Prenatal diagnosis of monogenic diseases, such as cystic fibrosis and ␤-thalassemia, is currently offered as part of public health programs. However, current methods based on chorionic villus sampling and amniocentesis for obtaining fetal genetic material pose a risk to the fetus. Since the discovery of cell-free fetal DNA in maternal plasma, the noninvasive prenatal assessment of paternally inherited traits or mutations has been achieved. Due to the presence of background maternal DNA, which interferes with the analysis of fetal DNA in maternal plasma, noninvasive prenatal diagnosis of maternally inherited mutations has not been possible. Here we describe a digital relative mutation dosage (RMD) approach that determines if the dosages of the mutant and wild-type alleles of a disease-causing gene are balanced or unbalanced in maternal plasma. When applied to the testing of women heterozygous for the CD41/42 (-CTTT) and hemoglobin E mutations on HBB, digital RMD allows the fetal genotype to be deduced. The diagnostic performance of digital RMD is dependent on interplay between the fractional fetal DNA concentration and number of DNA molecules in maternal plasma. To achieve fetal genotype diagnosis at lower volumes of maternal plasma, fetal DNA enrichment is desired. We thus developed a digital nucleic acid size selection (NASS) strategy that effectively enriches the fetal DNA without additional plasma sampling or experimental time. We show that digital NASS can work in concert with digital RMD to increase the proportion of cases with classifiable fetal genotypes and to bring noninvasive prenatal diagnosis of monogenic diseases closer to reality.digital PCR ͉ fetal DNA ͉ mass spectrometry ͉ microfluidics ͉ thalassemia

We explored children's early interpretation of numerals and linguistic number marking, in order to test the hypothesis (e.g., Carey (2004). Bootstrapping and the origin of concepts. Daedalus, 59-68) that children's initial distinction between one and other numerals (i.e., two, three, etc.) is bootstrapped from a prior distinction between singular and plural nouns. Previous studies have presented evidence that in languages without singular-plural morphology, like Japanese and Chinese, children acquire the meaning of the word one later than in singular-plural languages like English and Russian. In two experiments, we sought to corroborate this relation between grammatical number and integer acquisition within English. We found a significant correlation between children's comprehension of numerals and a large set of natural language quantifiers and determiners, even when controlling for effects due to age. However, we also found that 2-year-old children, who are just acquiring singular-plural morphology and the word one, fail to assign an exact interpretation to singular noun phrases (e.g., a banana), despite interpreting one as exact. For example, in a Truth-Value Judgment task, most children judged that a banana was consistent with a set of two objects, despite rejecting sets of two for the numeral one. Also, children who gave exactly one object for singular nouns did not have a better comprehension of numerals relative to children who did not give exactly one. Thus, we conclude that the correlation between quantifier comprehension and numeral comprehension in children of this age is not attributable to the singular-plural distinction facilitating the acquisition of the word one. We argue that quantifiers play a more general role in highlighting the semantic function of numerals, and that children distinguish between numerals and other quantifiers from the beginning, assigning exact interpretations only to numerals.

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