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2.
Epidemiol Psychiatr Sci ; 29: e37, 2019 05 15.
Article in English | MEDLINE | ID: mdl-31088588

ABSTRACT

AIM: Few personalised medicine investigations have been conducted for mental health. We aimed to generate and validate a risk tool that predicts adult attention-deficit/hyperactivity disorder (ADHD). METHODS: Using logistic regression models, we generated a risk tool in a representative population cohort (ALSPAC - UK, 5113 participants, followed from birth to age 17) using childhood clinical and sociodemographic data with internal validation. Predictors included sex, socioeconomic status, single-parent family, ADHD symptoms, comorbid disruptive disorders, childhood maltreatment, ADHD symptoms, depressive symptoms, mother's depression and intelligence quotient. The outcome was defined as a categorical diagnosis of ADHD in young adulthood without requiring age at onset criteria. We also tested Machine Learning approaches for developing the risk models: Random Forest, Stochastic Gradient Boosting and Artificial Neural Network. The risk tool was externally validated in the E-Risk cohort (UK, 2040 participants, birth to age 18), the 1993 Pelotas Birth Cohort (Brazil, 3911 participants, birth to age 18) and the MTA clinical sample (USA, 476 children with ADHD and 241 controls followed for 16 years from a minimum of 8 and a maximum of 26 years old). RESULTS: The overall prevalence of adult ADHD ranged from 8.1 to 12% in the population-based samples, and was 28.6% in the clinical sample. The internal performance of the model in the generating sample was good, with an area under the curve (AUC) for predicting adult ADHD of 0.82 (95% confidence interval (CI) 0.79-0.83). Calibration plots showed good agreement between predicted and observed event frequencies from 0 to 60% probability. In the UK birth cohort test sample, the AUC was 0.75 (95% CI 0.71-0.78). In the Brazilian birth cohort test sample, the AUC was significantly lower -0.57 (95% CI 0.54-0.60). In the clinical trial test sample, the AUC was 0.76 (95% CI 0.73-0.80). The risk model did not predict adult anxiety or major depressive disorder. Machine Learning approaches did not outperform logistic regression models. An open-source and free risk calculator was generated for clinical use and is available online at https://ufrgs.br/prodah/adhd-calculator/. CONCLUSIONS: The risk tool based on childhood characteristics specifically predicts adult ADHD in European and North-American population-based and clinical samples with comparable discrimination to commonly used clinical tools in internal medicine and higher than most previous attempts for mental and neurological disorders. However, its use in middle-income settings requires caution.


Subject(s)
Attention Deficit Disorder with Hyperactivity/epidemiology , Child Abuse/statistics & numerical data , Conduct Disorder/epidemiology , Depression/epidemiology , Intelligence , Single-Parent Family/statistics & numerical data , Social Class , Adolescent , Area Under Curve , Attention Deficit Disorder with Hyperactivity/psychology , Attention Deficit and Disruptive Behavior Disorders/epidemiology , Attention Deficit and Disruptive Behavior Disorders/psychology , Child , Cohort Studies , Conduct Disorder/psychology , Depression/psychology , Depressive Disorder , Female , Humans , Intelligence Tests , Logistic Models , Male , Mothers/psychology , Prospective Studies , Reproducibility of Results , Risk Assessment , Sex Factors , United Kingdom/epidemiology , Young Adult
3.
J Cell Biol ; 137(5): 1171-83, 1997 Jun 02.
Article in English | MEDLINE | ID: mdl-9166416

ABSTRACT

Type IV collagen in Caenorhabditis elegans is produced by two essential genes, emb-9 and let-2, which encode alpha1- and alpha2-like chains, respectively. The distribution of EMB-9 and LET-2 chains has been characterized using chain-specific antisera. The chains colocalize, suggesting that they may function in a single heterotrimeric collagen molecule. Type IV collagen is detected in all basement membranes except those on the pseudocoelomic face of body wall muscle and on the regions of the hypodermis between body wall muscle quadrants, indicating that there are major structural differences between some basement membranes in C. elegans. Using lacZ/green fluorescent protein (GFP) reporter constructs, both type IV collagen genes were shown to be expressed in the same cells, primarily body wall muscles, and some somatic cells of the gonad. Although the pharynx and intestine are covered with basement membranes that contain type IV collagen, these tissues do not express either type IV collagen gene. Using an epitope-tagged emb-9 construct, we show that type IV collagen made in body wall muscle cells can assemble into the pharyngeal, intestinal, and gonadal basement membranes. Additionally, we show that expression of functional type IV collagen only in body wall muscle cells is sufficient for C. elegans to complete development and be partially fertile. Since type IV collagen secreted from muscle cells only assembles into some of the basement membranes that it has access to, there must be a mechanism regulating its assembly. We propose that interaction with a cell surface-associated molecule(s) is required to facilitate type IV collagen assembly.


Subject(s)
Basement Membrane/chemistry , Caenorhabditis elegans/genetics , Collagen/genetics , Animals , Animals, Genetically Modified , Antibody Specificity , Blastomeres/cytology , Caenorhabditis elegans/chemistry , Caenorhabditis elegans/cytology , Collagen/analysis , Collagen/immunology , Fluorescent Antibody Technique , Gene Expression Regulation, Developmental/physiology , Muscles/chemistry , Muscles/cytology
4.
EMBO J ; 13(14): 3278-85, 1994 Jul 15.
Article in English | MEDLINE | ID: mdl-8045258

ABSTRACT

Type IV collagen forms a network that provides the major structural support of basement membranes. We have determined the nucleotide alterations and phenotypes of 17 mutant alleles of the Caenorhabditis elegans alpha 2(IV) collagen gene let-2. All 17 mutations are within the triple helical (Gly-X-Y) repeat domain of the molecule. Fifteen of the mutations are replacements of Gly-X-Y repeat glycines with aspartate, glutamate or arginine, and they cause a wide range of phenotypes. The mildest alleles are nearly wild-type at 15 and 20 degrees C but embryonic lethal at 25 degrees C, while the most severe allele is embryonic lethal at all three temperatures. Mutations resulting in severe phenotypes are generally located in areas of lower calculated thermal stability of the type IV collagen molecule. An alanine to threonine substitution at position X of a Gly-X-Y triplet immediately following an interruption results in a severe phenotype. This mutation is unusual because substitutions at positions X or Y have not generally been found to cause strong phenotypes in C. elegans or human collagens. An intron splice acceptor mutation causes a strict embryonic lethal phenotype, but does not completely abolish gene function. Pairs of independent mutations affect each of three glycines, indicating a non-random distribution of mutations in the molecule. It is suggested that this clustering results because many glycine substitutions may cause dominant lethal or sterile phenotypes.


Subject(s)
Basement Membrane/chemistry , Caenorhabditis elegans/genetics , Collagen/genetics , Genes, Helminth/genetics , Alleles , Amino Acid Sequence , Animals , Cold Temperature , Collagen/chemistry , Genetic Complementation Test , Glycine/genetics , Hot Temperature , Molecular Sequence Data , Phenotype , Point Mutation , RNA Splicing/genetics , Repetitive Sequences, Nucleic Acid/genetics , Structure-Activity Relationship
5.
J Cell Biol ; 123(1): 255-64, 1993 Oct.
Article in English | MEDLINE | ID: mdl-7691828

ABSTRACT

The nematode Caenorhabditis elegans has two type IV collagen genes homologous to the mammalian alpha 1(IV) and alpha 2(IV) collagen genes. We demonstrate by transgenic rescue of mutant animals that the genetic locus encoding the C. elegans alpha 2(IV) collagen gene is let-2 on the X chromosome. The most severe effect of mutations in let-2 is temperature-sensitive embryonic lethality. The embryonic lethal phenotype is similar to that seen in animals with mutations in the alpha 1(IV) collagen gene, emb-9. The sequence of the entire C. elegans alpha 2(IV) collagen gene is presented. Comparisons with mammalian type IV collagen sequences show high amino acid sequence conservation in the C-terminal NCl domain and of crosslinking residues (Cys and Lys) in the N-terminal 7S domain. RT-PCR analysis shows that transcripts of the C. elegans alpha 2(IV) collagen gene are alternatively spliced. Transcripts contain one of two mutually exclusive exons, exon 9 or 10. These exons encode very similar products, differing primarily in the sequence of a 9-10 amino acid Gly-X-Y interruption. The expression of these alternatively spliced alpha 2(IV) collagen transcripts is developmentally regulated. In embryos over 90% of the alpha 2(IV) collagen mRNA contains exon 9, while larval and adult RNAs contain 80-90% exon 10. This shift in expression of alternative alpha 2(IV) collagen transcripts suggests that C. elegans embryos may require a different form of alpha 2(IV) collagen than do larvae and adults.


Subject(s)
Alternative Splicing , Caenorhabditis elegans/genetics , Collagen/genetics , Genes, Helminth/genetics , Amino Acid Sequence , Animals , Animals, Genetically Modified , Base Sequence , Caenorhabditis elegans/embryology , Chromosome Mapping , Exons/genetics , Gene Expression Regulation , Genes, Lethal/genetics , Molecular Sequence Data , Polymerase Chain Reaction , RNA-Directed DNA Polymerase/metabolism , Sequence Analysis, DNA , Sequence Homology, Amino Acid , Transcription, Genetic , X Chromosome
6.
Plant Physiol ; 91(4): 1620-4, 1989 Dec.
Article in English | MEDLINE | ID: mdl-16667226

ABSTRACT

Light/dark modulation of the ribulose-5-phosphate kinase, NADP(+)-glyceraldehyde-3-phosphate dehydrogenase, and fructose- 1,6-bisphosphatase activity was measured in the developing primary leaf of barley (Hordeum vulgare L.) seedlings. Ribulose-5-phosphate kinase and NADP(+) -glyceraldehyde-3-phosphate dehydrogenase were fully light activated even at the earliest developmental stage sampled. In contrast, light modulation of fructose- 1,6-bisphosphatase exhibited a complex response to leaf developmental status. Light stimulation of fructose- 1,6-bisphosphatase activity (measured at pH 8.0) increased progressively during leaf development. On the other hand, acid fructose- 1,6-bisphosphatase activity (measured at pH 6.0) was inhibited by light, and this light inhibition was greater in the base of the leaf than in the tip of the leaf.

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