Replicability of simulation studies for the investigation of statistical methods: the RepliSims project.

Results of simulation studies evaluating the performance of statistical methods can have a major impact on the way empirical research is implemented. However, so far there is limited evidence of the replicability of simulation studies. Eight highly cited statistical simulation studies were selected, and their replicability was assessed by teams of replicators with formal training in quantitative methodology. The teams used information in the original publications to write simulation code with the aim of replicating the results. The primary outcome was to determine the feasibility of replicability based on reported information in the original publications and supplementary materials. Replicasility varied greatly: some original studies provided detailed information leading to almost perfect replication of results, whereas other studies did not provide enough information to implement any of the reported simulations. Factors facilitating replication included availability of code, detailed reporting or visualization of data-generating procedures and methods, and replicator expertise. Replicability of statistical simulation studies was mainly impeded by lack of information and sustainability of information sources. We encourage researchers publishing simulation studies to transparently report all relevant implementation details either in the research paper itself or in easily accessible supplementary material and to make their simulation code publicly available using permanent links.

Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

Analysis of the 2020 Taal Volcano tephra fall deposits from crowdsourced information and field data.

After 43 years of dormancy, Taal Volcano violently erupted in January 2020 forming a towering eruption plume. The fall deposits covered an area of 8605 km2, which includes Metro Manila of the National Capital Region of the Philippines. The tephra fall caused damage to crops, traffic congestion, roof collapse, and changes in air quality in the affected areas. In a tropical region where heavy rains are frequent, immediate collection of data is crucial in order to preserve the tephra fall deposit record, which is readily washed away by surface water runoff and prevailing winds. Crowdsourcing, field surveys, and laboratory analysis of the tephra fall deposits were conducted to document and characterize the tephra fall deposits of the 2020 Taal Volcano eruption and their impacts. Results show that the tephra fall deposit thins downwind exponentially with a thickness half distance of about 1.40 km and 9.49 km for the proximal and distal exponential segments, respectively. The total calculated volume of erupted fallout deposit is 0.057 km3, 0.042 km3, or 0.090 km3 using the exponential, power-law, and Weibull models, respectively, and all translate to a VEI of 3. However, using a probabilistic approach (Weibull method) with 90% confidence interval, the volume estimate is as high as 0.097 km3. With the addition of the base surge deposits amounting to 0.019 km3, the volume translates to a VEI of 4, consistent with the classification for the observed height and umbrella radius of the 2020 main eruption plume. VEI 4 is also consistent with the calculated median eruption plume height of 17.8 km and sub-plinian classification based on combined analysis of isopleth and isopach data. Phreatomagmatic activity originated from a vent located in Taal Volcano's Main Crater Lake (MCL), which contained 42 million m3 of water. This eruptive style is further supported by the characteristics of the ash grain components of the distal 12 January 2020 tephra fall deposits, consisting dominantly of andesitic vitric fragments (83-90%). Other components of the fall deposits are lithic (7-11%) and crystal (less than 6%) grains. Further textural and geochemical analysis of these tephra fall deposits contributes to better understand the volcanic processes that occurred at Taal Volcano, one of the 16 Decade Volcanoes identified by the International Association of Volcanology and Chemistry of the Earth's Interior (IAVCEI) because of its destructive nature and proximity to densely populated areas. The crowdsourcing initiative provided a significant portion of the data used for this study while at the same time educating and empowering the community to build resilience. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00445-022-01534-y.

Gender differences in characteristics of violent and sexual victimization in patients with psychosis: a cross-sectional study.

INTRODUCTION: Various studies have demonstrated that individuals with a psychotic disorder are at an increased risk of becoming a victim of crime. Little is known about gender differences in victimization types and in specific characteristics of victimization (e.g., perpetrator, location or disclosure). Knowledge on characteristics of victimization would provide clinicians with more insight which may be especially useful for tailoring interventions. The aim of this study is to examine gender differences in characteristics of violent and sexual victimization in patients with a psychotic disorder. METHODS: Information on violent (threats, physical abuse) and sexual victimization (harassment, assault) was assessed in 482 individuals with a psychotic disorder who received mental health care. Patients were recruited through a routine outcome monitoring study and a clinical trial. RESULTS: Men reported more threats with violence (20.7% vs. 10.5%, x2 = 7.68, p = 0.01), whereas women reported more sexual assault (13.3% vs. 3.6%, x2 = 15.43, p < 0.001). For violent victimization, women were more likely than men to be victimized by a partner, friend or family member (52.9% vs. 30.6%) as opposed to a stranger (11.8% vs. 40.3%; O.R. = 52.49) and to be victimized at home (60.0% vs. 29.3%) as opposed to on the street or elsewhere (40.0% vs. 70.3%; O.R. = 0.06). For sexual victimization, there was no difference in location and perpetrator between men and women. For sexual victimization and physical violence, no differences in disclosure were found, but women were more likely not to disclose threats with violence or to disclose threats to a professional or police (52.9% vs. 45.2%; O.R. = 30.33). All analyses were controlled for age, diagnosis and employment. DISCUSSION: Gender patterns of victimization types and characteristics are similar for individuals with a psychotic disorder in comparison to the general population. Men were at higher risk of violent victimization, whereas women were at higher risk for sexual victimization. Men were more likely to become victimized in the streets or elsewhere by a stranger, whereas women seemed to be more often victimized at home by a partner, friend or a family member. Future studies may tailor interventions preventing victimization in psychosis according to gender.

Impact of analysis technique on our understanding of the natural history of labour: a simulation study.

OBJECTIVE: To evaluate the discrepancy between historical and more recent descriptions of the first stage of labour by testing whether the statistical techniques used recently (repeated-measures polynomial and interval-censored regression) were appropriate for detection of periods of rapid acceleration of cervical dilatation as might occur at the time of transition from a latent to an active phase of labour. DESIGN AND SETTING: A simulation study using regression techniques. SAMPLE: We created a simulated data set for 500 000 labours with clearly defined latent and active phases using the parameters described by Friedman. Additionally, we created a data set comprising 500 000 labours with a progressively increasing rate of cervical dilatation. METHODS: Repeated-measures polynomial regression was used to create summary labour curves based on simulated cervical examinations. Interval-censored regression was used to create centimetre-by-centimetre estimates of rates of cervical dilatation and their 95th centiles. MAIN OUTCOME MEASURES: Labour summary curves and rates of cervical dilatation. RESULTS: Repeated-measures polynomial regression did not detect the rapid acceleration in cervical dilatation (i.e. acceleration phase) and overestimated lengths of labour, especially at smaller cervical dilatations. There was a two-fold overestimation in the mean rate of cervical dilatation from 4 to 6 cm. Interval-censored regression overestimated median transit times, at 4- to 5-cm cervical dilatation or when cervical examinations occurred less frequently than 0.5- to 1.5-hourly. CONCLUSION: Repeated-measures polynomial regression and interval-censored regression should not be routinely used to define labour progress because they do not accurately reflect the underlying data. TWEETABLE ABSTRACT: Repeated-measures polynomial and interval-censored regression techniques are not appropriate to model first stage of labour.

Comparing three machine learning approaches to design a risk assessment tool for future fractures: predicting a subsequent major osteoporotic fracture in fracture patients with osteopenia and osteoporosis.

Four machine learning models were developed and compared to predict the risk of a future major osteoporotic fracture (MOF), defined as hip, wrist, spine and humerus fractures, in patients with a prior fracture. We developed a user-friendly tool for risk calculation of subsequent MOF in osteopenia patients, using the best performing model. INTRODUCTION: Major osteoporotic fractures (MOFs), defined as hip, wrist, spine and humerus fractures, can have serious consequences regarding morbidity and mortality. Machine learning provides new opportunities for fracture prediction and may aid in targeting preventive interventions to patients at risk of MOF. The primary objective is to develop and compare several models, capable of predicting the risk of MOF as a function of time in patients seen at the fracture and osteoporosis outpatient clinic (FO-clinic) after sustaining a fracture. METHODS: Patients aged > 50 years visiting an FO-clinic were included in this retrospective study. We compared discriminative ability (concordance index) for predicting the risk on MOF with a Cox regression, random survival forests (RSF) and an artificial neural network (ANN)-DeepSurv model. Missing data was imputed using multiple imputations by chained equations (MICE) or RSF's imputation function. Analyses were performed for the total cohort and a subset of osteopenia patients without vertebral fracture. RESULTS: A total of 7578 patients were included, 805 (11%) patients sustained a subsequent MOF. The highest concordance-index in the total dataset was 0.697 (0.664-0.730) for Cox regression; no significant difference was determined between the models. In the osteopenia subset, Cox regression outperformed RSF (p = 0.043 and p = 0.023) and ANN-DeepSurv (p = 0.043) with a c-index of 0.625 (0.562-0.689). Cox regression was used to develop a MOF risk calculator on this subset. CONCLUSION: We show that predicting the risk of MOF in patients who already sustained a fracture can be done with adequate discriminative performance. We developed a user-friendly tool for risk calculation of subsequent MOF in patients with osteopenia.

De novo variants in MED12 cause X-linked syndromic neurodevelopmental disorders in 18 females.

PURPOSE: MED12 is a subunit of the Mediator multiprotein complex with a central role in RNA polymerase II transcription and regulation of cell growth, development, and differentiation. This might underlie the variable phenotypes in males carrying missense variants in MED12, including X-linked recessive Ohdo, Lujan, and FG syndromes. METHODS: By international matchmaking we assembled variant and clinical data on 18 females presenting with variable neurodevelopmental disorders (NDDs) and harboring de novo variants in MED12. RESULTS: Five nonsense variants clustered in the C-terminal region, two splice variants were found in the same exon 8 splice acceptor site, and 11 missense variants were distributed over the gene/protein. Protein truncating variants were associated with a severe, syndromic phenotype consisting of intellectual disability (ID), facial dysmorphism, short stature, skeletal abnormalities, feeding difficulties, and variable other abnormalities. De novo missense variants were associated with a less specific, but homogeneous phenotype including severe ID, autistic features, limited speech and variable other anomalies, overlapping both with females with truncating variants as well as males with missense variants. CONCLUSION: We establish de novo truncating variants in MED12 as causative for a distinct NDD and de novo missense variants as causative for a severe, less specific NDD in females.

Ultrasound features prior to 11 weeks' gestation and first-trimester maternal factors in prediction of hypertensive disorders of pregnancy.

OBJECTIVES: Maternal hypertensive disorders (MHD), including pregnancy-induced hypertension and pre-eclampsia, are estimated to occur in 7-10% of pregnancies worldwide and have significant short- and long-term implications for both mother and fetus. This study aimed to determine the association of conventional and novel early first-trimester ultrasound measures with MHD and whether these ultrasound measures, combined with maternal characteristics and biochemistry, improve the prediction of MHD. METHODS: This was a prospective cohort study of consecutive women with a singleton pregnancy, attending for an early (5 + 1 to 11 + 0 weeks' gestation) ultrasound examination at a private obstetric ultrasound practice between February 2016 and August 2018. Recorded ultrasound measurements included mean sac diameter, yolk sac diameter, crown-rump length, fetal heart rate (FHR), trophoblast thickness, trophoblast volume (TV) and mean uterine artery pulsatility index. Maternal biochemistry was assessed at 10-14 weeks and included beta-human chorionic gonadotropin, pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF) and maternal serum alpha-fetoprotein. Regression models were fitted for each ultrasound parameter and multiples of the median (MoM) were calculated. All measures were compared between women who had a normotensive outcome and those who subsequently developed MHD. Logistic regression analysis was used to create a prediction model for MHD based on maternal characteristics, ultrasound measurements at 5 + 1 to 11 + 0 weeks' gestation and maternal biochemistry at 10-14 weeks. RESULTS: In total, 1141 women were included in the analysis, of whom 1086 (95.2%) were normotensive at delivery and 55 (4.8%) developed MHD. Women who developed MHD weighed significantly more than did normotensive women (P < 0.0001). Mean MoM values for TV (P = 0.006), PAPP-A (P = 0.031) and PlGF (P = 0.044) were decreased significantly in pregnancies that subsequently developed MHD. The proposed logistic regression model includes maternal weight and height and MoM values for TV, FHR and PlGF, resulting in an area under the receiver-operating-characteristics curve of 0.80 (95% CI, 0.75-0.86). CONCLUSION: The combination of maternal weight and height, TV and FHR, measured prior to 11 weeks' gestation, and first-trimester PlGF appears to have good predictive value for development of MHD later in pregnancy. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Neural correlates of exercise training in individuals with schizophrenia and in healthy individuals: A systematic review.

A body of evidence has revealed positive effects of physical exercise on behavioral, cognitive and physical outcomes in patients with schizophrenia. Notably, the effect of exercise at the neural level may be particularly relevant as well as it is hypothesized that exercise may stimulate the brain in a way that might normalize neural alterations related to the disorder. The aim of the current systematic review was to provide an up to date overview of studies investigating the neural effects of exercise in individuals with a schizophrenia spectrum disorder and healthy individuals. The majority of included studies focused on hippocampal effects, reporting beneficial effects of exercise. In addition, in schizophrenia increased extrastriate body area (EBA) activation and increased white matter fiber integrity in tracts relevant to the disorder were found and in healthy individuals decreased connectivity of the dorsolateral prefrontal cortex (DLPFC) indicating greater cognitive efficiency was reported. Comparing individuals with a schizophrenia spectrum disorder and healthy individuals within a similar age range, most studies found similar effects on hippocampal volume and white matter tracts for both groups, although the effect in schizophrenia spectrum disorders may be attenuated which is in line with previous literature on brain plasticity. The current review indicates a lack of studies investigating neural correlates other than the hippocampus. Although those studies that did focus on other neural correlates revealed promising results, these have not been replicated in other studies and call for replication. Furthermore, future studies should expand their focus, by investigating neural mechanisms underlying positive effects of physical exercise on positive symptoms, negative symptoms and symptoms such as depression, social withdrawal and social cognition.

Contrasting catastrophic eruptions predicted by different intrusion and collapse scenarios.

Catastrophic volcanic eruptions triggered by landslide collapses can jet upwards or blast sideways. Magma intrusion is related to both landslide-triggered eruptive scenarios (lateral or vertical), but it is not clear how such different responses are produced, nor if any precursor can be used for forecasting them. We approach this problem with physical analogue modelling enhanced with X-ray Multiple Detector Computed Tomography scanning, used to track evolution of internal intrusion, and its related faulting and surface deformation. We find that intrusions produce three different volcano deformation patterns, one of them involving asymmetric intrusion and deformation, with the early development of a listric slump fault producing pronounced slippage of one sector. This previously undescribed early deep potential slip surface provides a unified explanation for the two different eruptive scenarios (lateral vs. vertical). Lateral blast only occurs in flank collapse when the intrusion has risen into the sliding block. Otherwise, vertical rather than lateral expansion of magma is promoted by summit dilatation and flank buttressing. The distinctive surface deformation evolution detected opens the possibility to forecast the possible eruptive scenarios: laterally directed blast should only be expected when surface deformation begins to develop oblique to the first major fault.

De novo variants in CDK13 associated with syndromic ID/DD: Molecular and clinical delineation of 15 individuals and a further review.

De novo variants in the gene encoding cyclin-dependent kinase 13 (CDK13) have been associated with congenital heart defects and intellectual disability (ID). Here, we present the clinical assessment of 15 individuals and report novel de novo missense variants within the kinase domain of CDK13. Furthermore, we describe 2 nonsense variants and a recurrent frame-shift variant. We demonstrate the synthesis of 2 aberrant CDK13 transcripts in lymphoblastoid cells from an individual with a splice-site variant. Clinical characteristics of the individuals include mild to severe ID, developmental delay, behavioral problems, (neonatal) hypotonia and a variety of facial dysmorphism. Congenital heart defects were present in 2 individuals of the current cohort, but in at least 42% of all known individuals. An overview of all published cases is provided and does not demonstrate an obvious genotype-phenotype correlation, although 2 individuals harboring a stop codons at the end of the kinase domain might have a milder phenotype. Overall, there seems not to be a clinically recognizable facial appearance. The variability in the phenotypes impedes an à vue diagnosis of this syndrome and therefore genome-wide or gene-panel driven genetic testing is needed. Based on this overview, we provide suggestions for clinical work-up and management of this recently described ID syndrome.

Diagnostic performance of gadofosveset-enhanced axillary MRI for nodal (re)staging in breast cancer patients: results of a validation study.

AIM: To evaluate diagnostic performance of gadofosveset (GDF)-enhanced magnetic resonance imaging (MRI) in addition to T2-weighted (T2W) MRI for nodal (re)staging in newly diagnosed breast cancer patients. MATERIALS AND METHODS: Ninety patients underwent axillary T2W- and GDF-MRI. Two radiologists independently scored each lymph node; first on T2W-MRI, subsequently adjusting their score on GDF-MRI. Diagnostic performance parameters were calculated on node-by-node and patient-by-patient validation with histopathology as the reference standard. Furthermore, learning curve analysis for reading GDF-MRI was performed. RESULTS: In patient-by-patient validation, overall reader performances for T2W- and GDF-MRI were similar with area under the receiver operating characteristic curves (AUC) of 0.75 and 0.77 (p=0.731) for reader 1 and 0.79 and 0.72 (p=0.156) for reader 2. For node-by-node validation, AUC values of T2W- and GDF-MRI were 0.76 and 0.82 (p=0.018) and 0.77 and 0.77 (p=0.998) for reader 1 and 2. The AUC for reader 1 was 0.71 for first one-third of nodes evaluated, improving to 0.80 and 0.95 for the next and last one-third, respectively. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) improved from 38%, 89%, 56%, and 79% to 60%, 93%, 64%, and 92%. The AUC of reader 2 improved from 0.69 to 0.79. CONCLUSION: The present study confirmed that GDF-MRI, in addition to T2W-MRI, has potential as a non-invasive method for nodal (re)staging in breast cancer.

Complications of external cephalic version: a retrospective analysis of 1121 patients at a tertiary hospital in Sydney.

OBJECTIVE: To report the complication rate associated with external cephalic version (ECV) at term. DESIGN: Single-centre retrospective study. SETTING: A major tertiary hospital in Sydney, Australia. POPULATION OR SAMPLE: All women who underwent an ECV at Royal Prince Alfred Hospital from 1995-2013 were included. METHODS: ECV was attempted on all consenting women with a breech presentation at term in the absence of contraindications. Complications were classified as minor (transient cardiotocography abnormalities, ruptured membranes, small antepartum haemorrhage) or serious (fetal death, placental abruption, fetal distress requiring emergency caesarean section, fetal bone injury, cord prolapse). ECV success rates and rate of reversion to breech were recorded. MAIN OUTCOME MEASURES: The primary outcome was the incidence of serious complications. Secondary outcome measures were the rate of minor complications and reversion to breech. RESULTS: Of 1121 patients that underwent ECV, five (0.45%) experienced a serious complication. There was one placental abruption, one emergency caesarean section for fetal distress and two cord prolapses. There was one fetal death attributable to a successful ECV. Forty-eight women (4.28%) experienced a minor complication. Reversion to the breech occurred in sixteen patients (3.32%). CONCLUSION: ECV at term is associated with a low rate of serious complications. TWEETABLE ABSTRACT: Study of 1121 consecutive ECV attempts shows low rate of complications although one fetal death reported.

Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism.

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Routine use of standard breast MRI compared to axillary ultrasound for differentiating between no, limited and advanced axillary nodal disease in newly diagnosed breast cancer patients.

OBJECTIVES: To compare standard breast MRI to dedicated axillary ultrasound (with or without tissue sampling) for differentiating between no, limited and advanced axillary nodal disease in breast cancer patients. METHODS: All patients who underwent breast MRI and dedicated axillary ultrasound between 2009 and 2014 were eligible. Exclusion criteria were recurrent disease, neoadjuvant systemic therapy and not receiving completion axillary lymph node dissection after positive sentinel lymph node biopsy (SLNB). Two radiologists independently reassessed all MRI exams. Axillary ultrasound findings were retrospectively collected. Probability of advanced axillary nodal disease (pN2-3) given clinically node negative (cN0) or limited (cN1) findings was calculated, with corresponding negative predictive value (NPV) to exclude pN2-3 and positive predictive value (PPV) to identify axillary nodal disease. Histopathology served as gold standard. RESULTS: A total of 377 cases resulted in 81.4% no, 14.4% limited and 4.2% advanced axillary nodal disease at final histopathology. Probability of pN2-3 given cN0 for breast MRI and axillary ultrasound was 0.7-0.9% versus 1.5% and probability of pN2-3 given cN1 was 11.6-15.4% versus 29.0%. When cN1 on breast MRI was observed, PPV to identify positive axillary nodal disease was 50.7% and 59.0%. CONCLUSIONS: Evaluation of axillary nodal status on standard breast MRI is comparable to dedicated axillary ultrasound in breast cancer patients. In patients who underwent preoperative standard breast MRI, axillary ultrasound is only required in case of suspicious nodal findings on MRI.

Heritable variation in maternally derived yolk androgens, thyroid hormones and immune factors.

Maternal reproductive investment can critically influence offspring phenotype, and thus these maternal effects are expected to be under strong natural selection. Knowledge on the extent of heritable variation in the physiological mechanisms underlying maternal effects is however limited. In birds, resource allocation to eggs is a key mechanism for mothers to affect their offspring and different components of the egg may or may not be independently adjusted. We studied the heritability of egg components and their genetic and phenotypic covariation in great tits (Parus major), using captive-bred full siblings of wild origin. Egg mass, testosterone (T) and androstenedione (A4) hormone concentrations showed moderate heritability, in agreement with earlier findings. Interestingly, yolk triiodothyronine hormone (T3), but not its precursor, thyroxine hormone (T4), concentration was heritable. An immune factor, albumen lysozyme, showed moderate heritability, but yolk immunoglobulins (IgY) did not. The genetic correlation estimates were moderate but statistically nonsignificant; a trend for a positive genetic correlation was found between A4 and egg mass, T and lysozyme and IgY and lysozyme, respectively. Interestingly, phenotypic correlations were found only between A4 and T, and T4 and T3, respectively. Given that these egg components are associated with fitness-related traits in the offspring (and mother), and that we show that some components are heritable, it opens the possibility that natural selection may shape the rate and direction of phenotypic change via egg composition.

Sentinel lymph node biopsy can be omitted in DCIS patients treated with breast conserving therapy.

Breast cancer guidelines advise sentinel lymph node biopsy (SLNB) in patients with ductal carcinoma in situ (DCIS) on core biopsy at high risk of invasive cancer or in case of mastectomy. This study investigates the incidence of SLNB and SLN metastases and the relevance of indications in guidelines and literature to perform SLNB in order to validate whether SLNB is justified in patients with DCIS on core biopsy in current era. Clinically node negative patients diagnosed from 2004 to 2013 with only DCIS on core needle biopsy were selected from a national database. Incidence of SLN biopsy and metastases was calculated. With Fisher exact tests correlation between SLNB indications and actual presence of SLN metastases was studied. Further, underestimation rate for invasive cancer and correlation with SLN metastases was analysed. 910 patients were included. SLNB was performed in 471 patients (51.8 %): 94.5 % had pN0, 3.0 % pN1mi and 2.5 % pN1. Patients undergoing mastectomy had 7 % SLN metastases versus 3.5 % for breast conserving surgery (BCS) (p = 0.107). The only factors correlating to SLN metastases were smaller core needle size (p = 0.01) and invasive cancer (p < 0.001). Invasive cancer was detected in 16.7 % by histopathology with 15.6 % SLN metastases versus only 2 % in pure DCIS. SLNB showed metastases in 5.5 % of patients; 3.5 % in case of BCS (any histopathology) and 2 % when pure DCIS was found at definitive histopathology (BCS and mastectomy). Consequently, SLNB should no longer be performed in patients diagnosed with DCIS on core biopsy undergoing BCS. If definitive histopathology shows invasive cancer, SLNB can still be considered after initial surgery.

De novo loss-of-function mutations in X-linked SMC1A cause severe ID and therapy-resistant epilepsy in females: expanding the phenotypic spectrum.

De novo missense mutations and in-frame coding deletions in the X-linked gene SMC1A (structural maintenance of chromosomes 1A), encoding part of the cohesin complex, are known to cause Cornelia de Lange syndrome in both males and females. For a long time, loss-of-function (LoF) mutations in SMC1A were considered incompatible with life, as such mutations had not been reported in neither male nor female patients. However, recently, the authors and others reported LoF mutations in females with intellectual disability (ID) and epilepsy. Here we present the detailed phenotype of two females with de novo LoF mutations in SMC1A, including a de novo mutation of single base deletion [c.2364del, p.(Asn788Lysfs*10)], predicted to result in a frameshift, and a de novo deletion of exon 16, resulting in an out-of-frame mRNA splice product [p.(Leu808Argfs*6)]. By combining our patients with the other recently reported females carrying SMC1A LoF mutations, we ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet. Our data show the existence of a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.

Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID.

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1A in patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1A mutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1A truncating mutations (P=0.00851) and an excess of de novo mutations (P=2.53 × 10(-10)) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1A define a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophila knockout models.