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Haplotype estimation, or phasing, has gained significant traction in large-scale projects due to its valuable contributions to population genetics, variant analysis, and the creation of reference panels for imputation and phasing of new samples. To scale with the growing number of samples, haplotype estimation methods designed for population scale rely on highly optimized statistical models to phase genotype data, and usually ignore read-level information. Statistical methods excel in resolving common variants, however, they still struggle at rare variants due to the lack of statistical information. In this study we introduce SAPPHIRE, a new method that leverages whole-genome sequencing data to enhance the precision of haplotype calls produced by statistical phasing. SAPPHIRE achieves this by refining haplotype estimates through the realignment of sequencing reads, particularly targeting low-confidence phase calls. Our findings demonstrate that SAPPHIRE significantly enhances the accuracy of haplotypes obtained from state of the art methods and also provides the subset of phase calls that are validated by sequencing reads. Finally, we show that our method scales to large data sets by its successful application to the extensive 3.6 Petabytes of sequencing data of the last UK Biobank 200,031 sample release. Author summary: Haplotype estimation, also known as phasing, is now applied to population scale projects, typically of hundreds of thousands of samples to millions of samples. Generally phasing relies on statistical methods as they provide very accurate results for common variations. However, for rare and very rare variants the lack of statistical power often results in poor phasing. The large amount of rare variations discovered with whole-genome sequencing as well as the number of samples makes it expensive to process. We have developed the SAPPHIRE method that leverages whole-genome sequencing data to verify and correct the phase at poorly phased variant loci. It does so by finding sequencing reads that contain both the poorly phased variant and an accurately phased common variant. SAPPHIRE scales with large data sets by specifically targeting variation where statistical phasing performed poorly, therefore it reduces the quantity of sequencing data to be processed and combines the advantages of both read-based and statistical approaches. We show the efficiency of SAPPHIRE by improving the estimated haplotypes for 200,031 samples in the UK Biobank. SAPPHIRE is free and available as open-source software. [ABSTRACT FROM AUTHOR]

When combining imputed and sequenced data in a single gene-based association analysis, the problem of reconstructing genetic correlation matrices arises. It is related to the fact that the correlations between genotypes of all imputed variants and the correlations between genotypes of all sequenced variants are known for a gene but we do not know the correlations between genotypes of variants, one of which is imputed, and the other is sequenced. To recover these correlations, we propose an efficient method based on maximising the determinant of the matrix. This method has a number of useful properties and an analytical solution for our task. Approbation of the proposed method was performed by comparing reconstructed and real correlation matrices constructed on individual genotypes from the UK Biobank. Comparison of the results of gene-based association analysis performed by the SKAT, BT, and PCA methods on reconstructed and real matrices using modelled summary statistics and calculated summary statistics on real phenotypes showed high quality of reconstruction and robustness of the method to different gene structures. [ABSTRACT FROM AUTHOR]

Non-response is common in longitudinal surveys, reducing efficiency and introducing the potential for bias. Principled methods, such as multiple imputation, are generally required to obtain unbiased estimates in surveys subject to missingness which is not completely at random. The inclusion of predictors of non-response in such methods, for example as auxiliary variables in multiple imputation, can help improve the plausibility of the missing at random assumption underlying these methods and hence reduce bias. We present a systematic data-driven approach used to identify predictors of non-response at Wave 8 (age 25-26) of Next Steps, a UK national cohort study that follows a sample of 15,770 young people from age 13-14 years. The identified predictors of non-response were across a number of broad categories, including personal characteristics, schooling and behaviour in school, activities and behaviour outside of school, mental health and well-being, socio-economic status, and practicalities around contact and survey completion. We found that including these predictors of non-response as auxiliary variables in multiple imputation analyses allowed us to restore sample representativeness in several different settings, though we acknowledge that this is unlikely to universally be the case. We propose that these variables are considered for inclusion in future analyses using principled methods to explore and attempt to reduce bias due to non-response in Next Steps. Our data-driven approach to this issue could also be used as a model for investigations in other longitudinal studies. [ABSTRACT FROM AUTHOR]

Motivation Multi-trait analysis has been shown to have greater statistical power than single-trait analysis. Most of the existing multi-trait analysis methods only work with a limited number of traits and usually prioritize high statistical power over identifying relevant traits, which heavily rely on domain knowledge. Results To handle diseases and traits with obscure etiology, we developed TraitScan, a powerful and fast algorithm that identifies potential pleiotropic traits from a moderate or large number of traits (e.g. dozens to thousands) and tests the association between one genetic variant and the selected traits. TraitScan can handle either individual-level or summary-level GWAS data. We evaluated TraitScan using extensive simulations and found that it outperformed existing methods in terms of both testing power and trait selection when sparsity was low or modest. We then applied it to search for traits associated with Ewing Sarcoma, a rare bone tumor with peak onset in adolescence, among 754 traits in UK Biobank. Our analysis revealed a few promising traits worthy of further investigation, highlighting the use of TraitScan for more effective multi-trait analysis as biobanks emerge. We also extended TraitScan to search and test association with a polygenic risk score and genetically imputed gene expression. Availability and implementation Our algorithm is implemented in an R package "TraitScan" available at https://github.com/RuiCao34/TraitScan. [ABSTRACT FROM AUTHOR]

Background: Mortality prediction is critical on long-term kidney replacement therapy (KRT), both for individual treatment decisions and resource planning. Many mortality prediction models already exist, but as a major shortcoming most of them have only been validated internally. This leaves reliability and usefulness of these models in other KRT populations, especially foreign, unknown. Previously two models were constructed for one- and two-year mortality prediction of Finnish patients starting long-term dialysis. These models are here internationally validated in KRT populations of the Dutch NECOSAD Study and the UK Renal Registry (UKRR). Methods: We validated the models externally on 2051 NECOSAD patients and on two UKRR patient cohorts (5328 and 45493 patients). We performed multiple imputation for missing data, used c-statistic (AUC) to assess discrimination, and evaluated calibration by plotting average estimated probability of death against observed risk of death. Results: Both prediction models performed well in the NECOSAD population (AUC 0.79 for the one-year model and 0.78 for the two-year model). In the UKRR populations, performance was slightly weaker (AUCs: 0.73 and 0.74). These are to be compared to the earlier external validation in a Finnish cohort (AUCs: 0.77 and 0.74). In all tested populations, our models performed better for PD than HD patients. Level of death risk (i.e., calibration) was well estimated by the one-year model in all cohorts but was somewhat overestimated by the two-year model. Conclusions: Our prediction models showed good performance not only in the Finnish but in foreign KRT populations as well. Compared to the other existing models, the current models have equal or better performance and fewer variables, thus increasing models' usability. The models are easily accessible on the web. These results encourage implementing the models into clinical decision-making widely among European KRT populations. [ABSTRACT FROM AUTHOR]

Background: In the interrupted time series (ITS) approach, it is common to average the outcome of interest at each time point and then perform a segmented regression (SR) analysis. In this study, we illustrate that such 'aggregate-level' analysis is biased when data are missing at random (MAR) and provide alternative analysis methods. Methods: Using electronic health records from the UK, we evaluated weight change over time induced by the initiation of antipsychotic treatment. We contrasted estimates from aggregate-level SR analysis against estimates from mixed models with and without multiple imputation of missing covariates, using individual-level data. Then, we conducted a simulation study for insight about the different results in a controlled environment. Results: Aggregate-level SR analysis suggested a substantial weight gain after initiation of treatment (average short-term weight change: 0.799kg/week) compared to mixed models (0.412kg/week). Simulation studies confirmed that aggregate-level SR analysis was biased when data were MAR. In simulations, mixed models gave less biased estimates than SR analysis and, in combination with multilevel multiple imputation, provided unbiased estimates. Mixed models with multiple imputation can be used with other types of ITS outcomes (eg, proportions). Other standard methods applied in ITS do not help to correct this bias problem. Conclusion: Aggregate-level SR analysis can bias the ITS estimates when individual-level data are MAR, because taking averages of individual-level data before SR means that data at the cluster level are missing not at random. Avoiding the averaging-step and using mixed models with or without multilevel multiple imputation of covariates is recommended. [ABSTRACT FROM AUTHOR]

Genomic selection enables cumulative genetic gains in key production traits such as disease resistance, playing an important role in the economic and environmental sustainability of aquaculture production. However, it requires genome-wide genetic marker data on large populations, which can be prohibitively expensive. Genotype imputation is a cost-effective method for obtaining high-density genotypes, but its value in aquaculture breeding programs which are characterized by large full-sibling families has yet to be fully assessed. The aim of this study was to optimize the use of low-density genotypes and evaluate genotype imputation strategies for cost-effective genomic prediction. Phenotypes and genotypes (78,362 SNPs) were obtained for 610 individuals from a Scottish Atlantic salmon breeding program population (Landcatch, UK) challenged with sea lice, Lepeophtheirus salmonis. The genomic prediction accuracy of genomic selection was calculated using GBLUP approaches and compared across SNP panels of varying densities and composition, with and without imputation. Imputation was tested when parents were genotyped for the optimal SNP panel, and offspring were genotyped for a range of lower density imputation panels. Reducing SNP density had little impact on prediction accuracy until 5,000 SNPs, below which the accuracy dropped. Imputation accuracy increased with increasing imputation panel density. Genomic prediction accuracy when offspring were genotyped for just 200 SNPs, and parents for 5,000 SNPs, was 0.53. This accuracy was similar to the full high density and optimal density dataset, and markedly higher than using 200 SNPs without imputation. These results suggest that imputation from very low to medium density can be a costeffective tool for genomic selection in Atlantic salmon breeding programs. [ABSTRACT FROM AUTHOR]

We present a new method to estimate individual knot volumes based on a knot geometry model coupled with observations on branch characteristics. X-ray computer tomography and image analysis were used to measure the volume and geometry of 424 knots of Sitka spruce (Picea sitchensis (Bong.) Carrière). Knot geometry can be described mathematically by deriving functions for relative vertical position, diameter, and slope dependent on radial position in the stem. These functions were parameterized using "seemingly unrelated regression" and mixed-modelling techniques. This provided a base model for typical knots. To estimate individual knot volume, we used available data for branch diameter and insertion angle to obtain conditional predictions. We imputed the most likely knot trajectory, as relative vertical position cannot be measured on branches. The model explained up to 96% of the variability in knot volume by incorporating the branch measurements, in contrast to the 43% explained using the typical knot model. Knot volume assessment based only on conditional predictions of diameter and marginal predictions of vertical position also accounted for 96% of the variability. Therefore, measurements of branch diameter alone would be enough to obtain highly precise predictions of individual knot volume. This estimator is a first step towards a knot model to be used for the management of Sitka spruce in Great Britain. [ABSTRACT FROM AUTHOR]

Background: Missing data is a common statistical problem in healthcare datasets from populations of older people. Some argue that arbitrarily assuming the mechanism responsible for the missingness and therefore the method for dealing with this missingness is not the best option-but is this always true? This paper explores what happens when extra information that suggests that a particular mechanism is responsible for missing data is disregarded and methods for dealing with the missing data are chosen arbitrarily. Regression models based on 2,533 intermediate care (IC) patients from the largest evaluation of IC done and published in the UK to date were used to explain variation in costs, EQ-5D and Barthel index. Three methods for dealing with missingness were utilised, each assuming a different mechanism as being responsible for the missing data: complete case analysis (assuming missing completely at random-MCAR), multiple imputation (assuming missing at random-MAR) and Heckman selection model (assuming missing not at random-MNAR). Differences in results were gauged by examining the signs of coefficients as well as the sizes of both coefficients and associated standard errors. Results: Extra information strongly suggested that missing cost data were MCAR. The results show that MCAR and MAR-based methods yielded similar results with sizes of most coefficients and standard errors differing by less than 3.4% while those based on MNAR-methods were statistically different (up to 730% bigger). Significant variables in all regression models also had the same direction of influence on costs. All three mechanisms of missingness were shown to be potential causes of the missing EQ-5D and Barthel data. The method chosen to deal with missing data did not seem to have any significant effect on the results for these data as they led to broadly similar conclusions with sizes of coefficients and standard errors differing by less than 54% and 322%, respectively. Conclusions: Arbitrary selection of methods to deal with missing data should be avoided. Using extra information gathered during the data collection exercise about the cause of missingness to guide this selection would be more appropriate. [ABSTRACT FROM AUTHOR]

We discuss methods for dealing with incomplete-data in the United Kingdom Women’s Cohort Study. We demonstrate by example how important it is to address the issues related to missing data with statistical integrity, illustrate the deficiencies of a data-reduction and a single-imputation method, and discuss how the method of multiple imputation overcomes them. Although the method entails some complexity, the computational activities can be organized in such a way that efficient analyses can be conducted by analysts who are not acquainted with all the details of the imputation method and who wish to rely on software they use and regard as standard. [ABSTRACT FROM AUTHOR]