A aplicação experimental mostrou que a escala é de fácil operacionalização. Conclusão: a escala demonstrou conteúdo válido para a avaliação de risco de quedas e de danos por quedas e ser de fácil operacionalização, podendo contribuir para a adequada identificação dos riscos e consequente direcionamento de ações assistenciais.

RESUMEN Objetivo: realizar la adaptación transcultural para ser usada en Brasil y confirmar la validez de contenido de la Johns Hopkins Fall Risk Assessment Tool que evalúa riesgo de caídas y de daños por caídas en pacientes adultos mayores. Método: adaptación transcultural que consistió en la traducción de la escala para el idioma portugués (Brasil); retrotraducción para el idioma de origen; y versión de consenso y análisis de la equivalencia transcultural por un comité de especialistas. La evaluación del contenido fue realizada por medio de un comité de jueces, siendo finalizado con el cálculo del índice de validez de contenido de los ítems y de la escala. Fue realizada la aplicación experimental del instrumento por enfermeros. Resultados: la versión traducida de la escala pasó por dos vueltas de evaluación por los jueces, a partir de las cuales los ítems con desempeño insatisfactorio fueron modificados. El índice de validez de contenido para los ítems fue ≥80,0% y el global fue 97,1%. La aplicación experimental mostró que la escala es de fácil ejecución. Conclusión: la escala demostró tener un contenido válido para la evaluación de riesgo de caídas y de daños por caídas, y de ser de fácil ejecución; esta escala puede contribuir para la adecuada identificación de los riesgos y consecuentemente para la orientación de acciones asistenciales.

[Validation of ultrasound diagnosis of fetal anomalies at a reference center in Pernambuco]. / Validação do diagnóstico ultrassonográfico de anomalias fetais em centro de referência.

OBJECTIVE: To validate ultrasound diagnoses of fetal anomalies made in a Fetal Medicine Center in Pernambuco. METHODS: A cross sectional study was performed to validate the diagnosis test, including all high risk pregnant women submitted to obstetrical morphological ultrasound at the 'Instituto de Medicina Integral Professor Fernando Figueira (I.M.I.P.)', from March 2002 to March 2006. Prenatal diagnosis was confirmed after birth. Socio demographic characteristics and pre and postnatal frequencies of fetal anomalies were the variables studied. Agreement between pre and postnatal diagnoses from congenital anomalies were evaluated with the Kappa indicator. Youden's test was applied to validate prenatal ultrasound diagnoses. RESULTS: Nine hundred and eighty nine patients were eligible. After evaluation of inclusion and exclusion criteria 457 patients were included in study. The average maternal age was 24.8 + 6.5 years. Fetal anomaly diagnoses postnatal were confirmed in 257 (56.2%) pregnant women. Prenatal ultrasound diagnosis of fetal anomalies disclosed 96% of sensibility and 79% of specificity, good agreement (K=0.76) between pre and postnatal diagnoses when compared to postnatal results and good diagnostic validity (Y=0.75). CONCLUSION: Prenatal diagnoses of fetal anomalies at a Fetal Medicine center in Pernambuco demonstrate good sensibility, specificity, agreement pre and postnatal and good diagnostic validity.

[Amniotic fluid volume associated with fetal anomalies diagnosed in a reference center in the Brazilian Northeast]. / Volume do líquido amniótico associado às anomalias fetais diagnosticadas em um centro de referência do nordeste brasileiro.

PURPOSE: to determine factors associated to amniotic fluid volume and frequencies of fetal anomalies, in a reference center in Pernambuco. METHODS: a transversal study performed in high-risk pregnant women submitted to obstetrical morphological ultrasound, from March 2002 to March 2006, at an institution from Recife, Pernambuco, Brasil. The intrauterine diagnosis was confirmed after birth. Sociodemographic and obstetrical characteristics, amniotic liquid volume and presence of fetal anomalies were the variables studied. Fisher's exact, chi2, and Student's t tests, at a significance level of 5% were applied to verify the correlation among the variables. Prevalence rate and confidence interval at 95% were calculated. Multiple logistic regression analysis was performed at a significance level of 5%. RESULTS: Two hundred and fifty-seven pregnant women (56.2%) with congenital anomalies and 200 (43.8%) without anomalies, confirmed in the postnatal, were included in the study. The average of maternal ages and gestation periods were 24.8+/-6.5 years and 35.9+/-3.7 weeks, respectively. The fetal anomalies were discovered in the central nervous system (50.6%) and genitourinary tract (23.0%). The presence of congenital anomalies were significantly linked with reduced liquid/oligohydramnios (p=0.0002) and increased liquid/polyhydramnios (p<0.0001). Intrauterine mortality was more frequent in the group with anomalies, as compared to the healthy fetuses (10.5 versus 2.5%; p<0.01). CONCLUSIONS: The rate of congenital anomalies in the high-risk pregnant women group was 56.2%. Most of the central nervous system malformations were diagnosed intrauterus. Changes in the amniotic fluid were the factors more strongly associated with congenital anomalies.

Importância da ultrassonografia de rotina na prática obstétrica segundo as evidências científicas / Importance of routine ultrasonography in obstetrics according to scientific evidence

O diagnóstico ultrassonográfico é empregado desde 1960 e não há relatos de efeitos deletérios maternos ou fetais produzidos com os níveis de energia usados clinicamente. A ultrassonografia favorece a exploração do embrião e, posteriormente, do feto com o seu ambiente, acompanhando seu desenvolvimento físico e funcional com grande riqueza de detalhes, considerando-se o concepto um verdadeiro paciente. As doenças da gestação e do feto podem ser diagnosticadas precocemente e, em consequência, podem-se acompanhar suas influências sobre o desenvolvimento morfológico fetal. Outro aspecto importante do exame ultrassonográfico refere-se ao estudo da placenta, do cordão umbilical e do líquido amniótico. A estimativa do peso pela ultrassonografia é importante para avaliar a evolução do crescimento no decorrer da gestação, assim como para reduzir a morbimortalidade associada aos desvios do crescimento intraútero por meio do seguimento e da adoção de protocolos específicos para vigilância da vitalidade fetal.

Obstetric evaluation through ultrasound has been used since 1960 and there are no reports of deleterious effects on the mother or the fetus with the usual level of energy used in clinical practice. Ultrasonography allows the exploration of the embryo and, further on, of the fetus and its environment, observing its physical and physiological development with many details. In this occasion, the fetus is considered to be a real patient. The diseases of gestation and of the fetus may be early detected and, in consequence, it is possible to follow its influence on the fetal morphological development. Another important aspect of the ultrasonography exam is with regard to the study of the placenta, the umbilical cord and the amniotic fluid. The fetal weight estimative through ultrasonography is important to evaluate the fetus development of growth throughout the pregnancy and to reduce perinatal mortality associated with deviations of normal intrauterine growth, for it allows a more precise following and adoption of specific protocols for the follow-up of the fetus vitality.

Volume do líquido amniótico associado às anomalias fetais diagnosticadas em um centro de referência do nordeste brasileiro / Amniotic fluid volume associated with fetal anomalies diagnosed in a reference center in the Brazilian Northeast

OBJETIVO: determinar fatores associados ao volume de líquido amniótico e frequências de anomalias fetais em um centro de referência. MÉTODOS: realizou-se um estudo de corte transversal, com gestantes de risco, avaliadas pela ultrassonografia morfológica, no período de março de 2002 a março de 2006, em uma instituição em Recife (PE) Brasil. O diagnóstico intraútero foi confirmado no pós-parto. As características sociodemográficas e obstétricas, o índice de líquido amniótico e a presença de anomalias fetais foram variáveis estudadas. Para verificar associação entre variáveis, foram utilizados testes χ2, exato de Fisher e t de Student, a um nível de significância de 5%. Foram calculados a razão de prevalência e o intervalo de confiança a 95%. Análise de regressão logística múltipla foi realizada, a um nível de significância de 5%. RESULTADOS: foram incluídas no estudo 257 (56,2%) gestantes com anomalias congênitas e 200 sem anomalias confirmadas no pós-natal. As médias das idades maternas e gestacionais do parto foram 24,8±6,5 anos e 35,9±3,7 semanas, respectivamente. As anomalias fetais foram mais encontradas no sistema nervoso central (50,6%) e trato geniturinário (23,0%). A presença de anomalias congênitas esteve associada significativamente ao líquido diminuído/oligohidrâmnio (p=0,0002) e líquido aumentado/polihidrâmnio (p<0,0001). A mortalidade intraútero foi mais frequente no grupo com anomalias, quando comparada aos fetos saudáveis (10,5 versus 2,5%; p<0,01). CONCLUSÕES: a frequência de anomalias congênitas em um grupo de gestações de alto risco foi de 56,2%. As malformações do sistema nervoso central foram mais frequentemente diagnosticadas intraútero. Os fatores que permaneceram fortemente associados às anomalias congênitas foram as alterações do volume do líquido amniótico.

PURPOSE: to determine factors associated to amniotic fluid volume and frequencies of fetal anomalies, in a reference center in Pernambuco. METHODS: a transversal study performed in high-risk pregnant women submitted to obstetrical morphological ultrasound, from March 2002 to March 2006, at an institution from Recife, Pernambuco, Brasil. The intrauterine diagnosis was confirmed after birth. Sociodemographic and obstetrical characteristics, amniotic liquid volume and presence of fetal anomalies were the variables studied. Fisher’s exact, χ2, and Student’s t tests, at a significance level of 5% were applied to verify the correlation among the variables. Prevalence rate and confidence interval at 95% were calculated. Multiple logistic regression analysis was performed at a significance level of 5%. RESULTS: Two hundred and fifty-seven pregnant women (56.2%) with congenital anomalies and 200 (43.8%) without anomalies, confirmed in the postnatal, were included in the study. The average of maternal ages and gestation periods were 24.8±6.5 years and 35.9±3.7 weeks, respectively. The fetal anomalies were discovered in the central nervous system (50.6%) and genitourinary tract (23.0%). The presence of congenital anomalies were significantly linked with reduced liquid/oligohydramnios (p=0.0002) and increased liquid/polyhydramnios (p<0.0001). Intrauterine mortality was more frequent in the group with anomalies, as compared to the healthy fetuses (10.5 versus 2.5%; p<0.01). CONCLUSIONS: The rate of congenital anomalies in the high-risk pregnant women group was 56.2%. Most of the central nervous system malformations were diagnosed intrauterus. Changes in the amniotic fluid were the factors more strongly associated with congenital anomalies.

Validação do diagnóstico ultrassonográfico de anomalias fetais em centro de referência / Validation of ultrasound diagnosis of fetal anomalies at a reference center in Pernambuco

OBJETIVO: Validar o diagnóstico ultrassonográfico de anomalias fetais em um centro de referência em Medicina Fetal de Pernambuco. MÉTODOS: Realizou-se um corte transversal para validação de teste diagnóstico com gestantes de risco que realizaram ultrassonografia morfológica no Instituto de Medicina Integral Professor Fernando Figueira (IMIP), de março de 2002 a março de 2006. O diagnóstico intraútero foi validado após o parto. Características sócio-demográficas e as frequências pré e pós-natais das anomalias congênitas foram as variáveis estudadas. A concordância entre os diagnósticos das anomalias congênitas e os achados pós-natais foi avaliada pelo indicador Kappa (K). O teste de Youden (Y) foi aplicado para validar o diagnóstico ultrassonográfico pré-natal. RESULTADOS: Identificaram-se 989 pacientes candidatas a inclusão no estudo, sendo que 457 gestantes foram incluídas no estudo. A média da idade materna foi de 24,8 +/- 6,51 anos. A ultrassonografia pré-natal demonstrou o diagnóstico de anomalias congênitas em 289 (63,2 por cento) pacientes, as quais foram confirmadas após o parto em 257 (56,2 por cento). Encontrou-se uma sensibilidade de 96 por cento, especificidade de 79 por cento, boa concordância (K=0,76) para os diagnósticos das anomalias congênitas pré-natais quando comparados aos resultados pós-natais e boa validade diagnóstica (Y=0,75). CONCLUSÃO: O diagnóstico pré-natal de anomalias fetais pela ultrassonografia morfológica em um centro de referência em medicina fetal de Pernambuco apresenta boa sensibilidade, especificidade, concordância pré e pós-natal e validade diagnóstica.

OBJECTIVE: To validate ultrasound diagnoses of fetal anomalies made in a Fetal Medicine Center in Pernambuco. METHODS: A cross sectional study was performed to validate the diagnosis test, including all high risk pregnant women submitted to obstetrical morphological ultrasound at the "Instituto de Medicina Integral Professor Fernando Figueira (I.M.I.P.)", from March 2002 to March 2006. Prenatal diagnosis was confirmed after birth. Socio demographic characteristics and pre and postnatal frequencies of fetal anomalies were the variables studied. Agreement between pre and postnatal diagnoses from congenital anomalies were evaluated with the Kappa indicator. Youden's test was applied to validate prenatal ultrasound diagnoses. RESULTS: Nine hundred and eighty nine patients were eligible. After evaluation of inclusion and exclusion criteria 457 patients were included in study. The average maternal age was 24.8 + 6.5 years. Fetal anomaly diagnoses postnatal were confirmed in 257 (56.2 percent) pregnant women. Prenatal ultrasound diagnosis of fetal anomalies disclosed 96 percent of sensibility and 79 percent of specificity, good agreement (K=0.76) between pre and postnatal diagnoses when compared to postnatal results and good diagnostic validity (Y=0.75). CONCLUSION: Prenatal diagnoses of fetal anomalies at a Fetal Medicine center in Pernambuco demonstrate good sensibility, specificity, agreement pre and postnatal and good diagnostic validity.

Is the number of antennal plate organs (sensilla placodea) greater in hygienic than in non-hygienic Africanized honey bees?

Hygienic behavior is a desirable trait in honey bees (Apis mellifera L.), as hygienic bees quickly remove diseased brood, interrupting the infectious cycle. Hygienic lines of honey bees appear to be more sensitive to the odors of dead and diseased honey bee brood, and Africanized honey bees are generally more hygienic than are European honey bees. We compared the number of sensilla placodea, antennal sensory structures involved in the perception of odor, in 10 bees from each of six hygienic and four non-hygienic colonies of Africanized honey bees. The sensilla placodea of three of the terminal segments (flagellomeres) of the right antenna of each bee were counted with a scanning electron microscope. There were no significant differences in the mean numbers of sensilla placodea between the hygienic and non-hygienic bees, though the variance was higher in the hygienic group. Flagellomere 4 had significantly more sensilla placodea than flagellomeres 6 and 8. However, there was no significant difference between the other two flagellomeres. As hygienic bees are capable of identifying dead, injured, or infested brood inside a capped brood cell, sensilla placodea probably have an important role in enabling worker bees to sense sick brood. However, we did not find greater numbers of this sensory structure in the antennae of hygienic, compared to non-hygienic Africanized honey bees.