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3. Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study.

Author

Mellemkjaer, L, Dahl, C, Olsen, JH, Bertelsen, L, Guldberg, P, Christensen, J, Børresen-Dale, A-L, Stovall, M, Langholz, B, Bernstein, L, Lynch, CF, Malone, KE, Haile, RW, Andersson, M, Thomas, DC, Concannon, P, Capanu, M, Boice, JD, WECARE Study Collaborative Group, and Bernstein, JL

Subjects
WECARE Study Collaborative Group, Humans, Breast Neoplasms, Protein-Serine-Threonine Kinases, SEER Program, Risk Factors, Case-Control Studies, Genotype, Germ-Line Mutation, Middle Aged, Female, Checkpoint Kinase 2, Oncology & Carcinogenesis, Oncology and Carcinogenesis, Public Health and Health Services
Abstract

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Published
2008

4. Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study

Author

Mellemkjær, L, Dahl, C, Olsen, JH, Bertelsen, L, Guldberg, P, Christensen, J, Børresen-Dale, A-L, Stovall, M, Langholz, B, Bernstein, L, Lynch, CF, Malone, KE, Haile, RW, Andersson, M, Thomas, DC, Concannon, P, Capanu, M, Boice, JD, The WECARE Study Collaborative Group, and Bernstein, JL

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Breast Cancer, Clinical Research, Prevention, Cancer, Genetics, Breast Neoplasms, Case-Control Studies, Checkpoint Kinase 2, Female, Genotype, Germ-Line Mutation, Humans, Middle Aged, Protein Serine-Threonine Kinases, Risk Factors, SEER Program, WECARE Study Collaborative Group, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis
Abstract

The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

Published
2008

5. Clinical characteristics with inflammation profiling of long COVID and association with 1-year recovery following hospitalisation in the UK: a prospective observational study

Author

Evans, RA, Leavy, OC, Richardson, M, Elneima, O, McCauley, HJC, Shikotra, A, Singapuri, A, Sereno, M, Saunders, RM, Harris, VC, Houchen-Wolloff, L, Aul, R, Beirne, P, Bolton, CE, Brown, JS, Choudhury, G, Diar-Bakerly, N, Easom, N, Echevarria, C, Fuld, J, Hart, N, Hurst, J, Jones, MG, Parekh, D, Pfeffer, P, Rahman, NM, Rowland-Jones, SL, Shah, AM, Wootton, DG, Chalder, T, Davies, MJ, De Soyza, A, Geddes, JR, Greenhalf, W, Greening, NJ, Heaney, LG, Heller, S, Howard, LS, Jacob, J, Jenkins, RG, Lord, JM, Man, WD-C, McCann, GP, Neubauer, S, Openshaw, PJM, Porter, JC, Rowland, MJ, Scott, JT, Semple, MG, Singh, SJ, Thomas, DC, Toshner, M, Lewis, KE, Thwaites, RS, Briggs, A, Docherty, AB, Kerr, S, Lone, NI, Quint, J, Sheikh, A, Thorpe, M, Zheng, B, Chalmers, JD, Ho, LP, Horsley, A, Marks, M, Poinasamy, K, Raman, B, Harrison, EM, Wain, LV, Brightling, CE, Abel, K, Adamali, H, Adeloye, D, Adeyemi, O, Adrego, R, Jimenez, LAA, Ahmad, S, Haider, NA, Ahmed, R, Ahwireng, N, Ainsworth, M, Al-Sheklly, B, Alamoudi, A, Ali, M, Aljaroof, M, All, AM, Allan, L, Allen, RJ, Allerton, L, Allsop, L, Almeida, P, Altmann, D, Corral, MA, Amoils, S, Anderson, D, Antoniades, C, Arbane, G, Arias, A, Armour, C, Armstrong, L, Armstrong, N, Arnold, D, Arnold, H, Ashish, A, Ashworth, A, Ashworth, M, Aslani, S, Assefa-Kebede, H, Atkin, C, Atkin, P, Aung, H, Austin, L, Avram, C, Ayoub, A, Babores, M, Baggott, R, Bagshaw, J, Baguley, D, Bailey, L, Baillie, JK, Bain, S, Bakali, M, Bakau, M, Baldry, E, Baldwin, D, Ballard, C, Banerjee, A, Bang, B, Barker, RE, Barman, L, Barratt, S, Barrett, F, Basire, D, Basu, N, Bates, M, Bates, A, Batterham, R, Baxendale, H, Bayes, H, Beadsworth, M, Beckett, P, Beggs, M, Begum, M, Bell, D, Bell, R, Bennett, K, Beranova, E, Bermperi, A, Berridge, A, Berry, C, Betts, S, Bevan, E, Bhui, K, Bingham, M, Birchall, K, Bishop, L, Bisnauthsing, K, Blaikely, J, Bloss, A, Bolger, A, Bonnington, J, Botkai, A, Bourne, C, Bourne, M, Bramham, K, Brear, L, Breen, G, Breeze, J, Bright, E, Brill, S, Brindle, K, Broad, L, Broadley, A, Brookes, C, Broome, M, Brown, A, Brown, J, Brown, M, Brown, V, Brown, CW, Brugha, T, Brunskill, N, Buch, M, Buckley, P, Bularga, A, Bullmore, E, Burden, L, Burdett, T, Burn, D, Burns, G, Burns, A, Busby, J, Butcher, R, Butt, A, Byrne, S, Cairns, P, Calder, PC, Calvelo, E, Carborn, H, Card, B, Carr, C, Carr, L, Carson, G, Carter, P, Casey, A, Cassar, M, Cavanagh, J, Chablani, M, Chambers, RC, Chan, F, Channon, KM, Chapman, K, Charalambou, A, Chaudhuri, N, Checkley, A, Chen, J, Cheng, Y, Chetham, L, Childs, C, Chilvers, ER, Chinoy, H, Chiribiri, A, Chong-James, K, Choudhury, N, Chowienczyk, P, Christie, C, Chrystal, M, Clark, D, Clark, C, Clarke, J, Clohisey, S, Coakley, G, Coburn, Z, Coetzee, S, Cole, J, Coleman, C, Conneh, F, Connell, D, Connolly, B, Connor, L, Cook, A, Cooper, B, Cooper, J, Cooper, S, Copeland, D, Cosier, T, Coulding, M, Coupland, C, Cox, E, Craig, T, Crisp, P, Cristiano, D, Crooks, MG, Cross, A, Cruz, I, Cullinan, P, Cuthbertson, D, Daines, L, Dalton, M, Daly, P, Daniels, A, Dark, P, Dasgin, J, David, A, David, C, Davies, E, Davies, F, Davies, G, Davies, GA, Davies, K, Dawson, J, Daynes, E, Deakin, B, Deans, A, Deas, C, Deery, J, Defres, S, Dell, A, Dempsey, K, Denneny, E, Dennis, J, Dewar, A, Dharmagunawardena, R, Dickens, C, Dipper, A, Diver, S, Diwanji, SN, Dixon, M, Djukanovic, R, Dobson, H, Dobson, SL, Donaldson, A, Dong, T, Dormand, N, Dougherty, A, Dowling, R, Drain, S, Draxlbauer, K, Drury, K, Dulawan, P, Dunleavy, A, Dunn, S, Earley, J, Edwards, S, Edwardson, C, El-Taweel, H, Elliott, A, Elliott, K, Ellis, Y, Elmer, A, Evans, D, Evans, H, Evans, J, Evans, R, Evans, RI, Evans, T, Evenden, C, Evison, L, Fabbri, L, Fairbairn, S, Fairman, A, Fallon, K, Faluyi, D, Favager, C, Fayzan, T, Featherstone, J, Felton, T, Finch, J, Finney, S, Finnigan, J, Finnigan, L, Fisher, H, Fletcher, S, Flockton, R, Flynn, M, Foot, H, Foote, D, Ford, A, Forton, D, Fraile, E, Francis, C, Francis, R, Francis, S, Frankel, A, Fraser, E, Free, R, French, N, Fu, X, Furniss, J, Garner, L, Gautam, N, George, J, George, P, Gibbons, M, Gill, M, Gilmour, L, Gleeson, F, Glossop, J, Glover, S, Goodman, N, Goodwin, C, Gooptu, B, Gordon, H, Gorsuch, T, Greatorex, M, Greenhaff, PL, Greenhalgh, A, Greenwood, J, Gregory, H, Gregory, R, Grieve, D, Griffin, D, Griffiths, L, Guerdette, A-M, Guio, BG, Gummadi, M, Gupta, A, Gurram, S, Guthrie, E, Guy, Z, Henson, HH, Hadley, K, Haggar, A, Hainey, K, Hairsine, B, Haldar, P, Hall, I, Hall, L, Halling-Brown, M, Hamil, R, Hancock, A, Hancock, K, Hanley, NA, Haq, S, Hardwick, HE, Hardy, E, Hardy, T, Hargadon, B, Harrington, K, Harris, E, Harrison, P, Harvey, A, Harvey, M, Harvie, M, Haslam, L, Havinden-Williams, M, Hawkes, J, Hawkings, N, Haworth, J, Hayday, A, Haynes, M, Hazeldine, J, Hazelton, T, Heeley, C, Heeney, JL, Heightman, M, Henderson, M, Hesselden, L, Hewitt, M, Highett, V, Hillman, T, Hiwot, T, Hoare, A, Hoare, M, Hockridge, J, Hogarth, P, Holbourn, A, Holden, S, Holdsworth, L, Holgate, D, Holland, M, Holloway, L, Holmes, K, Holmes, M, Holroyd-Hind, B, Holt, L, Hormis, A, Hosseini, A, Hotopf, M, Howard, K, Howell, A, Hufton, E, Hughes, AD, Hughes, J, Hughes, R, Humphries, A, Huneke, N, Hurditch, E, Husain, M, Hussell, T, Hutchinson, J, Ibrahim, W, Ilyas, F, Ingham, J, Ingram, L, Ionita, D, Isaacs, K, Ismail, K, Jackson, T, James, WY, Jarman, C, Jarrold, I, Jarvis, H, Jastrub, R, Jayaraman, B, Jezzard, P, Jiwa, K, Johnson, C, Johnson, S, Johnston, D, Jolley, CJ, Jones, D, Jones, G, Jones, H, Jones, I, Jones, L, Jones, S, Jose, S, Kabir, T, Kaltsakas, G, Kamwa, V, Kanellakis, N, Kaprowska, S, Kausar, Z, Keenan, N, Kelly, S, Kemp, G, Kerslake, H, Key, AL, Khan, F, Khunti, K, Kilroy, S, King, B, King, C, Kingham, L, Kirk, J, Kitterick, P, Klenerman, P, Knibbs, L, Knight, S, Knighton, A, Kon, O, Kon, S, Kon, SS, Koprowska, S, Korszun, A, Koychev, I, Kurasz, C, Kurupati, P, Laing, C, Lamlum, H, Landers, G, Langenberg, C, Lasserson, D, Lavelle-Langham, L, Lawrie, A, Lawson, C, Layton, A, Lea, A, Lee, D, Lee, J-H, Lee, E, Leitch, K, Lenagh, R, Lewis, D, Lewis, J, Lewis, V, Lewis-Burke, N, Li, X, Light, T, Lightstone, L, Lilaonitkul, W, Lim, L, Linford, S, Lingford-Hughes, A, Lipman, M, Liyanage, K, Lloyd, A, Logan, S, Lomas, D, Loosley, R, Lota, H, Lovegrove, W, Lucey, A, Lukaschuk, E, Lye, A, Lynch, C, MacDonald, S, MacGowan, G, Macharia, I, Mackie, J, Macliver, L, Madathil, S, Madzamba, G, Magee, N, Magtoto, MM, Mairs, N, Majeed, N, Major, E, Malein, F, Malim, M, Mallison, G, Mandal, S, Mangion, K, Manisty, C, Manley, R, March, K, Marciniak, S, Marino, P, Mariveles, M, Marouzet, E, Marsh, S, Marshall, B, Marshall, M, Martin, J, Martineau, A, Martinez, LM, Maskell, N, Matila, D, Matimba-Mupaya, W, Matthews, L, Mbuyisa, A, McAdoo, S, McCall, JW, McAllister-Williams, H, McArdle, A, McArdle, P, McAulay, D, McCormick, J, McCormick, W, McCourt, P, McGarvey, L, McGee, C, Mcgee, K, McGinness, J, McGlynn, K, McGovern, A, McGuinness, H, McInnes, IB, McIntosh, J, McIvor, E, McIvor, K, McLeavey, L, McMahon, A, McMahon, MJ, McMorrow, L, Mcnally, T, McNarry, M, McNeill, J, McQueen, A, McShane, H, Mears, C, Megson, C, Megson, S, Mehta, P, Meiring, J, Melling, L, Mencias, M, Menzies, D, Morillas, MM, Michael, A, Milligan, L, Miller, C, Mills, C, Mills, NL, Milner, L, Misra, S, Mitchell, J, Mohamed, A, Mohamed, N, Mohammed, S, Molyneaux, PL, Monteiro, W, Moriera, S, Morley, A, Morrison, L, Morriss, R, Morrow, A, Moss, AJ, Moss, P, Motohashi, K, Msimanga, N, Mukaetova-Ladinska, E, Munawar, U, Murira, J, Nanda, U, Nassa, H, Nasseri, M, Neal, A, Needham, R, Neill, P, Newell, H, Newman, T, Newton-Cox, A, Nicholson, T, Nicoll, D, Nolan, CM, Noonan, MJ, Norman, C, Novotny, P, Nunag, J, Nwafor, L, Nwanguma, U, Nyaboko, J, O'Donnell, K, O'Brien, C, O'Brien, L, O'Regan, D, Odell, N, Ogg, G, Olaosebikan, O, Oliver, C, Omar, Z, Orriss-Dib, L, Osborne, L, Osbourne, R, Ostermann, M, Overton, C, Owen, J, Oxton, J, Pack, J, Pacpaco, E, Paddick, S, Painter, S, Pakzad, A, Palmer, S, Papineni, P, Paques, K, Paradowski, K, Pareek, M, Parfrey, H, Pariante, C, Parker, S, Parkes, M, Parmar, J, Patale, S, Patel, B, Patel, M, Patel, S, Pattenadk, D, Pavlides, M, Payne, S, Pearce, L, Pearl, JE, Peckham, D, Pendlebury, J, Peng, Y, Pennington, C, Peralta, I, Perkins, E, Peterkin, Z, Peto, T, Petousi, N, Petrie, J, Phipps, J, Pimm, J, Hanley, KP, Pius, R, Plant, H, Plein, S, Plekhanova, T, Plowright, M, Polgar, O, Poll, L, Porter, J, Portukhay, S, Powell, N, Prabhu, A, Pratt, J, Price, A, Price, C, Price, D, Price, L, Prickett, A, Propescu, J, Pugmire, S, Quaid, S, Quigley, J, Qureshi, H, Qureshi, IN, Radhakrishnan, K, Ralser, M, Ramos, A, Ramos, H, Rangeley, J, Rangelov, B, Ratcliffe, L, Ravencroft, P, Reddington, A, Reddy, R, Redfearn, H, Redwood, D, Reed, A, Rees, M, Rees, T, Regan, K, Reynolds, W, Ribeiro, C, Richards, A, Richardson, E, Rivera-Ortega, P, Roberts, K, Robertson, E, Robinson, E, Robinson, L, Roche, L, Roddis, C, Rodger, J, Ross, A, Ross, G, Rossdale, J, Rostron, A, Rowe, A, Rowland, A, Rowland, J, Roy, K, Roy, M, Rudan, I, Russell, R, Russell, E, Saalmink, G, Sabit, R, Sage, EK, Samakomva, T, Samani, N, Sampson, C, Samuel, K, Samuel, R, Sanderson, A, Sapey, E, Saralaya, D, Sargant, J, Sarginson, C, Sass, T, Sattar, N, Saunders, K, Saunders, P, Saunders, LC, Savill, H, Saxon, W, Sayer, A, Schronce, J, Schwaeble, W, Scott, K, Selby, N, Sewell, TA, Shah, K, Shah, P, Shankar-Hari, M, Sharma, M, Sharpe, C, Sharpe, M, Shashaa, S, Shaw, A, Shaw, K, Shaw, V, Shelton, S, Shenton, L, Shevket, K, Short, J, Siddique, S, Siddiqui, S, Sidebottom, J, Sigfrid, L, Simons, G, Simpson, J, Simpson, N, Singh, C, Singh, S, Sissons, D, Skeemer, J, Slack, K, Smith, A, Smith, D, Smith, S, Smith, J, Smith, L, Soares, M, Solano, TS, Solly, R, Solstice, AR, Soulsby, T, Southern, D, Sowter, D, Spears, M, Spencer, LG, Speranza, F, Stadon, L, Stanel, S, Steele, N, Steiner, M, Stensel, D, Stephens, G, Stephenson, L, Stern, M, Stewart, I, Stimpson, R, Stockdale, S, Stockley, J, Stoker, W, Stone, R, Storrar, W, Storrie, A, Storton, K, Stringer, E, Strong-Sheldrake, S, Stroud, N, Subbe, C, Sudlow, CL, Suleiman, Z, Summers, C, Summersgill, C, Sutherland, D, Sykes, DL, Sykes, R, Talbot, N, Tan, AL, Tarusan, L, Tavoukjian, V, Taylor, A, Taylor, C, Taylor, J, Te, A, Tedd, H, Tee, CJ, Teixeira, J, Tench, H, Terry, S, Thackray-Nocera, S, Thaivalappil, F, Thamu, B, Thickett, D, Thomas, C, Thomas, S, Thomas, AK, Thomas-Woods, T, Thompson, T, Thompson, AAR, Thornton, T, Tilley, J, Tinker, N, Tiongson, GF, Tobin, M, Tomlinson, J, Tong, C, Touyz, R, Tripp, KA, Tunnicliffe, E, Turnbull, A, Turner, E, Turner, S, Turner, V, Turner, K, Turney, S, Turtle, L, Turton, H, Ugoji, J, Ugwuoke, R, Upthegrove, R, Valabhji, J, Ventura, M, Vere, J, Vickers, C, Vinson, B, Wade, E, Wade, P, Wainwright, T, Wajero, LO, Walder, S, Walker, S, Wall, E, Wallis, T, Walmsley, S, Walsh, JA, Walsh, S, Warburton, L, Ward, TJC, Warwick, K, Wassall, H, Waterson, S, Watson, E, Watson, L, Watson, J, Welch, C, Welch, H, Welsh, B, Wessely, S, West, S, Weston, H, Wheeler, H, White, S, Whitehead, V, Whitney, J, Whittaker, S, Whittam, B, Whitworth, V, Wight, A, Wild, J, Wilkins, M, Wilkinson, D, Williams, N, Williams, J, Williams-Howard, SA, Willicombe, M, Willis, G, Willoughby, J, Wilson, A, Wilson, D, Wilson, I, Window, N, Witham, M, Wolf-Roberts, R, Wood, C, Woodhead, F, Woods, J, Wormleighton, J, Worsley, J, Wraith, D, Wright, C, Wright, L, Wright, S, Wyles, J, Wynter, I, Xu, M, Yasmin, N, Yasmin, S, Yates, T, Yip, KP, Young, B, Young, S, Young, A, Yousuf, AJ, Zawia, A, Zeidan, L, Zhao, B, Zongo, O, Group, The PHOSP-COVID Collaborative, National Institute for Health Research, and UKRI MRC COVID-19 Rapid Response Call

Subjects
Adult, Male, Pulmonary and Respiratory Medicine, Adolescent, PHOSP-COVID Collaborative Group, 1117 Public Health and Health Services, Post-Acute COVID-19 Syndrome, SDG 3 - Good Health and Well-being, Humans, Longitudinal Studies, Obesity, Prospective Studies, long COVID, Retrospective Studies, Inflammation, SARS-CoV-2, COVID-19, 1103 Clinical Sciences, Middle Aged, prospective observational study, United Kingdom, Hospitalization, Quality of Life, Female, 1199 Other Medical and Health Sciences
Abstract

Background No effective pharmacological or non-pharmacological interventions exist for patients with long COVID. We aimed to describe recovery 1 year after hospital discharge for COVID-19, identify factors associated with patient-perceived recovery, and identify potential therapeutic targets by describing the underlying inflammatory profiles of the previously described recovery clusters at 5 months after hospital discharge. Methods The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study recruiting adults (aged ≥18 years) discharged from hospital with COVID-19 across the UK. Recovery was assessed using patient-reported outcome measures, physical performance, and organ function at 5 months and 1 year after hospital discharge, and stratified by both patient-perceived recovery and recovery cluster. Hierarchical logistic regression modelling was performed for patient-perceived recovery at 1 year. Cluster analysis was done using the clustering large applications k-medoids approach using clinical outcomes at 5 months. Inflammatory protein profiling was analysed from plasma at the 5-month visit. This study is registered on the ISRCTN Registry, ISRCTN10980107, and recruitment is ongoing. Findings 2320 participants discharged from hospital between March 7, 2020, and April 18, 2021, were assessed at 5 months after discharge and 807 (32·7%) participants completed both the 5-month and 1-year visits. 279 (35·6%) of these 807 patients were women and 505 (64·4%) were men, with a mean age of 58·7 (SD 12·5) years, and 224 (27·8%) had received invasive mechanical ventilation (WHO class 7–9). The proportion of patients reporting full recovery was unchanged between 5 months (501 [25·5%] of 1965) and 1 year (232 [28·9%] of 804). Factors associated with being less likely to report full recovery at 1 year were female sex (odds ratio 0·68 [95% CI 0·46–0·99]), obesity (0·50 [0·34–0·74]) and invasive mechanical ventilation (0·42 [0·23–0·76]). Cluster analysis (n=1636) corroborated the previously reported four clusters: very severe, severe, moderate with cognitive impairment, and mild, relating to the severity of physical health, mental health, and cognitive impairment at 5 months. We found increased inflammatory mediators of tissue damage and repair in both the very severe and the moderate with cognitive impairment clusters compared with the mild cluster, including IL-6 concentration, which was increased in both comparisons (n=626 participants). We found a substantial deficit in median EQ-5D-5L utility index from before COVID-19 (retrospective assessment; 0·88 [IQR 0·74–1·00]), at 5 months (0·74 [0·64–0·88]) to 1 year (0·75 [0·62–0·88]), with minimal improvements across all outcome measures at 1 year after discharge in the whole cohort and within each of the four clusters. Interpretation The sequelae of a hospital admission with COVID-19 were substantial 1 year after discharge across a range of health domains, with the minority in our cohort feeling fully recovered. Patient-perceived health-related quality of life was reduced at 1 year compared with before hospital admission. Systematic inflammation and obesity are potential treatable traits that warrant further investigation in clinical trials. Funding UK Research and Innovation and National Institute for Health Research.

Published
2022

8. Genome-Wide Interaction Analysis of Genetic Variants With Menopausal Hormone Therapy for Colorectal Cancer Risk

Author

Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, Chang-Claude, J, Tian, Y, Kim, AE, Bien, SA, Lin, Y, Qu, C, Harrison, TA, Carreras-Torres, R, Diez-Obrero, V, Dimou, N, Drew, DA, Hidaka, A, Huyghe, JR, Jordahl, KM, Morrison, J, Murphy, N, Obon-Santacana, M, Ulrich, CM, Ose, J, Peoples, AR, Ruiz-Narvaez, EA, Shcherbina, A, Stern, MC, Su, Y-R, van Duijnhoven, FJB, Arndt, V, Baurley, JW, Berndt, S, Bishop, DT, Brenner, H, Buchanan, DD, Chan, AT, Figueiredo, JC, Gallinger, S, Gruber, SB, Harlid, S, Hoffmeister, M, Jenkins, MA, Joshi, AD, Keku, TO, Larsson, SC, Le Marchand, L, Li, L, Giles, GG, Milne, RL, Nan, H, Nassir, R, Ogino, S, Budiarto, A, Platz, EA, Potter, JD, Prentice, RL, Rennert, G, Sakoda, LC, Schoen, RE, Slattery, ML, Thibodeau, SN, Van Guelpen, B, Visvanathan, K, White, E, Wolk, A, Woods, MO, Wu, AH, Campbell, PT, Casey, G, Conti, D, Gunter, MJ, Kundaje, A, Lewinger, JP, Moreno, V, Newcomb, PA, Pardamean, B, Thomas, DC, Tsilidis, KK, Peters, U, Gauderman, WJ, Hsu, L, and Chang-Claude, J

Abstract

BACKGROUND: The use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk. METHODS: We conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants. RESULTS: The use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P < 1.2 × 10-4). CONCLUSION: Genetic variants that modify the association between MHT and CRC risk were identified, offering new insights into pathways of CRC carcinogenesis and potential mechanisms involved.

Published
2022

9. Genetic architectures of proximal and distal colorectal cancer are partly distinct

Author

Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, Peters, U, Huyghe, JR, Harrison, TA, Bien, SA, Hampel, H, Figueiredo, JC, Schmit, SL, Conti, D, Chen, S, Qu, C, Lin, Y, Barfield, R, Baron, JA, Cross, AJ, Diergaarde, B, Duggan, D, Harlid, S, Imaz, L, Kang, HM, Levine, DM, Perduca, V, Perez-Cornago, A, Sakoda, LC, Schumacher, FR, Slattery, ML, Toland, AE, van Duijnhoven, FJB, Van Guelpen, B, Agudo, A, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Banbury, BL, Bassik, MC, Berndt, S, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Caan, BJ, Campbell, PT, Carr, PR, Castells, A, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Curtis, KR, de la Chapelle, A, Easton, DF, English, DR, Feskens, EJM, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Jenab, M, Jenkins, MA, Joshi, AD, Keku, TO, Kooperberg, C, Kuhn, T, Kury, S, Le Marchand, L, Lejbkowicz, F, Li, C, Li, L, Lieb, W, Lindblom, A, Lindor, NM, Mannisto, S, Markowitz, SD, Milne, RL, Moreno, L, Murphy, N, Nassir, R, Offit, K, Ogino, S, Panico, S, Parfrey, PS, Pearlman, R, Pharoah, PDP, Phipps, A, Platz, EA, Potter, JD, Prentice, RL, Qi, L, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Schafmayer, C, Schoen, RE, Seminara, D, Song, M, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Ulrich, CM, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Wolk, A, Woods, MO, Wu, AH, Abecasis, GR, Nickerson, DA, Scacheri, PC, Kundaje, A, Casey, G, Gruber, SB, Hsu, L, Moreno, V, Hayes, RB, Newcomb, PA, and Peters, U

Abstract

OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Published
2021

10. Interpretation isopinion: realigning the fact/opinion distinction in English defamation law

Author

Bennett, Thomas DC

Abstract

ABSTRACTStatements that interpret the words of others are – by their nature – interpretative. Their meaning is contingent and (inter)subjective; it is something that those who encounter those words or actions construct. As such, it makes little sense for the law to treat interpretative statements as purporting to set out provable facts. Yet English defamation law does precisely this. As a result, publicly criticising ambiguous words or actions that are put into the public domain by one person can cost a commentator dearly. This essay critiques the peculiarities of English defamation doctrine that have created this situation, arguing that all published statements that interpret or purport to interpret one or more earlier statements, whether expressly or impliedly, ought to be treated as statements of opinion. By adopting this approach, English defamation law can address an issue that has the potential to cause significant chilling effects on public discourse – particularly on social media.

Published
2023
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11. Novel Common Genetic Susceptibility Loci for Colorectal Cancer

Author

Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, Gruber, SB, Schmit, SL, Edlund, CK, Schumacher, FR, Gong, J, Harrison, TA, Huyghe, JR, Qu, C, Melas, M, Van den Berg, DJ, Wang, H, Tring, S, Plummer, SJ, Albanes, D, Alonso, MH, Amos, CI, Anton, K, Aragaki, AK, Arndt, V, Barry, EL, Berndt, SI, Bezieau, S, Bien, S, Bloomer, A, Boehm, J, Boutron-Ruault, M-C, Brenner, H, Brezina, S, Buchanan, DD, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castelao, JE, Chan, AT, Chang-Claude, J, Chanock, SJ, Cheng, I, Cheng, Y-W, Chin, LS, Church, JM, Church, T, Coetzee, GA, Cotterchio, M, Correa, MC, Curtis, KR, Duggan, D, Easton, DF, English, D, Feskens, EJM, Fischer, R, FitzGerald, LM, Fortini, BK, Fritsche, LG, Fuchs, CS, Gago-Dominguez, M, Gala, M, Gallinger, SJ, Gauderman, WJ, Giles, GG, Giovannucci, EL, Gogarten, SM, Gonzalez-Villalpando, C, Gonzalez-Villalpando, EM, Grady, WM, Greenson, JK, Gsur, A, Gunter, M, Haiman, CA, Hampe, J, Harlid, S, Harju, JF, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Huang, S-C, Huerta, JM, Hudson, TJ, Hunter, DJ, Idos, GE, Iwasaki, M, Jackson, RD, Jacobs, EJ, Jee, SH, Jenkins, MA, Jia, W-H, Jiao, S, Joshi, AD, Kolonel, LN, Kono, S, Kooperberg, C, Krogh, V, Kuehn, T, Kury, S, LaCroix, A, Laurie, CA, Lejbkowicz, F, Lemire, M, Lenz, H-J, Levine, D, Li, CI, Li, L, Lieb, W, Lin, Y, Lindor, NM, Liu, Y-R, Loupakis, F, Lu, Y, Luh, F, Ma, J, Mancao, C, Manion, FJ, Markowitz, SD, Martin, V, Matsuda, K, Matsuo, K, McDonnell, KJ, McNeil, CE, Milne, R, Molina, AJ, Mukherjee, B, Murphy, N, Newcomb, PA, Offit, K, Omichessan, H, Palli, D, Cotore, JPP, Perez-Mayoral, J, Pharoah, PD, Potter, JD, Raskin, L, Rennert, G, Rennert, HS, Riggs, BM, Schafmayer, C, Schoen, RE, Sellers, TA, Seminara, D, Severi, G, Shi, W, Shibata, D, Shu, X-O, Siegel, EM, Slattery, ML, Southey, M, Stadler, ZK, Stern, MC, Stintzing, S, Taverna, D, Thibodeau, SN, Thomas, DC, Trichopoulou, A, Tsugane, S, Ulrich, CM, van Duijnhoven, FJB, van Guelpan, B, Vijai, J, Virtamo, J, Weinstein, SJ, White, E, Win, AK, Wolk, A, Woods, M, Wu, AH, Wu, K, Xiang, Y-B, Yen, Y, Zanke, BW, Zeng, Y-X, Zhang, B, Zubair, N, Kweon, S-S, Figueiredo, JC, Zheng, W, Le Marchand, L, Lindblom, A, Moreno, V, Peters, U, Casey, G, Hsu, L, Conti, DV, and Gruber, SB

Abstract

BACKGROUND: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. METHODS: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. RESULTS: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. CONCLUSIONS: T

Published
2019

12. Discovery of common and rare genetic risk variants for colorectal cancer

Author

Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, Peters, U, Huyghe, JR, Bien, SA, Harrison, TA, Kang, HM, Chen, S, Schmit, SL, Conti, DV, Qu, C, Jeon, J, Edlund, CK, Greenside, P, Wainberg, M, Schumacher, FR, Smith, JD, Levine, DM, Nelson, SC, Sinnott-Armstrong, NA, Albanes, D, Alonso, MH, Anderson, K, Arnau-Collell, C, Arndt, V, Bamia, C, Banbury, BL, Baron, JA, Berndt, SI, Bezieau, S, Bishop, DT, Boehm, J, Boeing, H, Brenner, H, Brezina, S, Buch, S, Buchanan, DD, Burnett-Hartman, A, Butterbach, K, Caan, BJ, Campbell, PT, Carlson, CS, Castellvi-Bel, S, Chan, AT, Chang-Claude, J, Chanock, SJ, Chirlaque, M-D, Cho, SH, Connolly, CM, Cross, AJ, Cuk, K, Curtis, KR, de la Chapelle, A, Doheny, KF, Duggan, D, Easton, DF, Elias, SG, Elliott, F, English, DR, Feskens, EJM, Figueiredo, JC, Fischer, R, FitzGerald, LM, Forman, D, Gala, M, Gallinger, S, Gauderman, WJ, Giles, GG, Gillanders, E, Gong, J, Goodman, PJ, Grady, WM, Grove, JS, Gsur, A, Gunter, MJ, Haile, RW, Hampe, J, Hampel, H, Harlid, S, Hayes, RB, Hofer, P, Hoffmeister, M, Hopper, JL, Hsu, W-L, Huang, W-Y, Hudson, TJ, Hunter, DJ, Ibanez-Sanz, G, Idos, GE, Ingersoll, R, Jackson, RD, Jacobs, EJ, Jenkins, MA, Joshi, AD, Joshu, CE, Keku, TO, Key, TJ, Kim, HR, Kobayashi, E, Kolonel, LN, Kooperberg, C, Kuehn, T, Kury, S, Kweon, S-S, Larsson, SC, Laurie, CA, Le Marchand, L, Leal, SM, Lee, SC, Lejbkowicz, F, Lemire, M, Li, CI, Li, L, Lieb, W, Lin, Y, Lindblom, A, Lindor, NM, Ling, H, Louie, TL, Mannisto, S, Markowitz, SD, Martin, V, Masala, G, McNeil, CE, Melas, M, Milne, RL, Moreno, L, Murphy, N, Myte, R, Naccarati, A, Newcomb, PA, Offit, K, Ogino, S, Onland-Moret, NC, Pardini, B, Parfrey, PS, Pearlman, R, Perduca, V, Pharoah, PDP, Pinchev, M, Platz, EA, Prentice, RL, Pugh, E, Raskin, L, Rennert, G, Rennert, HS, Riboli, E, Rodriguez-Barranco, M, Romm, J, Sakoda, LC, Schafmayer, C, Schoen, RE, Seminara, D, Shah, M, Shelford, T, Shin, M-H, Shulman, K, Sieri, S, Slattery, ML, Southey, MC, Stadler, ZK, Stegmaier, C, Su, Y-R, Tangen, CM, Thibodeau, SN, Thomas, DC, Thomas, SS, Toland, AE, Trichopoulou, A, Ulrich, CM, Van den Berg, DJ, van Duijnhoven, FJB, Van Guelpen, B, van Kranen, H, Vijai, J, Visvanathan, K, Vodicka, P, Vodickova, L, Vymetalkova, V, Weigl, K, Weinstein, SJ, White, E, Win, AK, Wolf, CR, Wolk, A, Woods, MO, Wu, AH, Zaidi, SH, Zanke, BW, Zhang, Q, Zheng, W, Scacheri, PC, Potter, JD, Bassik, MC, Kundaje, A, Casey, G, Moreno, V, Abecasis, GR, Nickerson, DA, Gruber, SB, Hsu, L, and Peters, U

Abstract

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Published
2019

13. Current Challenges and New Opportunities for Gene-Environment Interaction Studies of Complex Diseases

Author

McAllister, K, Mechanic, LE, Amos, C, Aschard, H, Blair, IA, Chatterjee, N, Conti, D, Gauderman, WJ, Hsu, L, Hutter, CM, Jankowska, MM, Kerr, J, Kraft, P, Montgomery, SB, Mukherjee, B, Papanicolaou, GJ, Patel, CJ, Ritchie, MD, Ritz, BR, Thomas, DC, Wei, P, Witte, JS, and Participants, W

Subjects
genome-wide association study, environmental exposure, gene-environment interaction
Published
2017

14. Inclusion of biological knowledge in a Bayesian shrinkage model for joint estimation of SNP effects

Author

Pereira, M, Thompson, JR, Weichenberger, CX, Thomas, DC, Minelli, C, and National Heart & Lung Institute Foundation

Subjects
SELECTION, INFORMATION, genetic association studies, DATABASE, Epidemiology, Polymorphism, Single Nucleotide, DISEASE, Linkage Disequilibrium, GENETIC ASSOCIATION, Body Mass Index, Humans, Computer Simulation, MAXIMUM-LIKELIHOOD, Genetics & Heredity, 0604 Genetics, Science & Technology, prior knowledge, Models, Statistical, Models, Genetic, Respiration, Bayes Theorem, PRIORITIZATION, GENOME, shrinkage, 1117 Public Health And Health Services, Bayesian model, Mathematical & Computational Biology, Life Sciences & Biomedicine
Abstract

With the aim of improving detection of novel single-nucleotide polymorphisms (SNPs) in genetic association studies, we propose a method of including prior biological information in a Bayesian shrinkage model that jointly estimates SNP effects. We assume that the SNP effects follow a normal distribution centered at zero with variance controlled by a shrinkage hyperparameter. We use biological information to define the amount of shrinkage applied on the SNP effects distribution, so that the effects of SNPs with more biological support are less shrunk toward zero, thus being more likely detected. The performance of the method was tested in a simulation study (1,000 datasets, 500 subjects with ∼200 SNPs in 10 linkage disequilibrium (LD) blocks) using a continuous and a binary outcome. It was further tested in an empirical example on body mass index (continuous) and overweight (binary) in a dataset of 1,829 subjects and 2,614 SNPs from 30 blocks. Biological knowledge was retrieved using the bioinformatics tool Dintor, which queried various databases. The joint Bayesian model with inclusion of prior information outperformed the standard analysis: in the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model versus 3.6 for the standard analysis of individual SNPs; in the empirical example, the mean ranking of the six true blocks was 8.5 versus 9.3 in the standard analysis. These results suggest that our method is more powerful than the standard analysis. We expect its performance to improve further as more biological information about SNPs becomes available.

Published
2016

16. Eros is a novel transmembrane protein that controls the phagocyte respiratory burst and is essential for innate immunity

Author

Thomas, DC, Clare, S, Sowerby, JM, Pardo, M, Juss, JK, Goulding, DA, van der Weyden, L, Storisteanu, D, Prakash, A, Espeli, M, Flint, S, Lee, JC, Hoenderdos, K, Kane, L, Harcourt, K, Mukhopadhyay, S, Umrania, Y, Antrobus, R, Nathan, JA, Adams, DJ, Bateman, A, Choudhary, JS, Lyons, PA, Condliffe, AM, Chilvers, ER, Dougan, G, Smith, KGC, Thomas, DC, Clare, S, Sowerby, JM, Pardo, M, Juss, JK, Goulding, DA, van der Weyden, L, Storisteanu, D, Prakash, A, Espeli, M, Flint, S, Lee, JC, Hoenderdos, K, Kane, L, Harcourt, K, Mukhopadhyay, S, Umrania, Y, Antrobus, R, Nathan, JA, Adams, DJ, Bateman, A, Choudhary, JS, Lyons, PA, Condliffe, AM, Chilvers, ER, Dougan, G, and Smith, KGC

Abstract

The phagocyte respiratory burst is crucial for innate immunity. The transfer of electrons to oxygen is mediated by a membrane-bound heterodimer, comprising gp91phox and p22phox subunits. Deficiency of either subunit leads to severe immunodeficiency. We describe Eros (essential for reactive oxygen species), a protein encoded by the previously undefined mouse gene bc017643, and show that it is essential for host defense via the phagocyte NAPDH oxidase. Eros is required for expression of the NADPH oxidase components, gp91phox and p22phox Consequently, Eros-deficient mice quickly succumb to infection. Eros also contributes to the formation of neutrophil extracellular traps (NETS) and impacts on the immune response to melanoma metastases. Eros is an ortholog of the plant protein Ycf4, which is necessary for expression of proteins of the photosynthetic photosystem 1 complex, itself also an NADPH oxio-reductase. We thus describe the key role of the previously uncharacterized protein Eros in host defense.

Published
2017

17. Area wide for beginners

Author

N.Z.I.E. Transportation and Traffic Engineering Group Symposium (1979 : Wellington, N.Z.) and Thomas, DC

Published
1979

21. Differential shrinkage as a way of integrating prior knowledge in a Bayesian model to improve the analysis of genetic association studies

Author

Pereira, M, Thompson, JR, Weichenberger, CX, Thomas, DC, and Minelli, C

Subjects
Genetics & Heredity, 0604 Genetics, Science & Technology, 1117 Public Health And Health Services, Epidemiology, Mathematical & Computational Biology, Life Sciences & Biomedicine
Abstract

We propose a method of integrating external biological information about SNPs in a Bayesian hierarchical shrinkage model that jointly estimates SNP effects with the aim of increasing the power to detect variants in genetic association studies. Our method induces shrinkage on the SNP effects that is inversely proportional to prior information: SNPs with more information are subject to little shrinkage and more likely to be detected, while SNPs without prior information are strongly shrunk towards zero (no effect). The performance of the method was tested in a simulation study with 1000 datasets, each with 500 subjects and ∼1200 SNPs, divided in 10 Linkage Disequilibrium (LD) blocks. One LD block was simulated to be truly associated with the outcome. The method was further tested on an empirical example using BMI as the outcome and data from the European Community Respiratory Health Survey: 1,829 subjects and 2,614 SNPs from 30 blocks, 6 of which known to be truly associated with BMI. Prior knowledge was retrieved using the bioinformatic tool Dintor and incorporated in the model. The Bayesian model with inclusion of prior information outperformed the classical analysis. In the simulation study, the mean ranking of the true LD block was 2.8 for the Bayesian model vs. 3.6 for the classical analysis. Similarly, the mean ranking of the six true blocks in the empirical example was 8.3 vs. 11.7 in the classical analysis. These results suggest that our method represents a more powerful approach to detect new variants in genetic association studies.

Published
2016

22. GWASeq: targeted re-sequencing follow up to GWAS

Author

Salomon, MP, Li, WLS, Edlund, CK, Morrison, J, Fortini, BK, Win, AK, Conti, DV, Thomas, DC, Duggan, D, Buchanan, DD, Jenkins, MA, Hopper, JL, Gallinger, S, Le Marchand, L, Newcomb, PA, Casey, G, Marjoram, P, Salomon, MP, Li, WLS, Edlund, CK, Morrison, J, Fortini, BK, Win, AK, Conti, DV, Thomas, DC, Duggan, D, Buchanan, DD, Jenkins, MA, Hopper, JL, Gallinger, S, Le Marchand, L, Newcomb, PA, Casey, G, and Marjoram, P

Abstract

BACKGROUND: For the last decade the conceptual framework of the Genome-Wide Association Study (GWAS) has dominated the investigation of human disease and other complex traits. While GWAS have been successful in identifying a large number of variants associated with various phenotypes, the overall amount of heritability explained by these variants remains small. This raises the question of how best to follow up on a GWAS, localize causal variants accounting for GWAS hits, and as a consequence explain more of the so-called "missing" heritability. Advances in high throughput sequencing technologies now allow for the efficient and cost-effective collection of vast amounts of fine-scale genomic data to complement GWAS. RESULTS: We investigate these issues using a colon cancer dataset. After QC, our data consisted of 1993 cases, 899 controls. Using marginal tests of associations, we identify 10 variants distributed among six targeted regions that are significantly associated with colorectal cancer, with eight of the variants being novel to this study. Additionally, we perform so-called 'SNP-set' tests of association and identify two sets of variants that implicate both common and rare variants in the etiology of colorectal cancer. CONCLUSIONS: Here we present a large-scale targeted re-sequencing resource focusing on genomic regions implicated in colorectal cancer susceptibility previously identified in several GWAS, which aims to 1) provide fine-scale targeted sequencing data for fine-mapping and 2) provide data resources to address methodological questions regarding the design of sequencing-based follow-up studies to GWAS. Additionally, we show that this strategy successfully identifies novel variants associated with colorectal cancer susceptibility and can implicate both common and rare variants.

Published
2016

23. COMPREHENSIVE ANALYSES OF DNA REPAIR PATHWAYS, SMOKING, AND BLADDER CANCER RISK IN LOS ANGELES AND SHANGHAI

Author

Corral, R, Lewinger, JP, Van den Berg, D, Joshi, AD, Yuan, JM, Gago Dominguez, Manuela, Cortessis, VK, Pike, MC, Conti, DV, Thomas, DC, Edlund, CK, Gao, YT, Xiang, YB, Zhang, W, Su, YC, and Stern, MC

Subjects
Adult, Male, Carcinoma, Transitional Cell, China, DNA Repair, Smoking, Antigens, Nuclear, Middle Aged, Los Angeles, Polymorphism, Single Nucleotide, Article, DNA-Binding Proteins, Urinary Bladder Neoplasms, Risk Factors, Humans, Female, Genetic Predisposition to Disease, Ku Autoantigen, Aged, Sterol Regulatory Element Binding Protein 2
Abstract

Tobacco smoking is a bladder cancer risk factor and a source of carcinogens that induce DNA damage to urothelial cells. Using data and samples from 988 cases and 1,004 controls enrolled in the Los Angeles County Bladder Cancer Study and the Shanghai Bladder Cancer Study, we investigated associations between bladder cancer risk and 632 tagSNPs that comprehensively capture genetic variation in 28 DNA repair genes from four DNA repair pathways: base excision repair (BER), nucleotide excision repair (NER), non-homologous end-joining (NHEJ) and homologous recombination repair (HHR). Odds ratios (ORs) and 95% confidence intervals (CIs) for each tagSNP were corrected for multiple testing for all SNPs within each gene using pACT and for genes within each pathway and across pathways with Bonferroni. Gene and pathway summary estimates were obtained using ARTP. We observed an association between bladder cancer and POLB rs7832529 (BER) (pACT = 0.003; ppathway = 0.021) among all, and SNPs in XPC (NER) and OGG1 (BER) among Chinese men and women, respectively. The NER pathway showed an overall association with risk among Chinese males (ARTP NER p = 0.034). The XRCC6 SNP rs2284082 (NHEJ), also in LD with SREBF2, showed an interaction with smoking (smoking status interaction pgene = 0.001, ppathway = 0.008, poverall = 0.034). Our findings support a role in bladder carcinogenesis for regions that map close to or within BER (POLB, OGG1) and NER genes (XPC). A SNP that tags both the XRCC6 and SREBF2 genes strongly modifies the association between bladder cancer risk and smoking.

Published
2014

24. Genome-wide association study of colorectal cancer identifies six new susceptibility loci

Author

Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van Den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giocannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kury, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van Den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giocannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kury, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, and Peters, U

Abstract

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

Published
2015

25. Genome-wide association study of colorectal cancer identifies six new susceptibility loci (vol 6, 7138, 2015)

Author

Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giovannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kuery, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, Peters, U, Schumacher, FR, Schmit, SL, Jiao, S, Edlund, CK, Wang, H, Zhang, B, Hsu, L, Huang, S-C, Fischer, CP, Harju, JF, Idos, GE, Lejbkowicz, F, Manion, FJ, McDonnell, K, McNeil, CE, Melas, M, Rennert, HS, Shi, W, Thomas, DC, Van den Berg, DJ, Hutter, CM, Aragaki, AK, Butterbach, K, Caan, BJ, Carlson, CS, Chanock, SJ, Curtis, KR, Fuchs, CS, Gala, M, Giovannucci, EL, Gogarten, SM, Hayes, RB, Henderson, B, Hunter, DJ, Jackson, RD, Kolonel, LN, Kooperberg, C, Kuery, S, LaCroix, A, Laurie, CC, Laurie, CA, Lemire, M, Levine, D, Ma, J, Makar, KW, Qu, C, Taverna, D, Ulrich, CM, Wu, K, Kono, S, West, DW, Berndt, SI, Bezieau, S, Brenner, H, Campbell, PT, Chan, AT, Chang-Claude, J, Coetzee, GA, Conti, DV, Duggan, D, Figueiredo, JC, Fortini, BK, Gallinger, SJ, Gauderman, WJ, Giles, G, Green, R, Haile, R, Harrison, TA, Hoffmeister, M, Hopper, JL, Hudson, TJ, Jacobs, E, Iwasaki, M, Jee, SH, Jenkins, M, Jia, W-H, Joshi, A, Li, L, Lindor, NM, Matsuo, K, Moreno, V, Mukherjee, B, Newcomb, PA, Potter, JD, Raskin, L, Rennert, G, Rosse, S, Severi, G, Schoen, RE, Seminara, D, Shu, X-O, Slattery, ML, Tsugane, S, White, E, Xiang, Y-B, Zanke, BW, Zheng, W, Le Marchand, L, Casey, G, Gruber, SB, and Peters, U

Published
2015

26. A study of the distribution of the swede smudge Contarinia nasturtii Kieffer in Devon and symptoms of its attack on various host plants

Author

Thomas Dc

Subjects
food.ingredient, General symptoms, Ecology, business.industry, Diptera, food and beverages, Distribution (economics), Contarinia nasturtii, Biology, biology.organism_classification, food, Agronomy, Midge, Vegetables, Host plants, Animals, Contarinia, Life history, business, Agronomy and Crop Science, Plant Diseases
Abstract

A survey of swede midge damage in Devon is described, showing that the attack on cow cabbage is most severe in the north and west of the county, while attack on swedes is heaviest in the south and east of the county; the causes of this phenomenon are considered. The life history of the insect is discussed in relation to farming procedure with various crops. Short descriptions and photographs are given of the general symptoms of damage by the midge on the more important cruciferous crops.

Published
2010

27. Some observations on damage to potatoes by slugs

Author

Thomas Dc

Subjects
animal structures, biology, Slug, fungi, Gastropoda, food and beverages, biology.organism_classification, Crop, Agronomy, embryonic structures, Animals, Arion hortensis, Agronomy and Crop Science, Solanum tuberosum
Abstract

The garden slug, Arion hortensis Fer., and the keeled slugs, Milax spp., are the slugs mainly responsible for primary damage to potato tubers in the south-west of England. A variety trial clearly demonstrated the existence of significant differences in susceptibility to slug attack between the three varieties tested. Arran Banner was the most damaged variety, Arran Peak the least, while Majestic occupied an intermediate position. Varietal differences in the amount and time of damage to tubers were associated with differences in the dates of maturity, and little damage occurred prior to the maturing of the tuber. The results confirm the need for prompt lifting of the potato crop on maturity, in order to avoid damage by slugs.

Published
2010

28. A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age

Author

Ahsan, H, Halpern, J, Kibriya, MG, Pierce, BL, Tong, L, Gamazon, E, McGuire, V, Felberg, A, Shi, J, Jasmine, F, Roy, S, Brutus, R, Argos, M, Melkonian, S, Chang-Claude, J, Andrulis, I, Hopper, JL, John, EM, Malone, K, Ursin, G, Gammon, MD, Thomas, DC, Seminara, D, Casey, G, Knight, JA, Southey, MC, Giles, GG, Santella, RM, Lee, E, Conti, D, Duggan, D, Gallinger, S, Haile, R, Jenkins, M, Lindor, NM, Newcomb, P, Michailidou, K, Apicella, C, Park, DJ, Peto, J, Fletcher, O, Silva, IDS, Lathrop, M, Hunter, DJ, Chanock, SJ, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lochmann, M, Beckmann, L, Hein, R, Makalic, E, Schmidt, DF, Quang, MB, Stone, J, Flesch-Janys, D, Dahmen, N, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Hall, P, Czene, K, Irwanto, A, Liu, J, Rahman, N, Turnbull, C, Dunning, AM, Pharoah, P, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Nicolae, D, Easton, DF, Cox, NJ, Whittemore, AS, Ahsan, H, Halpern, J, Kibriya, MG, Pierce, BL, Tong, L, Gamazon, E, McGuire, V, Felberg, A, Shi, J, Jasmine, F, Roy, S, Brutus, R, Argos, M, Melkonian, S, Chang-Claude, J, Andrulis, I, Hopper, JL, John, EM, Malone, K, Ursin, G, Gammon, MD, Thomas, DC, Seminara, D, Casey, G, Knight, JA, Southey, MC, Giles, GG, Santella, RM, Lee, E, Conti, D, Duggan, D, Gallinger, S, Haile, R, Jenkins, M, Lindor, NM, Newcomb, P, Michailidou, K, Apicella, C, Park, DJ, Peto, J, Fletcher, O, Silva, IDS, Lathrop, M, Hunter, DJ, Chanock, SJ, Meindl, A, Schmutzler, RK, Mueller-Myhsok, B, Lochmann, M, Beckmann, L, Hein, R, Makalic, E, Schmidt, DF, Quang, MB, Stone, J, Flesch-Janys, D, Dahmen, N, Nevanlinna, H, Aittomaki, K, Blomqvist, C, Hall, P, Czene, K, Irwanto, A, Liu, J, Rahman, N, Turnbull, C, Dunning, AM, Pharoah, P, Waisfisz, Q, Meijers-Heijboer, H, Uitterlinden, AG, Rivadeneira, F, Nicolae, D, Easton, DF, Cox, NJ, and Whittemore, AS

Abstract

Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer.

Published
2014

32. Why so serious? Lachauxand the threshold of ‘serious harm’ in section 1 Defamation Act 2013

Author

Bennett, Thomas DC

Abstract

ABSTRACTIn Lachaux v Independent Print Ltd, the Court of Appeal held that s 1 Defamation Act 2013 was intended to “raise the bar” for defamation claims above the standard previously demanded at common law. However, despite finding that this was Parliament’s intention in enacting s 1, the Court held that this intention had not been successfully implemented by the wording of the Act. The notion that libel is a tort that is actionable per seis one that has a lengthy heritage at common law. However, an examination of case law between 2005 and 2013 reveals that libel had ceased to be actionable per selong before the new s 1 appeared on the statute books. The Court of Appeal thus based its ruling on a misunderstanding of the pre-Act common law position, resulting in a failure to interpret the Act in a manner consistent with the Parliamentary intention that the Court identified, thereby frustrating that very intention.

Published
2018
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33. Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

Author

Cicek, MS, Cunningham, JM, Fridley, BL, Serie, DJ, Bamlet, WR, Diergaarde, B, Haile, RW, Le Marchand, L, Krontiris, TG, Younghusband, HB, Gallinger, S, Newcomb, PA, Hopper, JL, Jenkins, MA, Casey, G, Schumacher, F, Chen, Z, DeRycke, MS, Templeton, AS, Winship, I, Green, RC, Green, JS, Macrae, FA, Parry, S, Young, GP, Young, JP, Buchanan, D, Thomas, DC, Bishop, DT, Lindor, NM, Thibodeau, SN, Potter, JD, Goode, EL, Cicek, MS, Cunningham, JM, Fridley, BL, Serie, DJ, Bamlet, WR, Diergaarde, B, Haile, RW, Le Marchand, L, Krontiris, TG, Younghusband, HB, Gallinger, S, Newcomb, PA, Hopper, JL, Jenkins, MA, Casey, G, Schumacher, F, Chen, Z, DeRycke, MS, Templeton, AS, Winship, I, Green, RC, Green, JS, Macrae, FA, Parry, S, Young, GP, Young, JP, Buchanan, D, Thomas, DC, Bishop, DT, Lindor, NM, Thibodeau, SN, Potter, JD, and Goode, EL

Abstract

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al.

Published
2012

39. An evidence-based domestic violence education program for internal medicine residents.

Author

Korenstein D, Thomas DC, Foldes C, Ross J, Halm E, and McGinn T

Abstract

BACKGROUND: Domestic violence (DV) is prevalent but often unrecognized, and it is a challenge to teach. This article presents an evidence-based DV education program for medical residents and incorporates it into a women's medicine curriculum. DESCRIPTION: An initial 3-hr seminar included video and case discussion, literature review, and role play. Participants then actively screened patients for 2 weeks and returned for a follow-up discussion session. The program was well received. EVALUATION: Six to 12 months after the intervention, key features questions were utilized to measure ability to correctly suspect DV in patient situations. Residents who had not attended the program served as controls. Three of the 8 questions were suspicious for abuse. Fifty-four percent of respondents in the intervention group correctly suspected DV in at least 2 out of 3 questions compared with 20% of controls (p = .02). CONCLUSIONS: An evidence-based DV education program was well received and helped correctly suspect DV. [ABSTRACT FROM AUTHOR]

Published
2003
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42. Statistical methods for analyzing effects of temporal patterns of exposure on cancer risks

Author

Thomas Dc

Subjects
Risk, Multivariate statistics, Lung Neoplasms, Time Factors, business.industry, Smoking, Statistics as Topic, Public Health, Environmental and Occupational Health, Cancer, Environmental Exposure, medicine.disease, medicine.disease_cause, Interaction, Asbestos, Median latency, Neoplasms, Asbestosis, Logistic analysis, medicine, Humans, Disease process, Lung cancer, business, Demography
Abstract

Two approaches to the inclusion of temporal factors in the analysis of exposure-response relations are compared: (i) multivariate logistic analysis incorporating simple exposure indices, together with additional temporal variables and their interactions, and (ii) direct fitting to models of the disease process. These approaches are illustrated on case-referent data relating lung cancer to asbestos and smoking. From approach i average age at exposure, age at risk, and duration of exposure were found to contribute direct or interaction effects. Two models of carcinogenesis were fit. In a two-stage initiation-latency model the median latency period was estimated at 11.0 years overall, but was somewhat longer for asbestos-induced and shorter for smoking-induced tumors. When this difference was allowed for, latency periods seemed to be inversely related to the average intensities of both asbestos and smoking. In the multistage model, the best fit was obtained with asbestos acting at the fourth and smoking at the fifth of six stages. Lifetime risks of lung cancer are projected under the different models.

Published
1983

45. Analysis of the B cell receptor repertoire in six immune-mediated diseases

Author

Bashford-Rogers, RJM, Bergamaschi, L, McKinney, EF, Pombal, DC, Mescia, F, Lee, JC, Thomas, DC, Flint, SM, Kellam, P, Jayne, DRW, Lyons, PA, and Smith, KGC

Subjects
Adult, Immunoglobulin Isotypes, Young Adult, Immune System Diseases, Immunoglobulin G, Humans, Receptors, Antigen, B-Cell, Middle Aged, Immunoglobulin Class Switching, 3. Good health, Aged, Clone Cells, Immunoglobulin A
Abstract

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.

46. Combining evidence on air pollution and daily mortality from the 20 largest US cities: a hierarchical modelling strategy - Discussion

Author

Clayton, D., Campbell, Mj, Longford, Nt, Armstrong, B., Richardson, S., Rushton, L., Raab, Gm, Quinn, M., Nelder, Ja, Bland, M., Macfarlane, A., Ian Dryden, Smith, Ri, Berhane, K., Thomas, Dc, Cotton, Jw, Coull, Ba, Mezzetti, M., Ryan, Lm, Cowles, K., Cox, C., Cox, Lh, Gupta, S., Hosmane, Bs, Gurrin, Lc, Pettitt, An, Saez, M., Sheppard, L., and Lumley, T.

47. Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study.

Author

Teraoka SN, Bernstein JL, Reiner AS, Haile RW, Bernstein L, Lynch CF, Malone KE, Stovall M, Capanu M, Liang X, Smith SA, Mychaleckyj J, Hou X, Mellemkjaer L, Boice JD Jr, Siniard A, Duggan D, Thomas DC, Concannon P, and WECARE Study Collaborative Group

Abstract

Introduction: Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.Methods: We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.Results: Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.Conclusions: Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor. [ABSTRACT FROM AUTHOR]

Published
2011
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49. Traffic density and the risk of childhood leukemia in a Los Angeles case-control study.

Author

Langholz B, Ebi KL, Thomas DC, Peters JM, London SJ, Langholz, Bryan, Ebi, Kristie L, Thomas, Duncan C, Peters, John M, and London, Stephanie J

Abstract

Purpose: To investigate the relationship between traffic density and the risk of childhood leukemia.Methods: The study group consisted of 212 cases and 202 controls from the London et al. (1991) study of childhood leukemia conducted in the Los Angeles area during 1978 to 1984. Using GIS methods, traffic counts on all streets within 1500 feet of each subject's residence of longest duration were determined. From these counts, an integrated distance-weighted traffic density measure was calculated for each subject for use as the analytic variable. Additional information, including magnetic fields and wire-code, was obtained from the original case-control study. Association between traffic density and leukemia, and confounding and effect modification by other variables, were assessed using standard matched case-control analyses.Results: Although the unadjusted traffic density-childhood leukemia rate ratios were slightly elevated, this weak association was explained by confounding by wire code. Wire code remained associated with leukemia after controlling for traffic density. There was little evidence of effect modification between traffic density and magnetic fields, wire code or other variables.Conclusions: There is no evidence of an association of traffic density with childhood leukemia in the Los Angeles case-control study. [ABSTRACT FROM AUTHOR]

Published
2002
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