Homozygosity mapping on a single patient: identification of homozygous regions of recent common ancestry by using population data

Homozygosity mapping has played an important role in detecting recessive mutations using families of consanguineous marriages. However, detection of regions identical and homozygosity by descent (HBD) when family data are not available, or when relationships are unknown, is still a challenge. Making use of population data from high-density SNP genotyping may allow detection of regions HBD from recent common founders in singleton patients without genealogy information. We report a novel algorithm that detects such regions by estimating the population haplotype frequencies (HF) for an entire homozygous region. We also developed a simulation method to evaluate the probability of HBD and linkage to disease for a homozygous region by examining the best regions in unaffected controls from the host population. The method can be applied to diseases of Mendelian inheritance but can also be extended to complex diseases to detect rare founder mutations that affect a very small number of patients using either multiplex families or sporadic cases. Testing of the method on both real cases (singleton affected) and simulated data demonstrated its superb sensitivity and robustness under genetic heterogeneity.     

Structure and evolution of neuronal wiring receptors and ligands

One of the fundamental properties of a neuronal circuit is the map of its connections. The cellular and developmental processes that allow for the growth of axons and dendrites, selection of synaptic targets, and formation of functional synapses use neuronal surface receptors and their interactions with other surface receptors, secreted ligands, and matrix molecules. Spatiotemporal regulation of the expression of these receptors and cues allows for specificity in the developmental pathways that wire stereotyped circuits. The families of molecules controlling axon guidance and synapse formation are generally conserved across animals, with some important exceptions, which have consequences for neuronal connectivity. Here, we summarize the distribution of such molecules across multiple taxa, with a focus on model organisms, evolutionary processes that led to the multitude of such molecules, and functional consequences for the diversification or loss of these receptors.     

Ascertainment Through Family History of Disease Often Decreases the Power of Family-based Association Studies

Selection of cases with additional affected relatives has been shown to increase the power of the case-control association design. We investigated whether this strategy can also improve the power of family-based association studies that use the transmission disequilibrium test (TDT), while accounting for the effects of residual polygenic and environmental factors on disease liability. Ascertainment of parent-offspring trios conditional on the proband having affected first-degree relatives almost always reduced the power of the TDT. For many disease models, this reduction was quite considerable. In contrast, for the same sample size, designs that analyzed more than one affected offspring per family often improved power when compared to the standard parent-offspring trio design. Together, our results suggest that (1) residual polygenic and environmental influences should be considered when estimating the power of the TDT for studies that ascertain families with multiple affected relatives; (2) if trios are selected conditional on having additional affected offspring, then it is important to genotype and include in the analysis the additional siblings; (3) the ascertainment strategy should be considered when interpreting results from TDT analyses. Our analytic approach to estimate the asymptotic power of the TDT is implemented online at http://pngu.mgh.harvard.edu/∼purcell/gpc/. Edited by David Allison     

High level of plasma inactive renin in Bartter's syndrome

In 10 cases of Bartter's syndrome, plasma active and inactive renin (AR and IR) were measured by two different methods. First, plasma renin activity (PRA), and total renin activity (TRA) after activating IR with trypsin, were measured by radioimmunoassay (RIA) of angiotensin I (AI) generated from endogenous substrate. And secondly, plasma active renin concentration (ARC) and total renin concentration (TRC) were measured by RIA of AI generated in the presence of an excess of exogenous substrate. The difference between TRA and PRA, and between TRC and ARC were designated as inactive renin activity (IRA) and inactive renin concentration (IRC), respectively. Small amounts of IRA were found only in 2 cases and no IRA in 8 cases. However, the existence of large amounts of IR in Bartter's syndrome was revealed by the IRC determination. This suggests that the shortage of endogenous renin substrate, consumed by the markedly increased AR, may have interfered with the detection of IRA in Bartter's syndrome, though the IR is markedly increased as well. The molecular weights of AR and IR were determined by Sephadex G-100 gel filtration in 3 cases. Both AR and IR seemed to be smaller than those of normal subjects.     

Extreme Learning Machine for Huge Hypotheses Re-ranking in Statistical Machine Translation

In statistical machine translation (SMT), a possibly infinite number of translation hypotheses can be decoded from a source sentence, among which re-ranking is applied to sort out the best translation result. Undoubtedly, re-ranking is an essential component of SMT for effective and efficient translation. A novel re-ranking method called Scaled Sorted Classification Re-ranking (SSCR) based on extreme learning machine (ELM) classification and minimum error rate training (MERT) is proposed. SSCR contains four steps: (1) the input features are normalized to the range of 0 to 1; (2) an ELM classification model is constructed for hypothesis ranking; (3) each translation hypothesis is ranked using the ELM classification model; and (4) the highest ranked subset of hypotheses are selected, in which the hypothesis with best predicted score based on MERT (system score) is returned as the final translation result. Compared with the baseline score (lower bound), SSCR with ELM classification can raise the translation quality up to 6.7% in IWSLT 2014 Chinese to English corpus. Compared with the state-of-the-art rank boosting, SSCR has a relatively 7.8% of improvement on BLEU in a larger WMT 2015 English-to-French corpus. Moreover, the training time of the proposed method is about 160 times faster than traditional regression-based re-ranking.     

The Prognostic Value of the Metabolic Tumor Volume in FIGO stage IA to IIB Cervical Cancer for Tumor Recurrence: Measured by F-18 FDG PET/CT

Purpose

The purpose of this study was to evaluate the prognostic value of the metabolic tumor volume (MTV), in FIGO stage IA–IIB cervical cancer patients, measured by F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging.

Methods

Forty-five patients with invasive cervical cancer who underwent FDG-PET imaging were recruited. Metabolically active tumor regions were delineated on the pretreatment FDG-PET scans by encompassing regions equal to or greater than an standardized uptake value (SUV) of 40% of the peak tumor intensity. The relationship of the metabolic tumor volume (MTV) to the disease-free survival was analyzed. The MTV of the cervical cancer was compared with pathological and clinical prognostic factors, including lymph node metastasis, parametrial invasion, the depth of invasion, resection margins, tumor differentiation and FIGO stages.

Results

Cox proportional hazard regression analysis showed that the MTV was a significant independent predictor of recurrence of cervical cancer (p = 0.027). Patients with an MTV of >20 cm³ had a significantly reduced disease-free survival compared with patients with an MTV ≤ 20 cm³ (p = 0.029). The correlation of the MTV with traditional prognostic factors showed significantly higher values in patients that were lymph node (LN) metastasis positive (p = 0.028) and parametrial invasion positive (p = 0.022). The MTV significantly differed among the groups according to tumor differentiation (p = 0.0319) and FIGO stage (p = 0.001).

Conclusion

The MTV measured by FDG-PET was an independent prognostic factor for tumor recurrence in patients with stage IA–IIB cervical cancer. These findings must be confirmed by large population based prospective studies.