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103. Novel Approach Identifies SNPs in SLC2A10 and KCNK9 with Evidence for Parent-of-Origin Effect on Body Mass Index

Author

Hoggart, C, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, J, Teumer, A, Winkler, T, Tšernikova, N, Luan, J, Mihailov, E, Ehret, G, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, P, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, D, Hayward, C, Lopez, M, Franke, L, Russo, A, Heid, I, Salvi, E, Vendantam, S, Arking, D, Boerwinkle, E, Chambers, J, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, J, Porteous, D, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, BRAMBILLA, PAOLO, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hebebrand, J, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Peters, A, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Cusi, D, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Metspalu, A, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Vollenweider, P, Wallaschofski, H, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Scherag, A, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Moradpour, D, Iranzo, A, Kemp, J, Lammers, G, Aubert, V, Heim, M, Peraita Adrados, R, Santamaria, J, Negro, F, Schmidt, C, Scott, R, Strauch, K, Völzke, H, Yuan, W, Bell, J, Chakravarti, A, Kooner, J, Matullo, G, Whitfield, J, Paccaud, F, Bergmann, S, Beckmann, J, Tafti, M, Hastie, N, Bochud, M, Da Smith, G, Rousson, V, Rivolta, C, Kutalik, Z., Stem Cell Aging Leukemia and Lymphoma (SALL), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Biological Psychology, EMGO+ - Lifestyle, Overweight and Diabetes, Hoggart, Clive J, Venturini, Giulia, Mangino, Massimo, Gomez, Felicia, Benyamin, Beben, Kutalik, Zoltan, Generation Scotland Consortium, GIANT Consortium, LifeLines Cohort study, Cardiology, Vascular Medicine, Plastic, Reconstructive and Hand Surgery, Amsterdam Cardiovascular Sciences, Medical Research Council (MRC), Psychiatry, EMGO - Lifestyle, overweight and diabetes, Haartman Institute (-2014), Transplantation Laboratory, Luan, Jian'an [0000-0003-3137-6337], Wareham, Nicholas [0000-0003-1422-2993], Apollo - University of Cambridge Repository, Hoggart, Cj, Venturini, G, Mangino, M, Gomez, F, Ascari, G, Zhao, Jh, Teumer, A, Winkler, Tw, Tšernikova, N, Luan, J, Mihailov, E, Ehret, Gb, Zhang, W, Lamparter, D, Esko, T, Macé, A, Rüeger, S, Bochud, Py, Barcella, M, Dauvilliers, Y, Benyamin, B, Evans, Dm, Hayward, C, Lopez, Mf, Franke, L, Russo, A, Heid, Im, Salvi, E, Vendantam, S, Arking, De, Boerwinkle, E, Chambers, Jc, Fiorito, G, Grallert, H, Guarrera, S, Homuth, G, Huffman, Je, Porteous, D, GENERATION SCOTLAND, Consortium, LIFELINES COHORT, Study, Giant, Consortium, Manunta, Paolo, Moradpour, D, Iranzo, A, Hebebrand, J, Kemp, Jp, Lammers, Gj, Aubert, V, Heim, Mh, Martin, Ng, Montgomery, Gw, PERAITA ADRADOS, R, Santamaria, J, Negro, F, Schmidt, Co, Scott, Ra, Spector, Td, Strauch, K, Völzke, H, Wareham, Nj, Yuan, W, Bell, Jt, Chakravarti, A, Kooner, J, Peters, A, Matullo, G, Wallaschofski, H, Whitfield, Jb, Paccaud, F, Vollenweider, P, Bergmann, S, Beckmann, J, Tafti, M, Hastie, Nd, Cusi, D, Bochud, M, Frayling, Tm, Metspalu, A, Jarvelin, Mr, Scherag, A, Smith, Gd, Borecki, Ib, Rousson, V, Hirschhorn, Jn, Rivolta, C, Loos, Rj, Kutalik, Z., Hoggart, C, Zhao, J, Winkler, T, Ehret, G, Bochud, P, Evans, D, Lopez, M, Heid, I, Arking, D, Chambers, J, Huffman, J, Berg, J, Blackwood, D, Campbell, H, Cavanagh, J, Connell, J, Connor, M, Cunningham Burley, S, Deary, I, Dominiczak, A, Ellis, P, Fitzpatrick, B, Ford, I, Gertz, R, Grau, A, Haddow, G, Jackson, C, Kerr, S, Lindsay, R, Mcgilchrist, M, Mcintyre, D, Morris, A, Morton, R, Muir, W, Murray, G, Palmer, C, Pell, J, Philp, A, Porteous, M, Procter, R, Ralston, S, Reid, D, Sinnott, R, Smith, B, St Clair, D, Sullivan, F, Sweetland, M, Ure, J, Watt, G, Wolf, R, Wright, A, de Bakker, P, Bültmann, U, Geleijnse, M, Harst, P, Koppelman, G, Rosmalen, J, van Rossum, L, Smidt, H, Swertz, M, Stolk, R, Alizadeh, B, de Boer, R, Boezen, H, Bruinenberg, M, van der Harst, P, Hillege, H, van der Klauw, M, Navis, G, Ormel, J, Postma, D, Slaets, J, Snieder, H, Wolffenbuttel, B, Wijmenga, C, Berndt, S, Gustafsson, S, Mägi, R, Ganna, A, Wheeler, E, Feitosa, M, Justice, A, Monda, K, Croteau Chonka, D, Day, F, Fall, T, Ferreira, T, Gentilini, D, Jackson, A, Randall, J, Vedantam, S, Willer, C, Wood, A, Workalemahu, T, Hu, Y, Lee, S, Liang, L, Lin, D, Min, J, Neale, B, Thorleifsson, G, Yang, J, Albrecht, E, Amin, N, Bragg Gresham, J, Cadby, G, den Heijer, M, Eklund, N, Fischer, K, Goel, A, Hottenga, J, Jarick, I, Johansson, A, Johnson, T, Kanoni, S, Kleber, M, König, I, Kristiansson, K, Kutalik, Z, Lamina, C, Lecoeur, C, Li, G, Mcardle, W, Medina Gomez, C, Müller Nurasyid, M, Ngwa, J, Nolte, I, Paternoster, L, Pechlivanis, S, Perola, M, Peters, M, Preuss, M, Rose, L, Shi, J, Shungin, D, Smith, A, Strawbridge, R, Surakka, I, Trip, M, Tyrer, J, Van Vliet Ostaptchouk, J, Vandenput, L, Waite, L, Absher, D, Asselbergs, F, Atalay, M, Attwood, A, Balmforth, A, Basart, H, Beilby, J, Bonnycastle, L, Brambilla, P, Chasman, D, Chines, P, Collins, F, Cookson, W, de Faire, U, de Vegt, F, Dei, M, Dimitriou, M, Edkins, S, Estrada, K, Farrall, M, Ferrario, M, Ferrières, J, Frau, F, Gejman, P, Grönberg, H, Gudnason, V, Hall, A, Hall, P, Hartikainen, A, Heard Costa, N, Heath, A, Hu, F, Hunt, S, Hyppönen, E, Iribarren, C, Jacobs, K, Jansson, J, Jula, A, Kähönen, M, Kathiresan, S, Kee, F, Khaw, K, Kivimaki, M, Koenig, W, Kraja, A, Kumari, M, Karikuulasmaa, N, Kuusisto, J, Laitinen, J, Lakka, T, Langenberg, C, Launer, L, Lind, L, Lindström, J, Liu, J, Liuzzi, A, Lokki, M, Lorentzon, M, Madden, P, Magnusson, P, Manunta, P, Marek, D, März, W, Leach, I, Mcknight, B, Medland, S, Milani, L, Montgomery, G, Mooser, V, Mühleisen, T, Munroe, P, Musk, A, Narisu, N, Nicholson, G, Nohr, E, Ong, K, Oostra, B, Palotie, A, Peden, J, Pedersen, N, Polasek, O, Pouta, A, Pramstaller, P, Prokopenko, I, Pütter, C, Radhakrishnan, A, Raitakari, O, Rendon, A, Rivadeneira, F, Rudan, I, Saaristo, T, Sambrook, J, Sanders, A, Sanna, S, Saramies, J, Schipf, S, Schreiber, S, Schunkert, H, Shin, S, Signorini, S, Sinisalo, J, Skrobek, B, Soranzo, N, Stancakova, A, Stark, K, Stephens, J, Stirrups, K, Stumvoll, M, Swift, A, Theodoraki, E, Thorand, B, Tregouet, D, Tremoli, E, Van der Klauw, M, van Meurs, J, Vermeulen, S, Viikari, J, Virtamo, J, Vitart, V, Waeber, G, Wang, Z, Widen, E, Wild, S, Willemsen, G, Winkelmann, B, Witteman, J, Wong, A, Zillikens, M, Amouyel, P, Boehm, B, Boomsma, D, Caulfield, M, Chanock, S, Cupples, L, Dedoussis, G, Erdmann, J, Eriksson, J, Franks, P, Froguel, P, Gieger, C, Gyllensten, U, Hamsten, A, Harris, T, Hengstenberg, C, Hicks, A, Hingorani, A, Hinney, A, Hofman, A, Hovingh, K, Hveem, K, Illig, T, Jarvelin, M, Jöckel, K, Keinanen Kiukaanniemi, S, Kiemeney, L, Kuh, D, Laakso, M, Lehtimäki, T, Levinson, D, Martin, N, Nieminen, M, Njølstad, I, Ohlsson, C, Oldehinkel, A, Ouwehand, W, Palmer, L, Penninx, B, Power, C, Province, M, Psaty, B, Qi, L, Rauramaa, R, Ridker, P, Ripatti, S, Salomaa, V, Samani, N, Sørensen, T, Spector, T, Stefansson, K, Tönjes, A, Tuomilehto, J, Uitterlinden, A, Uusitupa, M, Wareham, N, Watkins, H, Wichmann, H, Wilson, J, Abecasis, G, Assimes, T, Barroso, I, Boehnke, M, Borecki, I, Deloukas, P, Fox, C, Frayling, T, Groop, L, Haritunian, T, Hunter, D, Kaplan, R, Karpe, F, Miriammoffatt, N, Mohlke, K, O'Connell, J, Pawitan, Y, Schadt, E, Schlessinger, D, Steinthorsdottir, V, Strachan, D, Thorsteinsdottir, U, van Duijn, C, Visscher, P, Di Blasio, A, Hirschhorn, J, Lindgren, C, Meyre, D, Mccarthy, M, Speliotes, E, North, K, Loos, R, Ingelsson, E, Kemp, J, Lammers, G, Heim, M, Peraita Adrados, R, Schmidt, C, Scott, R, Bell, J, Whitfield, J, Hastie, N, and Da Smith, G

Subjects
Epigenomics, Male, Netherlands Twin Register (NTR), body mass index, gene, SNP, Cancer Research, BIO/12 - BIOCHIMICA CLINICA E BIOLOGIA MOLECOLARE CLINICA, Potassium Channels, Glucose Transport Proteins, Facilitative, Medizin, Genome-wide association study, CHILDREN, ddc:616.07, FAMILIES, Body Mass Index, 0302 clinical medicine, Polymorphism (computer science), Genotype, LifeLines Cohort study, GENETICS & HEREDITY, Tandem Pore Domain, Genetics (clinical), ASSOCIATIONS, ddc:616, Genetics, 0303 health sciences, QUANTITATIVE TRAIT LOCI, Ecology, Genomics, Single Nucleotide, Generation Scotland Consortium, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], OBESITY, Physical Sciences, KCNK9 protein, Epigenetics, Female, ALCOHOLISM, Glucose Transport Proteins, Life Sciences & Biomedicine, Statistics (Mathematics), Human, Research Article, VARIANCES, Adult, PENETRANCE, GENES, lcsh:QH426-470, Evolution, European Continental Ancestry Group, Single-nucleotide polymorphism, Biostatistics, Biology, Quantitative trait locus, Polymorphism, Single Nucleotide, White People, 03 medical and health sciences, Genomic Imprinting, Potassium Channels, Tandem Pore Domain, Genetic, Behavior and Systematics, SDG 3 - Good Health and Well-being, Genetic linkage, GIANT Consortium, Genome-Wide Association Studies, Humans, Genetic Predisposition to Disease, Statistical Methods, Allele, Polymorphism, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Gene Expression Regulation, Genome-Wide Association Study, Obesity, 030304 developmental biology, 0604 Genetics, Science & Technology, LINKAGE ANALYSIS, SLC2A10 protein, Biology and Life Sciences, Computational Biology, Facilitative, Genome Analysis, Ecology, Evolution, Behavior and Systematic, lcsh:Genetics, Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5], 3111 Biomedicine, Genomic imprinting, Mathematics, 030217 neurology & neurosurgery, Developmental Biology
Abstract

The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of ∼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (beta = 0.11 (SD), P, Author Summary Large genetic association studies have revealed many genetic factors influencing common traits, such as body mass index (BMI). These studies assume that the effect of genetic variants is the same regardless of whether they are inherited from the mother or the father. In our study, we have developed a new approach that allows us to investigate variants whose impact depends on their parental origin (parent-of-origin effects), in unrelated samples when the parental origin cannot be inferred. This is feasible because at genetic markers at which such effects occur there is increased variability of the trait among individuals who inherited different genetic codes from their mother and their father compared to individuals who inherited the same genetic code from both parents. We applied this methodology to discover genetic markers with parent-of-origin effects (POEs) on BMI. This resulted in six candidate markers showing strong POE association. We then attempted to replicate the POE effects of these markers in family studies (where one can infer the parental origin of the inherited variants). Two of our candidates showed significant association in the family studies, the paternal and maternal effects of these markers were in the opposite direction.

Published
2014
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104. Strategies to improve recruitment to research studies

Author

Treweek, S, Pitkethly, M, Cook, JAC, Kjeldstrom, M, Taskil, T, Johansen, M, Sullivan, F, Wilson, S, Jackson, C, Jones, R, and Mitchell, E

Abstract

BACKGROUND: Recruiting participants to trials can be extremely difficult. Identifying strategies that improve trial recruitment would benefit both trialists and health research. OBJECTIVES: To quantify the effects of strategies to improve recruitment of participants to randomised controlled trials. SEARCH STRATEGY: We searched the Cochrane Methodology Review Group Specialised Register - CMR (The Cochrane Library (online) Issue 1 2008) (searched 20 February 2008); MEDLINE, Ovid (1950 to date of search) (searched 06 May 2008); EMBASE, Ovid (1980 to date of search) (searched 16 May 2008); ERIC, CSA (1966 to date of search) (searched 19 March 2008); Science Citation Index Expanded, ISI Web of Science (1975 to date of search) (searched 19 March 2008); Social Sciences Citation Index, ISI Web of Science (1975 to date of search) (searched 19 March 2008); and National Research Register (online) (Issue 3 2007) (searched 03 September 2007); C2-SPECTR (searched 09 April 2008). We also searched PubMed (25 March 2008) to retrieve "related articles" for 15 studies included in a previous version of this review. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of methods to increase recruitment to randomised controlled trials. This includes non-healthcare studies and studies recruiting to hypothetical trials. Studies aiming to increase response rates to questionnaires or trial retention, or which evaluated incentives and disincentives for clinicians to recruit patients were excluded. DATA COLLECTION AND ANALYSIS: Data were extracted on the method evaluated; country in which the study was carried out; nature of the population; nature of the study setting; nature of the study to be recruited into; randomisation or quasi-randomisation method; and numbers and proportions in each intervention group. We used risk ratios and their 95% confidence intervals to describe the effects in individual trials, and assessed heterogeneity of these ratios between trials. MAIN RESULTS: We identified 27 eligible trials with more than 26,604 participants. There were 24 studies involving interventions aimed directly at trial participants, while three evaluated interventions aimed at people recruiting participants. All studies were in health care. Some interventions were effective in increasing recruitment: telephone reminders to non-respondents (RR 2.66, 95% CI 1.37 to 5.18), use of opt-out, rather than opt-in, procedures for contacting potential trial participants (RR 1.39, 95% CI 1.06 to 1.84) and open designs where participants know which treatment they are receiving in the trial (RR 1.25, 95% CI 1.18 to 1.34). However, some of these strategies have disadvantages, which may limit their widespread use. For example, opt-out procedures are controversial and open designs are by definition unblinded. The effects of many other recruitment strategies are unclear; examples include the use of video to provide trial information to potential participants and modifying the training of recruiters. Many studies looked at recruitment to hypothetical trials and it is unclear how applicable these results are to real trials. AUTHORS' CONCLUSIONS: Trialists can increase recruitment to their trials by using the strategies shown to be effective in this review: telephone reminders; use of opt-out, rather than opt-in; procedures for contacting potential trial participants and open designs. Some strategies (e.g. open trial designs) need to be considered carefully before use because they also have disadvantages. For example, opt-out procedures are controversial and open designs are by definition unblinded.

Published
2016
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106. Detection in blood of autoantibodies to tumour antigens as a case-finding method in lung cancer using the EarlyCDT®-Lung Test (ECLS): study protocol for a randomized controlled trial

Author

Sullivan, F. M., primary, Farmer, Eoghan, additional, Mair, Frances S., additional, Treweek, Shaun, additional, Kendrick, Denise, additional, Jackson, Cathy, additional, Robertson, Chris, additional, Briggs, Andrew, additional, McCowan, Colin, additional, Bedford, Laura, additional, Young, Ben, additional, Vedhara, Kavita, additional, Gallant, Stephanie, additional, Littleford, Roberta, additional, Robertson, John, additional, Sewell, Herb, additional, Dorward, Alistair, additional, Sarvesvaran, Joseph, additional, and Schembri, Stuart, additional

Published
2017
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116. The development of a potent, KDR/VEGFR2-sparing RET kinase inhibitor for treating patients with RET-dependent cancers

Author

Brandhuber, B., primary, Haas, J., additional, Tuch, B., additional, Ebata, K., additional, Bouhana, K., additional, McFaddin, E., additional, Williams, L., additional, Winski, S., additional, Brown, E., additional, Burkhard, M., additional, Nanda, N., additional, Hamor, R., additional, Sullivan, F., additional, Hanson, L., additional, Morales, T., additional, Vigers, G., additional, Wallace, R.D., additional, Blake, J., additional, Andrews, S., additional, and Rothenberg, S.M., additional

Published
2016
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117. The development of LOXO-195, a second generation TRK kinase inhibitor that overcomes acquired resistance to 1st generation inhibitors observed in patients with TRK-fusion cancers

Author

Blake, J., primary, Kolakowski, G.R., additional, Tuch, B., additional, Ebata, K., additional, Brandhuber, B., additional, Winski, S., additional, Bouhana, K., additional, Nanda, N., additional, Wu, W.I., additional, Parker, A., additional, Hamor, R., additional, Larsen, P.D., additional, Sullivan, F., additional, DeWolf, W., additional, Neitzel, N., additional, Wollenberg, L., additional, Andrews, S., additional, and Rothenberg, S.M., additional

Published
2016
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119. S132 A randomised controlled study of lung cancer screening in scotland using the detection of autoantibodies to tumour antigens (earlycdt-lung test)

Author

Dorward, A, primary, Mair, F Frances, additional, Sullivan, F, additional, Vedhara, K, additional, Kendrick, D, additional, Treweek, S, additional, McCowan, C, additional, McConnachie, A, additional, Sproule, M, additional, Briggs, A, additional, Ritchie, L, additional, Milroy, R, additional, Taylor, T, additional, Littleford, R, additional, Brewster, D, additional, and Schembri, S, additional

Published
2016
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120. ‘Thinking that somebody's going to delay [a tonsillectomy] for one to two years is quite horrifying really’: a qualitative feasibility study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 2)

Author

McSweeney, L.A., primary, O'Hara, J.T., additional, Rousseau, N.S., additional, Stocken, D.D., additional, Sullivan, F., additional, Vale, L., additional, Wilkes, S., additional, Wilson, J.A., additional, and Haighton, C.A., additional

Published
2016
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122. Defining a Standard Set of Patient-centered Outcomes for Men with Localized Prostate Cancer

Author

Martin, N E, Massey, L, Stowell, C, Bangma, C.H., Briganti, A, Bill-Axelson, A, Blute, M, Catto, J, Chen, R C, D'Amico, AV, Feick, G, Fitzpatrick, JM, Frank, S J, Froehner, M, Frydenberg, M, Glaser, A, Graefen, M, Hamstra, D, Kibel, A, Mendenhall, N, Moretti, K, Ramon, J, Roos, I, Sandler, H, Sullivan, F J, Swanson, D, Tewari, A, Vickers, A, Wiegel, T, Huland, H, Martin, N E, Massey, L, Stowell, C, Bangma, C.H., Briganti, A, Bill-Axelson, A, Blute, M, Catto, J, Chen, R C, D'Amico, AV, Feick, G, Fitzpatrick, JM, Frank, S J, Froehner, M, Frydenberg, M, Glaser, A, Graefen, M, Hamstra, D, Kibel, A, Mendenhall, N, Moretti, K, Ramon, J, Roos, I, Sandler, H, Sullivan, F J, Swanson, D, Tewari, A, Vickers, A, Wiegel, T, and Huland, H

Published
2015

124. Irish neurological association: Proceedings of the 22nd Annual Meeting of the Irish Neurological Association, 5–6th June, 1986

Author

Farrell, M. A., Ebers, G. C., Anderson, C., Keohane, C., Kennedy, Peter G. E., Fok-Seang, J., Chee, C. P., Fannin, T. F., Bailey, Ian C., McNeill, A., Gordon, D., Gibson, J. M., Lyttle, J. A., Archbold, G. P. R., O’Laoire, S. A., Tamas, L., Young, S., Briscoe, D. M., McMenamin, J. B., O’Donohoe, N. V., Hawkins, S. A., Nevin, N. C., Harding, A. E., Haller, Alice, McClelland, R. J., Eyre, D., Calvert, G. J., Lumsden, J., Dusoir, Hazel, Casey, C., Murphy, S., Broe, P., Bouchier-Hayes, D., Lorigan, G., Doorly, T., Toland, J., Patterson, Victor, Lyttle, Jo, Alderdice, Ruth, Haire, Margaret, Sullivan, F., Hutchinson, H., and Moore, R.

Published
1987
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125. Abstracts of papers 1966 Short Course Michigan State University August 29 to September 1, 1966

Author

Good, R. D., Bates, R. W., Sullivan, F. E., Hutchins, R. P., Rich, A. D., Zehnder, C. T., McMichael, C. E., Ralston, E. L., Allen, R. R., Eijadi, M., Going, L. H., Hoerr, C. W., Latondress, E. G., Wiedermann, L. H., Weiss, T. J., Erickson, D. R., Friestone, David, Maher, G. R., Sherwin, E. R., Dutton, H. J., Welch, E. S., Andrews, H. P., Thomas, R., MacDonald, Ira A., Truax, H. M., and Goldman, J. M.

Published
1966
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126. Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study

Author

Livingstone, S.J., Looker, H.C., Hothersall, E.J., Wild, S.H., Lindsay, R.S., Chalmers, J., Cleland, S., Leese, G.P., McKnight, J., Morris, A.D., Pearson, D.W.M., Peden, N.R., Petrie, J.R., Philip, S., Sattar, N., Sullivan, F., and Colhoun, H.M.

Abstract

Background: Randomized controlled trials have shown the importance of tight glucose control in type 1 diabetes (T1DM), but few recent studies have evaluated the risk of cardiovascular disease (CVD) and all-cause mortality among adults with T1DM. We evaluated these risks in adults with T1DM compared with the non-diabetic population in a nationwide study from Scotland and examined control of CVD risk factors in those with T1DM.\ud \ud Methods and Findings: The Scottish Care Information-Diabetes Collaboration database was used to identify all people registered with T1DM and aged ≥20 years in 2005–2007 and to provide risk factor data. Major CVD events and deaths were obtained from the national hospital admissions database and death register. The age-adjusted incidence rate ratio (IRR) for CVD and mortality in T1DM (n = 21,789) versus the non-diabetic population (3.96 million) was estimated using Poisson regression. The age-adjusted IRR for first CVD event associated with T1DM versus the non-diabetic population was higher in women (3.0: 95% CI 2.4–3.8, p\ud \ud Conclusions: Although the relative risks for CVD and total mortality associated with T1DM in this population have declined relative to earlier studies, T1DM continues to be associated with higher CVD and death rates than the non-diabetic population. Risk factor management should be improved to further reduce risk but better treatment approaches for achieving good glycaemic control are badly needed.

Published
2012

127. Demodex-Associated Bacillus Proteins Induce an Aberrant Wound Healing Response in a Corneal Epithelial Cell Line: Possible Implications for Corneal Ulcer Formation in Ocular Rosacea

Author

O Reilly, N., Gallagher, C., Reddy Katikireddy, K., Clynes, M., O Sullivan, F., and Kevin Kavanagh

Subjects
Biology
Abstract

PURPOSE. The aim of the work presented here was to establish the response of a corneal epithelial cell line (hTCEpi) to protein extracted from a bacterium (Bacillus oleronius) previously isolated from a Demodex mite from a rosacea patient. METHODS. The response of the corneal epithelial cell line to Bacillus proteins was measured in terms of alterations in cell migration and invasiveness. Changes in the expression of metalloproteinase genes and proteins were also assessed. RESULTS. The results indicated increased cell migration (14.5- fold, P ¼ 0.001) as measured using 8-lm PET inserts (BD Falcon) in a transwell assay and invasiveness (1.7-fold, P ¼ 0.003) as measured using 8-lm Matrigel (BD Biocoat) invasion inserts in a 24-well plate assay format, following exposure to the Bacillus proteins. Cells exposed to the Bacillus protein showed a dose-dependent increase in expression of genes coding for matrix metalloprotease (MMP)-3 (61-fold) and MPP-9 (301-fold). This dose-dependent increase in gene expression was also reflected in elevated levels of MMP-9 protein (1.34- fold, P ¼ 0.033) and increased matrix metalloprotease activity (1.96-fold, P¼0.043) being present in the culture supernatant. Cells also displayed reduced levels of b-integrin (1.25-fold, P ¼ 0.01), indicative of increased motility and elevated levels of vinculin (2.7-fold, P ¼ 0.0009), suggesting altered motility. CONCLUSIONS. The results indicate that exposure of corneal epithelial cells to Bacillus proteins results in an aberrant wound healing response as visualized using a scratch wound assay. These results suggest a possible link between the high density of Demodex mites on the eyelashes of ocular rosacea patients and the development of corneal ulcers. (Invest Ophthalmol Vis Sci. 2012;53:3250–3259) DOI:10.1167/ iovs.11-9295

Published
2012

135. Proteomic screening of glucose-responsive and glucose non-reponsive MIN-6 beta cells reveals differential expression of protein involved in protein folding, secretion and oxidative stress

Author

Dowling, P., O´Driscoll, L., O´Sullivan, F., Dowd, A., Henry, M., Jeppesen, Per Bendix, Meleady, P., and Clynes, M

Subjects
Diabetes
Abstract

The glucose-sensitive insulin-secretion (GSIS) phenotype is relatively unstable in long-term culture of beta cells. The purpose of this study was to investigate relative changes in the proteome between glucose-responsive (low passage) and glucose non-responsive (high passage) murine MIN-6 pancreatic beta cells. The 2D-DIGE and subsequent DeCyder analysis detected 3351 protein spots in the pH range of 4-7. Comparing MIN-6(H) to MIN-6(L) and using a threshold of 1.2-fold, the number of proteins with a decrease in expression level was 152 (4.5%), similar was 3140 (93.7%) and increased 59 (1.8%). From the differentially expressed proteins identified in this study, groups of proteins associated with the endoplasmic reticulum (ER) and proteins involved in oxidative stress were found to be significantly decreased in the high-passage (H passage) cells. These proteins included endoplasmic reticulum protein 29 (ERp29); 78-kDa glucose-related protein, (GRP78); 94-kDa glucose-related protein (GRP94); protein disulphide isomerase; carbonyl reductase 3; peroxidoxin 4 and superoxide dismutase 1. These results suggest that non-GSIS MIN-6 cells do not have the same ability/capacity of glucose-responsive MIN-6 cells to successfully fold, modify or secrete proteins and counteract the problems associated with oxidative stress

Published
2006

137. 'Thinking that somebody's going to delay [a tonsillectomy] for one to two years is quite horrifying really': a qualitative feasibility study for the NAtional Trial of Tonsillectomy IN Adults (NATTINA Part 2).

Author

McSweeney, L.A., O'Hara, J.T., Rousseau, N.S., Stocken, D.D., Sullivan, F., Vale, L., Wilkes, S., Wilson, J.A., and Haighton, C.A.

Subjects
TONSILLECTOMY complications, TONSILLECTOMY, SURGERY, DISEASE management, HEALTH services administration, PHYSIOLOGY
Abstract

Objectives Level one evidence on the value of adult tonsillectomy versus non-surgical management remains scarce. Before embarking on a costly national randomised controlled trial, it is essential to establish its feasibility. Design Feasibility study with in-depth qualitative and cognitive interviews. Setting ENT staff and patients were recruited from nine hospital centres across England and Scotland. Participants Patients who were referred for tonsillectomy ( n = 15), a convenience sample of general practitioners ( n = 11) and ear, nose and throat staff ( n = 22). Main outcome measures To ascertain whether ear, nose and throat staff would be willing to randomise patients to the treatment arms., To assess general practitioners' willingness to refer patients to the NAtional Trial of Tonsillectomy IN Adults (NATTINA) centres., To assess patients' willingness to be randomised and the acceptability of the deferred surgery treatment arm., To ascertain whether the study could progress to the pilot trial stage., Results Ear, nose and throat staff and general practitioners were willing to randomise patients to the proposed NATTINA. Not all ENT staff were in equipoise concerning the treatment pathways. Patients were reluctant to be randomised into the deferred surgery group if they had already waited a substantial time before being referred. Conclusions Findings suggest that the NATTINA may not be feasible. Proposed methods could not be realistically assessed without a pilot trial. Due to the importance of the question, as evidenced by NATTINA clinicians, and strong support from ENT staff, the pilot trial proceeded, with modifications. [ABSTRACT FROM AUTHOR]

Published
2017
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142. A Validated Logistic Regression Model to Identify Coronary Heart Disease patients (CHD) within Primary Care Databases in the United Kingdom

Author

Krish Thiru, Peter Donnan, and Sullivan, F.

Subjects
Adult, Male, Medical Records Systems, Computerized, Primary Health Care, Age Factors, Information Storage and Retrieval, Coronary Disease, Article, United Kingdom, Logistic Models, Sex Factors, Databases as Topic, ROC Curve, Vocabulary, Controlled, Humans, Female, Registries
Abstract

We established the optimal search strategy for identifying coronary heart disease (CHD) patients within the Electronic Patient Record (EPR) of 'paperless' family practices in the UK. Multiple logistic regression modelling (MLRM) and Receiver Operating Characteristic (ROC) curves were used to develop the query. The selected search strategy was validated at 2 additional paperless family practices.

Published
2003

144. Development and progress of Ireland's biobank network: Ethical, legal, and social implications (ELSI), Standardized documentation, sample and data release, and international perspective

Author

Mee, B., Gaffney, E., Glynn, S., Donatello, S., Carroll, P., Connolly, E., Mc Garrigle, S., Boyle, Terry, Flannery, D., Sullivan, F., McCormick, P., Griffin, M., Muldoon, C., Fay, J., O'Grady, T., Kay, E., Eustace, J., Burke, L., Sheikh, A., Finn, S., Flavin, R., Giles, F., Mee, B., Gaffney, E., Glynn, S., Donatello, S., Carroll, P., Connolly, E., Mc Garrigle, S., Boyle, Terry, Flannery, D., Sullivan, F., McCormick, P., Griffin, M., Muldoon, C., Fay, J., O'Grady, T., Kay, E., Eustace, J., Burke, L., Sheikh, A., Finn, S., Flavin, R., and Giles, F.

Abstract

Biobank Ireland Trust (BIT) was established in 2004 to promote and develop an Irish biobank network to benefit patients, researchers, industry, and the economy. The network commenced in 2008 with two hospital biobanks and currently consists of biobanks in the four main cancer hospitals in Ireland. The St. James's Hospital (SJH) Biobank coordinates the network. Procedures, based on ISBER and NCI guidelines, are standardized across the network. Policies and documents - Patient Consent Policy, Patient Information Sheet, Biobank Consent Form, Sample and Data Access Policy (SAP), and Sample Application Form have been agreed upon (after robust discussion) for use in each hospital. An optimum sequence for document preparation and submission for review is outlined. Once consensus is reached among the participating biobanks, the SJH biobank liaises with the Research and Ethics Committees, the Office of the Data Protection Commissioner, The National Cancer Registry (NCR), patient advocate groups, researchers, and other stakeholders. The NCR provides de-identified data from its database for researchers via unique biobank codes. ELSI issues discussed include the introduction of prospective consent across the network and the return of significant research results to patients. Only 4 of 363 patients opted to be re-contacted and re-consented on each occasion that their samples are included in a new project. It was decided, after multidisciplinary discussion, that results will not be returned to patients. The SAP is modeled on those of several international networks. Biobank Ireland is affiliated with international biobanking groups - Marble Arch International Working Group, ISBER, and ESBB. The Irish government continues to deliberate on how to fund and implement biobanking nationally. Meanwhile BIT uses every opportunity to promote awareness of the benefits of biobanking in events and in the media. Copyright © 2013, Mary Ann Liebert, Inc. 2013.

Published
2013

147. Developing and evaluating interventions to reduce inappropriate prescribing by general practitioners of antibiotics for upper respiratory tract infections: A randomised controlled trial to compare paper-based and web-based modelling experiments

Author

Treweek, S, Ricketts, IW, Francis, J, Eccles, M, Bonetti, D, Pitts, NB, MacLennan, G, Sullivan, F, Jones, C, Weal, M, Barnett, K, Treweek, S, Ricketts, IW, Francis, J, Eccles, M, Bonetti, D, Pitts, NB, MacLennan, G, Sullivan, F, Jones, C, Weal, M, and Barnett, K

Abstract

BACKGROUND: Much implementation research is focused on full-scale trials with little evidence of preceding modelling work. The Medical Research Council Framework for developing and evaluating complex interventions has argued for more and better theoretical and exploratory work prior to a trial as a means of improving intervention development. Intervention modelling experiments (IMEs) are a way of exploring and refining an intervention before moving to a full-scale trial. They do this by delivering key elements of the intervention in a simulation that approximates clinical practice by, for example, presenting general practitioners (GPs) with a clinical scenario about making a treatment decision. METHODS: The current proposal will run a full, web-based IME involving 250 GPs that will advance the methodology of IMEs by directly comparing results with an earlier paper-based IME. Moreover, the web-based IME will evaluate an intervention that can be put into a full-scale trial that aims to reduce antibiotic prescribing for upper respiratory tract infections in primary care. The study will also include a trial of email versus postal invitations to participate. DISCUSSION: More effective behaviour change interventions are needed and this study will develop one such intervention and a system to model and test future interventions. This system will be applicable to any situation in the National Health Service where behaviour needs to be modified, including interventions aimed directly at the public. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01206738.

Published
2011

150. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Author

Purcell, Shaun M., Wray, R, Stone, L, Visscher, M, O'Donovan, C, Sullivan, F, Sklar, Pamela, Ruderfer, M, McQuillin, Andrew, Morris, W, O'Dushlaine, T, Corvin, Aiden, Holmans, A, Macgregor, Stuart, Gurling, Hugh, Blackwood, R, Craddock, J, Gill, Michael, Hultman, Christina M., Kirov, K, Lichtenstein, Paul, Muir, J, Owen, J, Pato, N, Scolnick, M, St Clair, David, Williams, M, Georgieva, Lyudmila, Nikolov, Ivan, Norton, N, Williams, H, Toncheva, Draga, Milanova, Vihra, Thelander, F, Sullivan, Patrick, Kenny, Elaine, Quinn, M, Choudhury, Khalid, Datta, Susmita, Pimm, Jonathan, Thirumalai, Srinivasa, Puri, Vinay, Krasucki, Robert, Lawrence, Jacob, Quested, Digby, Bass, Nicholas, Crombie, Caroline, Fraser, Gillian, Kuan, Leh, Walker, Nicholas, McGhee, A, Pickard, Ben, Malloy, Pat, Maclean, W, Van Beck, Margaret, Pato, T, Medeiros, Helena, Middleton, Frank, Carvalho, Celia, Morley, Christopher, Fanous, Ayman, Conti, David, Knowles, A, Ferreira, Paz, Macedo, Antonio, Azevedo, Helena, Kirby, N, Ferreira, R, Daly, J, Chambert, Kimberly, Kuruvilla, Finny, Gabriel, B, Ardlie, Kristin, Moran, Jennifer L., Purcell, Shaun M., Wray, R, Stone, L, Visscher, M, O'Donovan, C, Sullivan, F, Sklar, Pamela, Ruderfer, M, McQuillin, Andrew, Morris, W, O'Dushlaine, T, Corvin, Aiden, Holmans, A, Macgregor, Stuart, Gurling, Hugh, Blackwood, R, Craddock, J, Gill, Michael, Hultman, Christina M., Kirov, K, Lichtenstein, Paul, Muir, J, Owen, J, Pato, N, Scolnick, M, St Clair, David, Williams, M, Georgieva, Lyudmila, Nikolov, Ivan, Norton, N, Williams, H, Toncheva, Draga, Milanova, Vihra, Thelander, F, Sullivan, Patrick, Kenny, Elaine, Quinn, M, Choudhury, Khalid, Datta, Susmita, Pimm, Jonathan, Thirumalai, Srinivasa, Puri, Vinay, Krasucki, Robert, Lawrence, Jacob, Quested, Digby, Bass, Nicholas, Crombie, Caroline, Fraser, Gillian, Kuan, Leh, Walker, Nicholas, McGhee, A, Pickard, Ben, Malloy, Pat, Maclean, W, Van Beck, Margaret, Pato, T, Medeiros, Helena, Middleton, Frank, Carvalho, Celia, Morley, Christopher, Fanous, Ayman, Conti, David, Knowles, A, Ferreira, Paz, Macedo, Antonio, Azevedo, Helena, Kirby, N, Ferreira, R, Daly, J, Chambert, Kimberly, Kuruvilla, Finny, Gabriel, B, Ardlie, Kristin, and Moran, Jennifer L.

Abstract

Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

Published
2009
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