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13. Machine learning did not beat logistic regression in time series prediction for severe asthma exacerbations

Author

Hond, A.A.H. de, Kant, I.M.J., Honkoop, P.J., Smith, A.D., Steyerberg, E.W., and Sont, J.K.

Subjects
Machine Learning, Logistic Models, Time Factors, Multidisciplinary, Humans, Sensitivity and Specificity, Asthma
Abstract

Early detection of severe asthma exacerbations through home monitoring data in patients with stable mild-to-moderate chronic asthma could help to timely adjust medication. We evaluated the potential of machine learning methods compared to a clinical rule and logistic regression to predict severe exacerbations. We used daily home monitoring data from two studies in asthma patients (development: n = 165 and validation: n = 101 patients). Two ML models (XGBoost, one class SVM) and a logistic regression model provided predictions based on peak expiratory flow and asthma symptoms. These models were compared with an asthma action plan rule. Severe exacerbations occurred in 0.2% of all daily measurements in the development (154/92,787 days) and validation cohorts (94/40,185 days). The AUC of the best performing XGBoost was 0.85 (0.82–0.87) and 0.88 (0.86–0.90) for logistic regression in the validation cohort. The XGBoost model provided overly extreme risk estimates, whereas the logistic regression underestimated predicted risks. Sensitivity and specificity were better overall for XGBoost and logistic regression compared to one class SVM and the clinical rule. We conclude that ML models did not beat logistic regression in predicting short-term severe asthma exacerbations based on home monitoring data. Clinical application remains challenging in settings with low event incidence and high false alarm rates with high sensitivity.

Published
2022

15. 437TiP An open-label, multicenter, phase II study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting HER2, in previously treated patients (pts) with HER2+ or HER2-low unresectable or metastatic (M) breast cancer (BC)

Author

George, M., Frenel, J-S., Cortés, J., Schmidt, M., Saenz, J.Á. García, Blau, S., Abdulla, N.E., Nishimura, M., Sakai, H., Babu, S., McAndrew, N.P., Ali, A., Pavic, M., Jhaveri, K., Jones, J.M., Rugo, H.S., Mody, K., Smith, A.D., and Yamashita, T.

Published
2024
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17. Global urban environmental change drives adaptation in white clover

Author

Santangelo, J.S., Ness, R.W., Cohan, B., Fitzpatrick, C.R., Innes, S.G., Koch, S., Miles, L.S., Munim, S., Peres-Neto, P.R., Prashad, C., Tong, A.T., Aguirre, W.E., Akinwole, P.O., Alberti, M., Álvarez, J., Anderson, J.T., Anderson, J.J., Ando, Y., Andrew, N.R., Angeoletto, F., Anstett, D.N., Anstett, J., Aoki-Gonçalves, F., Arietta, A.Z.A., Arroyo, M.T.K., Austen, E.J., Baena-Díaz, F., Barker, C.A., Baylis, H.A., Beliz, J.M., Benitez-Mora, A., Bickford, D., Biedebach, G., Blackburn, G.S., Boehm, M.M.A., Bonser, S.P., Bonte, D., Bragger, J.R., Branquinho, C., Brans, K.I., Bresciano, J.C., Brom, P.D., Bucharova, A., Burt, B., Cahill, J.F., Campbell, K.D., Carlen, E.J., Carmona, D., Castellanos, M.C., Centenaro, G., Chalen, I., Chaves, J.A., Chávez-Pesqueira, M., Chen, X-Y, Chilton, A.M., Chomiak, K.M., Cisneros-Heredia, D.F., Cisse, I.K., Classen, A.T., Comerford, M.S., Fradinger, C.C., Corney, H., Crawford, A.J., Crawford, K.M., Dahirel, M., David, S., De Haan, R., Deacon, N.J., Dean, C., del-Val, E., Deligiannis, E.K., Denney, D., Dettlaff, M.A., DiLeo, M.F., Ding, Y-Y, Domínguez-López, M.E., Dominoni, D.M., Draud, S.L., Dyson, K., Ellers, J., Espinosa, C.I., Essi, L., Falahati-Anbaran, M., Falcão, J.C.F., Fargo, H.T., Fellowes, M.D.E., Fitzpatrick, R.M., Flaherty, L.E., Flood, P. J., Flores, M.F., Fornoni, J., Foster, A.G., Frost, C.J., Fuentes, T.L., Fulkerson, J.R., Gagnon, E., Garbsch, F., Garroway, C.J., Gerstein, A.C., Giasson, M.M., Girdler, E.B., Gkelis, S., Godsoe, W., Golemiec, A.M., Golemiec, M., González-Lagos, C., Gorton, A.J., Gotanda, K.M., Granath, G., Greiner, S., Griffiths, J.S., Grilo, F., Gundel, P.E., Hamilton, B., Hardin, J.M., He, T., Heard, S.B., Henriques, A.F., Hernández-Poveda, M., Hetherington-Rauth, M.C., Hill, S.J., Hochuli, D.F., Hodgins, K.A., Hood, G.R., Hopkins, G.R., Hovanes, K.A., Howard, A.R., Hubbard, S.C., Ibarra-Cerdeña, C.N., Iñiguez-Armijos, C., Jara-Arancio, P., Jarrett, B.J.M., Jeannot, M., Jiménez-Lobato, V., Johnson, M., Johnson, O., Johnson, P.P., Johnson, R., Josephson, M.P., Jung, M.C., Just, M.G., Kahilainen, A., Kailing, O.S., Kariñho-Betancourt, E., Karousou, R., Kirn, L.A., Kirschbaum, A., Laine, A-L, LaMontagne, J.M., Lampei, C., Lara, C., Larson, E.L., Lázaro-Lobo, A., Le, J.H., Leandro, D.S., Lee, C., Lei, Y., León, C.A., Lequerica Tamara, M.E., Levesque, D.C., Liao, W-J, Ljubotina, M., Locke, H., Lockett, M.T., Longo, T.C., Lundholm, J.T., MacGillavry, T., Mackin, C.R., Mahmoud, A.R., Manju, I.A., Mariën, J., Martínez, D.N., Martínez-Bartolomé, M., Meineke, E.K., Mendoza-Arroyo, W., Merritt, T. J.S., Merritt, L.E.L., Migiani, G., Minor, E.S., Mitchell, N., Mohammadi Bazargani, M., Moles, A.T., Monk, J.D., Moore, C.M., Morales-Morales, P.A., Moyers, B.T., Muñoz-Rojas, M., Munshi-South, J., Murphy, S.M., Murúa, M.M., Neila, M., Nikolaidis, O., Njunjić, I., Nosko, P., Núñez-Farfán, J., Ohgushi, T., Olsen, K.M., Opedal, Ø.H., Ornelas, C., Parachnowitsch, A.L., Paratore, A.S., Parody-Merino, A.M., Paule, J., Paulo, O.S., Pena, J.C., Pfeiffer, V.W., Pinho, P., Piot, A., Porth, I.M., Poulos, N., Puentes, A., Qu, J., Quintero-Vallejo, E., Raciti, S.M., Raeymaekers, J.A.M., Raveala, K.M., Rennison, D.J., Ribeiro, M.C., Richardson, J.L., Rivas-Torres, G., Rivera, B. J., Roddy, A.B., Rodriguez-Muñoz, E., Román, J.R., Rossi, L.S., Rowntree, J.K., Ryan, T.J., Salinas, S., Sanders, N.J., Santiago-Rosario, L.Y., Savage, A.M., Scheepens, J.F., Schilthuizen, M., Schneider, A.C., Scholier, T., Scott, J.L., Shaheed, S.A., Shefferson, R.P., Shepard, C.A., Shykoff, J.A., Silveira, G., Smith, A.D., Solis-Gabriel, L., Soro, A., Spellman, K.V., Whitney, K.S., Starke-Ottich, I., Stephan, J.G., Stephens, J.D., Szulc, J., Szulkin, M., Tack, A.J.M., Tamburrino, Í., Tate, T.D., Tergemina, E., Theodorou, P., Thompson, K.A., Threlfall, C.G., Tinghitella, R.M., Toledo-Chelala, L., Tong, X., Uroy, L., Utsumi, S., Vandegehuchte, M.L., VanWallendael, A., Vidal, P.M., Wadgymar, S.M., Wang, A-Y, Wang, N., Warbrick, M.L., Whitney, K.D., Wiesmeier, M., Wiles, J.T., Wu, J., Xirocostas, Z.A., Yan, Z., Yao, J., Yoder, J.B., Yoshida, O., Zhang, J., Zhao, Z., Ziter, C.D., Zuellig, M.P., Zufall, R.A., Zurita, J.E., Zytynska, S.E., Johnson, M.T.J., Santangelo, J.S., Ness, R.W., Cohan, B., Fitzpatrick, C.R., Innes, S.G., Koch, S., Miles, L.S., Munim, S., Peres-Neto, P.R., Prashad, C., Tong, A.T., Aguirre, W.E., Akinwole, P.O., Alberti, M., Álvarez, J., Anderson, J.T., Anderson, J.J., Ando, Y., Andrew, N.R., Angeoletto, F., Anstett, D.N., Anstett, J., Aoki-Gonçalves, F., Arietta, A.Z.A., Arroyo, M.T.K., Austen, E.J., Baena-Díaz, F., Barker, C.A., Baylis, H.A., Beliz, J.M., Benitez-Mora, A., Bickford, D., Biedebach, G., Blackburn, G.S., Boehm, M.M.A., Bonser, S.P., Bonte, D., Bragger, J.R., Branquinho, C., Brans, K.I., Bresciano, J.C., Brom, P.D., Bucharova, A., Burt, B., Cahill, J.F., Campbell, K.D., Carlen, E.J., Carmona, D., Castellanos, M.C., Centenaro, G., Chalen, I., Chaves, J.A., Chávez-Pesqueira, M., Chen, X-Y, Chilton, A.M., Chomiak, K.M., Cisneros-Heredia, D.F., Cisse, I.K., Classen, A.T., Comerford, M.S., Fradinger, C.C., Corney, H., Crawford, A.J., Crawford, K.M., Dahirel, M., David, S., De Haan, R., Deacon, N.J., Dean, C., del-Val, E., Deligiannis, E.K., Denney, D., Dettlaff, M.A., DiLeo, M.F., Ding, Y-Y, Domínguez-López, M.E., Dominoni, D.M., Draud, S.L., Dyson, K., Ellers, J., Espinosa, C.I., Essi, L., Falahati-Anbaran, M., Falcão, J.C.F., Fargo, H.T., Fellowes, M.D.E., Fitzpatrick, R.M., Flaherty, L.E., Flood, P. J., Flores, M.F., Fornoni, J., Foster, A.G., Frost, C.J., Fuentes, T.L., Fulkerson, J.R., Gagnon, E., Garbsch, F., Garroway, C.J., Gerstein, A.C., Giasson, M.M., Girdler, E.B., Gkelis, S., Godsoe, W., Golemiec, A.M., Golemiec, M., González-Lagos, C., Gorton, A.J., Gotanda, K.M., Granath, G., Greiner, S., Griffiths, J.S., Grilo, F., Gundel, P.E., Hamilton, B., Hardin, J.M., He, T., Heard, S.B., Henriques, A.F., Hernández-Poveda, M., Hetherington-Rauth, M.C., Hill, S.J., Hochuli, D.F., Hodgins, K.A., Hood, G.R., Hopkins, G.R., Hovanes, K.A., Howard, A.R., Hubbard, S.C., Ibarra-Cerdeña, C.N., Iñiguez-Armijos, C., Jara-Arancio, P., Jarrett, B.J.M., Jeannot, M., Jiménez-Lobato, V., Johnson, M., Johnson, O., Johnson, P.P., Johnson, R., Josephson, M.P., Jung, M.C., Just, M.G., Kahilainen, A., Kailing, O.S., Kariñho-Betancourt, E., Karousou, R., Kirn, L.A., Kirschbaum, A., Laine, A-L, LaMontagne, J.M., Lampei, C., Lara, C., Larson, E.L., Lázaro-Lobo, A., Le, J.H., Leandro, D.S., Lee, C., Lei, Y., León, C.A., Lequerica Tamara, M.E., Levesque, D.C., Liao, W-J, Ljubotina, M., Locke, H., Lockett, M.T., Longo, T.C., Lundholm, J.T., MacGillavry, T., Mackin, C.R., Mahmoud, A.R., Manju, I.A., Mariën, J., Martínez, D.N., Martínez-Bartolomé, M., Meineke, E.K., Mendoza-Arroyo, W., Merritt, T. J.S., Merritt, L.E.L., Migiani, G., Minor, E.S., Mitchell, N., Mohammadi Bazargani, M., Moles, A.T., Monk, J.D., Moore, C.M., Morales-Morales, P.A., Moyers, B.T., Muñoz-Rojas, M., Munshi-South, J., Murphy, S.M., Murúa, M.M., Neila, M., Nikolaidis, O., Njunjić, I., Nosko, P., Núñez-Farfán, J., Ohgushi, T., Olsen, K.M., Opedal, Ø.H., Ornelas, C., Parachnowitsch, A.L., Paratore, A.S., Parody-Merino, A.M., Paule, J., Paulo, O.S., Pena, J.C., Pfeiffer, V.W., Pinho, P., Piot, A., Porth, I.M., Poulos, N., Puentes, A., Qu, J., Quintero-Vallejo, E., Raciti, S.M., Raeymaekers, J.A.M., Raveala, K.M., Rennison, D.J., Ribeiro, M.C., Richardson, J.L., Rivas-Torres, G., Rivera, B. J., Roddy, A.B., Rodriguez-Muñoz, E., Román, J.R., Rossi, L.S., Rowntree, J.K., Ryan, T.J., Salinas, S., Sanders, N.J., Santiago-Rosario, L.Y., Savage, A.M., Scheepens, J.F., Schilthuizen, M., Schneider, A.C., Scholier, T., Scott, J.L., Shaheed, S.A., Shefferson, R.P., Shepard, C.A., Shykoff, J.A., Silveira, G., Smith, A.D., Solis-Gabriel, L., Soro, A., Spellman, K.V., Whitney, K.S., Starke-Ottich, I., Stephan, J.G., Stephens, J.D., Szulc, J., Szulkin, M., Tack, A.J.M., Tamburrino, Í., Tate, T.D., Tergemina, E., Theodorou, P., Thompson, K.A., Threlfall, C.G., Tinghitella, R.M., Toledo-Chelala, L., Tong, X., Uroy, L., Utsumi, S., Vandegehuchte, M.L., VanWallendael, A., Vidal, P.M., Wadgymar, S.M., Wang, A-Y, Wang, N., Warbrick, M.L., Whitney, K.D., Wiesmeier, M., Wiles, J.T., Wu, J., Xirocostas, Z.A., Yan, Z., Yao, J., Yoder, J.B., Yoshida, O., Zhang, J., Zhao, Z., Ziter, C.D., Zuellig, M.P., Zufall, R.A., Zurita, J.E., Zytynska, S.E., and Johnson, M.T.J.

Abstract

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale.

Published
2022

21. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author

de Rojas, I. Moreno-Grau, S. Tesi, N. Grenier-Boley, B. Andrade, V. Jansen, I.E. Pedersen, N.L. Stringa, N. Zettergren, A. Hernández, I. Montrreal, L. Antúnez, C. Antonell, A. Tankard, R.M. Bis, J.C. Sims, R. Bellenguez, C. Quintela, I. González-Perez, A. Calero, M. Franco-Macías, E. Macías, J. Blesa, R. Cervera-Carles, L. Menéndez-González, M. Frank-García, A. Royo, J.L. Moreno, F. Huerto Vilas, R. Baquero, M. Diez-Fairen, M. Lage, C. García-Madrona, S. García-González, P. Alarcón-Martín, E. Valero, S. Sotolongo-Grau, O. Ullgren, A. Naj, A.C. Lemstra, A.W. Benaque, A. Pérez-Cordón, A. Benussi, A. Rábano, A. Padovani, A. Squassina, A. de Mendonça, A. Arias Pastor, A. Kok, A.A.L. Meggy, A. Pastor, A.B. Espinosa, A. Corma-Gómez, A. Martín Montes, A. Sanabria, Á. DeStefano, A.L. Schneider, A. Haapasalo, A. Kinhult Ståhlbom, A. Tybjærg-Hansen, A. Hartmann, A.M. Spottke, A. Corbatón-Anchuelo, A. Rongve, A. Borroni, B. Arosio, B. Nacmias, B. Nordestgaard, B.G. Kunkle, B.W. Charbonnier, C. Abdelnour, C. Masullo, C. Martínez Rodríguez, C. Muñoz-Fernandez, C. Dufouil, C. Graff, C. Ferreira, C.B. Chillotti, C. Reynolds, C.A. Fenoglio, C. Van Broeckhoven, C. Clark, C. Pisanu, C. Satizabal, C.L. Holmes, C. Buiza-Rueda, D. Aarsland, D. Rujescu, D. Alcolea, D. Galimberti, D. Wallon, D. Seripa, D. Grünblatt, E. Dardiotis, E. Düzel, E. Scarpini, E. Conti, E. Rubino, E. Gelpi, E. Rodriguez-Rodriguez, E. Duron, E. Boerwinkle, E. Ferri, E. Tagliavini, F. Küçükali, F. Pasquier, F. Sanchez-Garcia, F. Mangialasche, F. Jessen, F. Nicolas, G. Selbæk, G. Ortega, G. Chêne, G. Hadjigeorgiou, G. Rossi, G. Spalletta, G. Giaccone, G. Grande, G. Binetti, G. Papenberg, G. Hampel, H. Bailly, H. Zetterberg, H. Soininen, H. Karlsson, I.K. Alvarez, I. Appollonio, I. Giegling, I. Skoog, I. Saltvedt, I. Rainero, I. Rosas Allende, I. Hort, J. Diehl-Schmid, J. Van Dongen, J. Vidal, J.-S. Lehtisalo, J. Wiltfang, J. Thomassen, J.Q. Kornhuber, J. Haines, J.L. Vogelgsang, J. Pineda, J.A. Fortea, J. Popp, J. Deckert, J. Buerger, K. Morgan, K. Fließbach, K. Sleegers, K. Molina-Porcel, L. Kilander, L. Weinhold, L. Farrer, L.A. Wang, L.-S. Kleineidam, L. Farotti, L. Parnetti, L. Tremolizzo, L. Hausner, L. Benussi, L. Froelich, L. Ikram, M.A. Deniz-Naranjo, M.C. Tsolaki, M. Rosende-Roca, M. Löwenmark, M. Hulsman, M. Spallazzi, M. Pericak-Vance, M.A. Esiri, M. Bernal Sánchez-Arjona, M. Dalmasso, M.C. Martínez-Larrad, M.T. Arcaro, M. Nöthen, M.M. Fernández-Fuertes, M. Dichgans, M. Ingelsson, M. Herrmann, M.J. Scherer, M. Vyhnalek, M. Kosmidis, M.H. Yannakoulia, M. Schmid, M. Ewers, M. Heneka, M.T. Wagner, M. Scamosci, M. Kivipelto, M. Hiltunen, M. Zulaica, M. Alegret, M. Fornage, M. Roberto, N. van Schoor, N.M. Seidu, N.M. Banaj, N. Armstrong, N.J. Scarmeas, N. Scherbaum, N. Goldhardt, O. Hanon, O. Peters, O. Skrobot, O.A. Quenez, O. Lerch, O. Bossù, P. Caffarra, P. Dionigi Rossi, P. Sakka, P. Hoffmann, P. Holmans, P.A. Fischer, P. Riederer, P. Yang, Q. Marshall, R. Kalaria, R.N. Mayeux, R. Vandenberghe, R. Cecchetti, R. Ghidoni, R. Frikke-Schmidt, R. Sorbi, S. Hägg, S. Engelborghs, S. Helisalmi, S. Botne Sando, S. Kern, S. Archetti, S. Boschi, S. Fostinelli, S. Gil, S. Mendoza, S. Mead, S. Ciccone, S. Djurovic, S. Heilmann-Heimbach, S. Riedel-Heller, S. Kuulasmaa, T. del Ser, T. Lebouvier, T. Polak, T. Ngandu, T. Grimmer, T. Bessi, V. Escott-Price, V. Giedraitis, V. Deramecourt, V. Maier, W. Jian, X. Pijnenburg, Y.A.L. Smith, A.D. Saenz, A. Bizzarro, A. Lauria, A. Vacca, A. Solomon, A. Anastasiou, A. Richardson, A. Boland, A. Koivisto, A. Daniele, A. Greco, A. Marianthi, A. McGuinness, B. Fin, B. Ferrari, C. Custodero, C. Ferrarese, C. Ingino, C. Mangone, C. Reyes Toso, C. Martínez, C. Cuesta, C. Muchnik, C. Joachim, C. Ortiz, C. Besse, C. Johansson, C. Zoia, C.P. Laske, C. Anastasiou, C. Palacio, D.L. Politis, D.G. Janowitz, D. Craig, D. Mann, D.M. Neary, D. Jürgen, D. Daian, D. Belezhanska, D. Kohler, E. Castaño, E.M. Koutsouraki, E. Chipi, E. De Roeck, E. Costantini, E. Vardy, E.R.L.C. Piras, F. Roveta, F. Piras, F. Prestia, F.A. Assogna, F. Salani, F. Sala, G. Lacidogna, G. Novack, G. Wilcock, G. Thonberg, H. Kölsch, H. Weber, H. Boecker, H. Etchepareborda, I. Piaceri, I. Tuomilehto, J. Lindström, J. Laczo, J. Johnston, J. Deleuze, J.-F. Harris, J. Schott, J.M. Priller, J. Bacha, J.I. Snowden, J. Lisso, J. Mihova, K.Y. Traykov, L. Morelli, L. Brusco, L.I. Rainer, M. Takalo, M. Bjerke, M. Del Zompo, M. Serpente, M. Sanchez Abalos, M. Rios, M. Peltonen, M. Herrman, M.J. Kosmidis, M.H. Kohler, M. Rojo, M. Jones, M. Orsini, M. Medel, N. Olivar, N. Fox, N.C. Salvadori, N. Hooper, N.M. Galeano, P. Solis, P. Bastiani, P. Mecocci, P. Passmore, P. Heun, R. Antikainen, R. Olaso, R. Perneczky, R. Germani, S. López-García, S. Love, S. Mehrabian, S. Bagnoli, S. Kochen, S. Andreoni, S. Teipel, S. Todd, S. Pickering-Brown, S. Natunen, T. Tegos, T. Laatikainen, T. Strandberg, T. Polvikoski, T.M. Matoska, V. Ciullo, V. Cores, V. Solfrizzi, V. Lisetti, V. Sevillano, Z. Abdelnour, C. Aguilera, N. Alarcon, E. Alegret, M. Benaque, A. Boada, M. Buendia, M. Cañabate, P. Carracedo, A. Corbatón-Anchuelo, A. Diego, S. Espinosa, A. Gailhajenet, A. Gil, S. Guitart, M. Hernández, I. Ibarria, M. Lafuente, A. Macias, J. Maroñas, O. Martín, E. Martínez, M.T. Marquié, M. Mauleón, A. Montrreal, L. Moreno-Grau, S. Moreno, M. Orellana, A. Ortega, G. Pancho, A. Pelejá, E. Pérez-Cordon, A. Pineda, J.A. Preckler, S. Quintela, I. Real, L.M. Rosende-Roca, M. Ruiz, A. Sáez, M.E. Sanabria, A. Serrano-Rios, M. Sotolongo-Grau, O. Tárraga, L. Valero, S. Vargas, L. Adarmes-Gómez, A.D. Alarcón-Martín, E. Alonso, M.D. Álvarez, I. Álvarez, V. Amer-Ferrer, G. Antequera, M. Antúnez, C. Baquero, M. Bernal, M. Blesa, R. Boada, M. Buiza-Rueda, D. Bullido, M.J. Burguera, J.A. Calero, M. Carrillo, F. Carrión-Claro, M. Casajeros, M.J. Clarimón, J. Cruz-Gamero, J.M. de Pancorbo, M.M. del Ser, T. Diez-Fairen, M. Escuela, R. Garrote-Espina, L. Fortea, J. Franco-Macías, E. Frank-García, A. García-Alberca, J.M. Garcia Madrona, S. Garcia-Ribas, G. Gómez-Garre, P. Hernández, I. Hevilla, S. Jesús, S. Labrador Espinosa, M.A. Lage, C. Legaz, A. Lleó, A. Lopez de Munain, A. López-García, S. Macias-García, D. Manzanares, S. Marín, M. Marín-Muñoz, J. Marín, T. Marquié, M. Martín Montes, A. Martínez, B. Martínez, C. Martínez, V. Martínez-Lage Álvarez, P. Medina, M. Mendioroz Iriarte, M. Mir, P. Molinuevo, J.L. Pastor, P. Pérez Tur, J. Periñán-Tocino, T. Pineda-Sanchez, R. Piñol-Ripoll, G. Rábano, A. Real de Asúa, D. Rodrigo, S. Rodríguez-Rodríguez, E. Royo, J.L. Ruiz, A. Sanchez del Valle Díaz, R. Sánchez-Juan, P. Sastre, I. Valero, S. Vicente, M.P. Vigo-Ortega, R. Vivancos, L. Macleod, C. McCracken, C. Brayne, C. Bresner, C. Grozeva, D. Bellou, E. Sommerville, E.W. Matthews, F. Leonenko, G. Menzies, G. Windle, G. Harwood, J. Phillips, J. Bennett, K. Luckuck, L. Clare, L. Woods, R. Saad, S. Burholt, V. Jansen, I.E. Rongve, A. Kehoe, P.G. Garcia-Ribas, G. Sánchez-Juan, P. Pastor, P. Pérez-Tur, J. Piñol-Ripoll, G. Lopez de Munain, A. García-Alberca, J.M. Bullido, M.J. Álvarez, V. Lleó, A. Real, L.M. Scheltens, P. Holstege, H. Marquié, M. Sáez, M.E. Carracedo, Á. Amouyel, P. Schellenberg, G.D. Williams, J. Seshadri, S. van Duijn, C.M. Mather, K.A. Sánchez-Valle, R. Serrano-Ríos, M. Orellana, A. Tárraga, L. Blennow, K. Huisman, M. Andreassen, O.A. Posthuma, D. Clarimón, J. Boada, M. van der Flier, W.M. Ramirez, A. Lambert, J.-C. van der Lee, S.J. Ruiz, A. EADB contributors The GR@ACE study group DEGESCO consortium IGAP (ADGC, CHARGE, EADI, GERAD) PGC-ALZ consortia

Abstract

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease. © 2021, The Author(s).

Published
2021

23. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author

de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I.E., Pedersen, N.L., Stringa, N., Zettergren, A., Hernández, I., Montrreal, L., Antúnez, C., Antonell, A., Tankard, R.M., Bis, J.C., Sims, R., Bellenguez, C., Quintela, I., González-Perez, A., Calero, M., Franco-Macías, E., Macías, J., Blesa, R., Cervera-Carles, L., Menéndez-González, M., Frank-García, A., Royo, J.L., Moreno, F., Huerto Vilas, R., Baquero, M., Diez-Fairen, M., Lage, C., García-Madrona, S., García-González, P., Alarcón-Martín, E., Valero, S., Sotolongo-Grau, O., Ullgren, A., Naj, A.C., Lemstra, A.W., Benaque, A., Pérez-Cordón, A., Benussi, A., Rábano, A., Padovani, A., Squassina, A., de Mendonça, A., Arias Pastor, A., Kok, A.A.L., Meggy, A., Pastor, A.B., Espinosa, A., Corma-Gómez, A., Martín Montes, A., Sanabria, Á., DeStefano, A.L., Schneider, A., Haapasalo, A., Kinhult Ståhlbom, A., Tybjærg-Hansen, A., Hartmann, A.M., Spottke, A., Corbatón-Anchuelo, A., Rongve, A., Borroni, B., Arosio, B., Nacmias, B., Nordestgaard, B.G., Kunkle, B.W., Charbonnier, C., Abdelnour, C., Masullo, C., Martínez Rodríguez, C., Muñoz-Fernandez, C., Dufouil, C., Graff, C., Ferreira, C.B., Chillotti, C., Reynolds, C.A., Fenoglio, C., Van Broeckhoven, C., Clark, C., Pisanu, C., Satizabal, C.L., Holmes, C., Buiza-Rueda, D., Aarsland, D., Rujescu, D., Alcolea, D., Galimberti, D., Wallon, D., Seripa, D., Grünblatt, E., Dardiotis, E., Düzel, E., Scarpini, E., Conti, E., Rubino, E., Gelpi, E., Rodriguez-Rodriguez, E., Duron, E., Boerwinkle, E., Ferri, E., Tagliavini, F., Küçükali, F., Pasquier, F., Sanchez-Garcia, F., Mangialasche, F., Jessen, F., Nicolas, G., Selbæk, G., Ortega, G., Chêne, G., Hadjigeorgiou, G., Rossi, G, Spalletta, G., Giaccone, G., Grande, G., Binetti, G., Papenberg, G., Hampel, H., Bailly, H., Zetterberg, H., Soininen, H., Karlsson, I.K., Alvarez, I., Appollonio, I., Giegling, I., Skoog, I., Saltvedt, I., Rainero, I., Rosas Allende, I., Hort, J., Diehl-Schmid, J., Van Dongen, J., Vidal, J-S, Lehtisalo, J., Wiltfang, J., Thomassen, J.Q., Kornhuber, J., Haines, J.L., Vogelgsang, J., Pineda, J.A., Fortea, J., Popp, J., Deckert, J., Buerger, K., Morgan, K., Fließbach, K., Sleegers, K., Molina-Porcel, L., Kilander, L., Weinhold, L., Farrer, L.A., Wang, L-S, Kleineidam, L., Farotti, L., Parnetti, L., Tremolizzo, L., Hausner, L., Benussi, L., Froelich, L., Ikram, M.A., Deniz-Naranjo, M.C., Tsolaki, M., Rosende-Roca, M., Löwenmark, M., Hulsman, M., Spallazzi, M., Pericak-Vance, M.A., Esiri, M., Bernal Sánchez-Arjona, M., Dalmasso, M.C., Martínez-Larrad, M.T., Arcaro, M., Nöthen, M.M., Fernández-Fuertes, M., Dichgans, M., Ingelsson, M., Herrmann, M.J., Scherer, M., Vyhnalek, M., Kosmidis, M.H., Yannakoulia, M., Schmid, M., Ewers, M., Heneka, M.T., Wagner, M., Scamosci, M., Kivipelto, M., Hiltunen, M., Zulaica, M., Alegret, M., Fornage, M., Roberto, N., van Schoor, N.M., Seidu, N.M., Banaj, N., Armstrong, N.J., Scarmeas, N., Scherbaum, N., Goldhardt, O., Hanon, O., Peters, O., Skrobot, O.A., Quenez, O., Lerch, O., Bossù, P., Caffarra, P., Dionigi Rossi, P., Sakka, P., Hoffmann, P., Holmans, P.A., Fischer, P., Riederer, P., Yang, Q., Marshall, R., Kalaria, R.N., Mayeux, R., Vandenberghe, R., Cecchetti, R., Ghidoni, R., Frikke-Schmidt, R., Sorbi, S., Hägg, S., Engelborghs, S., Helisalmi, S., Botne Sando, S., Kern, S., Archetti, S., Boschi, S., Fostinelli, S., Gil, S., Mendoza, S., Mead, S., Ciccone, S., Djurovic, S., Heilmann-Heimbach, S., Riedel-Heller, S., Kuulasmaa, T., del Ser, T., Lebouvier, T., Polak, T., Ngandu, T., Grimmer, T., Bessi, V., Escott-Price, V., Giedraitis, V., Deramecourt, V., Maier, W., Jian, X., Pijnenburg, Y.A.L., Smith, A.D., Saenz, A., Bizzarro, A., Lauria, A., Vacca, A., Solomon, A., Anastasiou, A., Richardson, A., Boland, A., Koivisto, A., Daniele, A., Greco, A., Marianthi, A., McGuinness, B., Fin, B., Ferrari, Ca., Custodero, C., Ferrarese, C., Ingino, C., Mangone, C., Reyes Toso, C., Martinez, C., Cuesta, C., Muchnik, C., Joachim, C., Ortiz, C., Besse, C., Johansson, C., Zoia, C.P., Laske, C., Anastasiou, C., Palacio, D.L., Politis, D.G., Janowitz, D., Craig, D., Mann, D.M., Neary, D., Jürgen, D., Daian, D., Belezhanska, D., Kohler, E., Castaño, E.M., Koutsouraki, E., Chipi, E., De Roeck, E., Costantini, E., Vardy, E.R.L.C., Piras, F., Roveta, F., Prestia, F.A., Assogna, F., Salani, F., Sala, G., Lacidogna, G., Novack, G., Wilcock, G., Thonberg, H., Kölsch, H., Weber, H., Boecker, H., Etchepareborda, I., Piaceri, I., Tuomilehto, J., Lindström, J., Laczo, J., Johnston, J., Deleuze, J-F, Harris, J., Schott, J.M., Priller, J., Bacha, J.I., Snowden, J., Lisso, J., Mihova, K.Y., Traykov, L., Morelli, L., Brusco, L.I., Rainer, M., Takalo, M., Bjerke, M., Del Zompo, M., Serpente, M., Sanchez Abalos, M., Rios, M., Peltonen, M., Herrman, M.J., Kohler, M., Rojo, M., Jones, M., Orsini, M., Medel, N., Olivar, N., Fox, N.C., Salvadori, N., Hooper, N.M., Galeano, P., Solis, P., Bastiani, P., Mecocci, P., Passmore, P., Heun, R., Antikainen, R., Olaso, R., Perneczky, R., Germani, S., López-García, S., Love, S., Mehrabian, S., Bagnoli, S., Kochen, S., Andreoni, S., Teipel, S., Todd, S., Pickering-Brown, S., Natunen, T., Tegos, T., Laatikainen, T., Strandberg, T., Polvikoski, T.M., Matoska, V., Ciullo, V., Cores, V., Solfrizzi, V., Lisetti, V., Sevillano, Z., Aguilera, N., Alarcon, E., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Diego, S., Gailhajenet, A., Guitart, M., González-Pérez, A., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M. T., Marquié, M., Mauleón, A., Moreno, M., Orellana, A., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J. A., Preckler, S., Real, L. M., Ruiz, A., Sáez, M. E., Sanabria, A., Serrano-Rios, M., Tárraga, L., Vargas, L., Adarmes-Gómez, A. D., Alonso, M. D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Bernal, M., Bullido, M.J., Burguera, J.A., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., Escuela, R., Garrote-Espina, L., García-Alberca, J.M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M.A., Legaz, A., Lleó, A., Lopez de Munain, A., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Mir, P., Molinuevo, J.L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, C., Bresner, C., Grozeva, D., Bellou, E., Sommerville, E.W., Matthews, F., Leonenko, G., Menzies, G., Windle, G., Harwood, J., Phillips, J., Bennett, K., Luckuck, L., Clare, L., Woods, R., Saad, S., Burholt, V., Kehoe, P.G., Pérez-Tur, J., Real, L.M., Scheltens, P., Holstege, H., Sáez, M.E., Carracedo, Á., Amouyel, P., Schellenberg, G.D., Williams, J., Seshadri, S., van Duijn, C.M., Mather, K.A., Sánchez-Valle, R., Serrano-Ríos, M., Blennow, K., Huisman, M., Andreassen, O.A., Posthuma, D., van der Flier, W.M., Ramirez, A., Lambert, J-C, van der Lee, S.J., de Rojas, I., Moreno-Grau, S., Tesi, N., Grenier-Boley, B., Andrade, V., Jansen, I.E., Pedersen, N.L., Stringa, N., Zettergren, A., Hernández, I., Montrreal, L., Antúnez, C., Antonell, A., Tankard, R.M., Bis, J.C., Sims, R., Bellenguez, C., Quintela, I., González-Perez, A., Calero, M., Franco-Macías, E., Macías, J., Blesa, R., Cervera-Carles, L., Menéndez-González, M., Frank-García, A., Royo, J.L., Moreno, F., Huerto Vilas, R., Baquero, M., Diez-Fairen, M., Lage, C., García-Madrona, S., García-González, P., Alarcón-Martín, E., Valero, S., Sotolongo-Grau, O., Ullgren, A., Naj, A.C., Lemstra, A.W., Benaque, A., Pérez-Cordón, A., Benussi, A., Rábano, A., Padovani, A., Squassina, A., de Mendonça, A., Arias Pastor, A., Kok, A.A.L., Meggy, A., Pastor, A.B., Espinosa, A., Corma-Gómez, A., Martín Montes, A., Sanabria, Á., DeStefano, A.L., Schneider, A., Haapasalo, A., Kinhult Ståhlbom, A., Tybjærg-Hansen, A., Hartmann, A.M., Spottke, A., Corbatón-Anchuelo, A., Rongve, A., Borroni, B., Arosio, B., Nacmias, B., Nordestgaard, B.G., Kunkle, B.W., Charbonnier, C., Abdelnour, C., Masullo, C., Martínez Rodríguez, C., Muñoz-Fernandez, C., Dufouil, C., Graff, C., Ferreira, C.B., Chillotti, C., Reynolds, C.A., Fenoglio, C., Van Broeckhoven, C., Clark, C., Pisanu, C., Satizabal, C.L., Holmes, C., Buiza-Rueda, D., Aarsland, D., Rujescu, D., Alcolea, D., Galimberti, D., Wallon, D., Seripa, D., Grünblatt, E., Dardiotis, E., Düzel, E., Scarpini, E., Conti, E., Rubino, E., Gelpi, E., Rodriguez-Rodriguez, E., Duron, E., Boerwinkle, E., Ferri, E., Tagliavini, F., Küçükali, F., Pasquier, F., Sanchez-Garcia, F., Mangialasche, F., Jessen, F., Nicolas, G., Selbæk, G., Ortega, G., Chêne, G., Hadjigeorgiou, G., Rossi, G, Spalletta, G., Giaccone, G., Grande, G., Binetti, G., Papenberg, G., Hampel, H., Bailly, H., Zetterberg, H., Soininen, H., Karlsson, I.K., Alvarez, I., Appollonio, I., Giegling, I., Skoog, I., Saltvedt, I., Rainero, I., Rosas Allende, I., Hort, J., Diehl-Schmid, J., Van Dongen, J., Vidal, J-S, Lehtisalo, J., Wiltfang, J., Thomassen, J.Q., Kornhuber, J., Haines, J.L., Vogelgsang, J., Pineda, J.A., Fortea, J., Popp, J., Deckert, J., Buerger, K., Morgan, K., Fließbach, K., Sleegers, K., Molina-Porcel, L., Kilander, L., Weinhold, L., Farrer, L.A., Wang, L-S, Kleineidam, L., Farotti, L., Parnetti, L., Tremolizzo, L., Hausner, L., Benussi, L., Froelich, L., Ikram, M.A., Deniz-Naranjo, M.C., Tsolaki, M., Rosende-Roca, M., Löwenmark, M., Hulsman, M., Spallazzi, M., Pericak-Vance, M.A., Esiri, M., Bernal Sánchez-Arjona, M., Dalmasso, M.C., Martínez-Larrad, M.T., Arcaro, M., Nöthen, M.M., Fernández-Fuertes, M., Dichgans, M., Ingelsson, M., Herrmann, M.J., Scherer, M., Vyhnalek, M., Kosmidis, M.H., Yannakoulia, M., Schmid, M., Ewers, M., Heneka, M.T., Wagner, M., Scamosci, M., Kivipelto, M., Hiltunen, M., Zulaica, M., Alegret, M., Fornage, M., Roberto, N., van Schoor, N.M., Seidu, N.M., Banaj, N., Armstrong, N.J., Scarmeas, N., Scherbaum, N., Goldhardt, O., Hanon, O., Peters, O., Skrobot, O.A., Quenez, O., Lerch, O., Bossù, P., Caffarra, P., Dionigi Rossi, P., Sakka, P., Hoffmann, P., Holmans, P.A., Fischer, P., Riederer, P., Yang, Q., Marshall, R., Kalaria, R.N., Mayeux, R., Vandenberghe, R., Cecchetti, R., Ghidoni, R., Frikke-Schmidt, R., Sorbi, S., Hägg, S., Engelborghs, S., Helisalmi, S., Botne Sando, S., Kern, S., Archetti, S., Boschi, S., Fostinelli, S., Gil, S., Mendoza, S., Mead, S., Ciccone, S., Djurovic, S., Heilmann-Heimbach, S., Riedel-Heller, S., Kuulasmaa, T., del Ser, T., Lebouvier, T., Polak, T., Ngandu, T., Grimmer, T., Bessi, V., Escott-Price, V., Giedraitis, V., Deramecourt, V., Maier, W., Jian, X., Pijnenburg, Y.A.L., Smith, A.D., Saenz, A., Bizzarro, A., Lauria, A., Vacca, A., Solomon, A., Anastasiou, A., Richardson, A., Boland, A., Koivisto, A., Daniele, A., Greco, A., Marianthi, A., McGuinness, B., Fin, B., Ferrari, Ca., Custodero, C., Ferrarese, C., Ingino, C., Mangone, C., Reyes Toso, C., Martinez, C., Cuesta, C., Muchnik, C., Joachim, C., Ortiz, C., Besse, C., Johansson, C., Zoia, C.P., Laske, C., Anastasiou, C., Palacio, D.L., Politis, D.G., Janowitz, D., Craig, D., Mann, D.M., Neary, D., Jürgen, D., Daian, D., Belezhanska, D., Kohler, E., Castaño, E.M., Koutsouraki, E., Chipi, E., De Roeck, E., Costantini, E., Vardy, E.R.L.C., Piras, F., Roveta, F., Prestia, F.A., Assogna, F., Salani, F., Sala, G., Lacidogna, G., Novack, G., Wilcock, G., Thonberg, H., Kölsch, H., Weber, H., Boecker, H., Etchepareborda, I., Piaceri, I., Tuomilehto, J., Lindström, J., Laczo, J., Johnston, J., Deleuze, J-F, Harris, J., Schott, J.M., Priller, J., Bacha, J.I., Snowden, J., Lisso, J., Mihova, K.Y., Traykov, L., Morelli, L., Brusco, L.I., Rainer, M., Takalo, M., Bjerke, M., Del Zompo, M., Serpente, M., Sanchez Abalos, M., Rios, M., Peltonen, M., Herrman, M.J., Kohler, M., Rojo, M., Jones, M., Orsini, M., Medel, N., Olivar, N., Fox, N.C., Salvadori, N., Hooper, N.M., Galeano, P., Solis, P., Bastiani, P., Mecocci, P., Passmore, P., Heun, R., Antikainen, R., Olaso, R., Perneczky, R., Germani, S., López-García, S., Love, S., Mehrabian, S., Bagnoli, S., Kochen, S., Andreoni, S., Teipel, S., Todd, S., Pickering-Brown, S., Natunen, T., Tegos, T., Laatikainen, T., Strandberg, T., Polvikoski, T.M., Matoska, V., Ciullo, V., Cores, V., Solfrizzi, V., Lisetti, V., Sevillano, Z., Aguilera, N., Alarcon, E., Boada, M., Buendia, M., Cañabate, P., Carracedo, A., Diego, S., Gailhajenet, A., Guitart, M., González-Pérez, A., Ibarria, M., Lafuente, A., Macias, J., Maroñas, O., Martín, E., Martínez, M. T., Marquié, M., Mauleón, A., Moreno, M., Orellana, A., Pancho, A., Pelejá, E., Pérez-Cordon, A., Pineda, J. A., Preckler, S., Real, L. M., Ruiz, A., Sáez, M. E., Sanabria, A., Serrano-Rios, M., Tárraga, L., Vargas, L., Adarmes-Gómez, A. D., Alonso, M. D., Álvarez, I., Álvarez, V., Amer-Ferrer, G., Antequera, M., Bernal, M., Bullido, M.J., Burguera, J.A., Carrillo, F., Carrión-Claro, M., Casajeros, M.J., Clarimón, J., Cruz-Gamero, J.M., de Pancorbo, M.M., Escuela, R., Garrote-Espina, L., García-Alberca, J.M., Garcia Madrona, S., Garcia-Ribas, G., Gómez-Garre, P., Hevilla, S., Jesús, S., Labrador Espinosa, M.A., Legaz, A., Lleó, A., Lopez de Munain, A., Macias-García, D., Manzanares, S., Marín, M., Marín-Muñoz, J., Marín, T., Martínez, B., Martínez, C., Martínez, V., Martínez-Lage Álvarez, P., Medina, M., Mendioroz Iriarte, M., Mir, P., Molinuevo, J.L., Pastor, P., Pérez Tur, J., Periñán-Tocino, T., Pineda-Sanchez, R., Piñol-Ripoll, G., Real de Asúa, D., Rodrigo, S., Rodríguez-Rodríguez, E., Sanchez del Valle Díaz, R., Sánchez-Juan, P., Sastre, I., Vicente, M.P., Vigo-Ortega, R., Vivancos, L., Macleod, C., McCracken, C., Brayne, C., Bresner, C., Grozeva, D., Bellou, E., Sommerville, E.W., Matthews, F., Leonenko, G., Menzies, G., Windle, G., Harwood, J., Phillips, J., Bennett, K., Luckuck, L., Clare, L., Woods, R., Saad, S., Burholt, V., Kehoe, P.G., Pérez-Tur, J., Real, L.M., Scheltens, P., Holstege, H., Sáez, M.E., Carracedo, Á., Amouyel, P., Schellenberg, G.D., Williams, J., Seshadri, S., van Duijn, C.M., Mather, K.A., Sánchez-Valle, R., Serrano-Ríos, M., Blennow, K., Huisman, M., Andreassen, O.A., Posthuma, D., van der Flier, W.M., Ramirez, A., Lambert, J-C, and van der Lee, S.J.

Abstract

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.

Published
2021

24. Type 1 diabetes in pregnancy is associated with distinct changes in the composition and function of the gut microbiome.

Author

Roth-Schulze A.J., Penno M.A.S., Ngui K.M., Oakey H., Bandala-Sanchez E., Smith A.D., Allnutt T.R., Thomson R.L., Vuillermin P.J., Craig M.E., Rawlinson W.D., Davis E.A., Harris M., Soldatos G., Colman P.G., Wentworth J.M., Haynes A., Barry S.C., Sinnott R.O., Morahan G., Bediaga N.G., Smyth G.K., Papenfuss A.T., Couper J.J., Harrison L.C., Roth-Schulze A.J., Penno M.A.S., Ngui K.M., Oakey H., Bandala-Sanchez E., Smith A.D., Allnutt T.R., Thomson R.L., Vuillermin P.J., Craig M.E., Rawlinson W.D., Davis E.A., Harris M., Soldatos G., Colman P.G., Wentworth J.M., Haynes A., Barry S.C., Sinnott R.O., Morahan G., Bediaga N.G., Smyth G.K., Papenfuss A.T., Couper J.J., and Harrison L.C.

Abstract

Background: The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. Result(s): Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. Conclusion(s): Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means. [MediaObject not available: see fulltext.]Copyright © 2021, The Author(s).

Published
2021

30. Olfactory impairment is more marked in patients with mild dementia with Lewy bodies than those with mild Alzheimer disease

Author

Williams, S.S., Williams, J., Combrinck, M., Christie, S., Smith, A.D., and McShane, R.

Subjects
Smell disorders -- Diagnosis, Dementia -- Physiological aspects, Dementia -- Comparative analysis, Dementia -- Diagnosis, Alzheimer's disease -- Physiological aspects, Alzheimer's disease -- Comparative analysis, Alzheimer's disease -- Diagnosis, Medical screening -- Usage, Health, Psychology and mental health
Published
2009

31. Plasma vitamin B12 status and cerebral white-matter lesions

Author

de Lau, L.M.L., Smith, A.D., Refsum, H., Johnston, C., and Breteler, M.M.B.

Subjects
Vitamin B12 -- Research, Vitamin B12 -- Physiological aspects, Brain diseases -- Research, Brain diseases -- Physiological aspects, Homocysteine -- Research, Homocysteine -- Physiological aspects, Health, Psychology and mental health
Published
2009

35. Apolipoprotein E (sub epsilon)4 and impaired episodic memory in community-dwelling elderly people: a marked sex difference: the Hordaland Health Study

Author

Lehmann, D.J., Refsum, H., Nurk, E., Warden, D.R., Tell, G.S., Vollset, S.E., Engedal, K., Nygaard, H.A., and Smith, A.D.

Subjects
Apolipoproteins -- Research, Apolipoproteins -- Physiological aspects, Aged patients -- Research, Aged patients -- Physiological aspects, Cognition disorders -- Research, Sex research -- Evaluation, Health, Psychology and mental health
Published
2006

36. Levels of CSF prostaglandin E2, cognitive decline, and survival in Alzheimer's disease

Author

Combrinck, M., Williams, J., De Berardinis, M.A., Warden, D., Puopolo, M., Smith, A.D., and Minghetti, L.

Subjects
Alzheimer's disease -- Patient outcomes, Alzheimer's disease -- Research, Cerebrospinal fluid -- Research, Cyclooxygenases -- Analysis, Prostaglandins E -- Analysis, Health, Psychology and mental health
Published
2006

37. Frequency-domain SQUID multiplexing of transition-edge sensors

Author

Lanting, T.M., Hsiao-Mei Cho, Clarke, John, Dobbs, Matt A., Holzapfel, W.L., Lee, Adrian T., Lueker, M., Richards, P.L., Smith, A.D., and Spieler, Helmuth G.

Subjects
Multiplexers -- Design and construction, Bolometers -- Design and construction, Superconducting quantum interference devices -- Design and construction, Multiplexer, Business, Electronics, Electronics and electrical industries
Abstract

Frequency-domain readout multiplexer for transition-edge sensor (TES) bolometers is described and measurements of an eight-channel multiplexer are presented. The demodulated noise spectra from multiplexed sensors are found to show the expected white noise levels at frequencdcies above 200 mHz.

Published
2005

38. A frequency-domain SQUID multiplexer for arrays of transition-edge superconducting sensors

Author

Lanting, T.M., Cho, Hsiao-Mei, Clarke, John, Dobbs, Matt, Lee, Adrian T., Richards, P.L., Smith, A.D., and Spieler, H.G.

Subjects
Multiplexers -- Research, Superconductive devices -- Research, Edge detection (Image processing) -- Research, Bolometers -- Research, Multiplexer, Business, Electronics, Electronics and electrical industries
Abstract

Design of a frequency-domain multiplexer (MUX) for reading out arrays of superconducting transition-edge sensors (TES) is described.

Published
2003

39. Measurement and analysis of brain deformation during neurosurgery

Author

Hartkens, T., Hill, D.L.G., Castellano-Smith, A.D., Hawkes, D.J., Maurer, C.R., Martin, Jr. A.J., Hall, W.A., Liu, H., and Truwit, C.L.

Subjects
Brain damage, Magnetic resonance imaging, Business, Electronics, Electronics and electrical industries, Health care industry
Abstract

Recent studies have shown that the surface of the brain is deformed by up to 20 mm after the skull is opened during neurosurgery, which could lead to substantial error in commercial image-guided surgery systems. We quantitatively analyze the intraoperative brain deformation of 24 subjects to investigate whether simple rules can describe or predict the deformation. Interventional magnetic resonance images acquired at the start and end of the procedure are registered nonrigidly to obtain deformation values throughout the brain. Deformation patterns are investigated quantitatively with respect to the location and magnitude of deformation, and to the distribution and principal direction of the displacements. We also measure the volume change of the lateral ventricles by manual segmentation. Our study indicates that brain shift occurs predominantly in the hemisphere ipsi-lateral to the craniotomy, and that there is more brain deformation during resection procedures than during biopsy or functional procedures. However, the brain deformation patterns are extremely complex in this group of subjects. This paper quantitatively demonstrates that brain deformation occurs not only at the surface, but also in deeper brain structure, and that the principal direction of displacement does not always correspond with the direction of gravity. Therefore, simple computational algorithms that utilize limited intraoperative information (e.g., brain surface shift) will not always accurately predict brain deformation at the lesion. Index Terms--Interventional MRI, intraoperative brain deformation, nonrigid image registration.

Published
2003

43. Measures of folding applied to the development of the human fetal brain

Author

Batchelor, Ph.G., Smith, A.D. Castellano, Hill, D.L.G., Hawkes, D.J., Cox, T.C.S., and Dean, A.F.

Subjects
Fetal brain -- Medical examination, Diagnostic imaging -- Research, Brain -- Abnormalities, Business, Electronics, Electronics and electrical industries, Health care industry
Abstract

Previous work has suggested the existence of differences between the cerebral cortex of normal individuals, and those of patients with diseases such as epilepsy and schizophrenia. These shape abnormalities may be of developmental origin. Improved shape measures could provide useful tools for neuroscience research and patient diagnosis. We consider the theoretically desirable properties of measures of brain shape. We have implemented seven measures, three from the neuroscience literature, and four new to this field. Three of the measures are zero-order and four are second-order with respect to the surface. We validate the measures using simple geometrical shapes, and a collection of magnetic resonance scans of ten histologically normal ex vivo fetal brains with gestational ages from 19-42 weeks. We then apply the measures to MR scans from two histologically abnormal ex vivo brains. We demonstrate that our implementation of the measures is sensitive to anatomical variability rather than to the discreteness of the image data. All the measures were sensitive to changes in shape during fetal development. Several of the measures could distinguish between the normal and abnormal fetal brains. We propose a multivariate approach to studying the shape of the cerebral cortex, in which both zero-order and second-order measures are used to quantify folding. Index Terms--Brain folding, cortical shape, curvature, development, fetal.

Published
2002

44. Descartes and the Late Scholastics

Author

Smith, A.D.

Subjects
Descartes and the Late Scholastics (Book), Books -- Book reviews, Philosophy and religion
Published
2002

45. O'Shaughnessy's consciousness

Author

Smith, A.D.

Subjects
Consciousness and the World (Book), Books -- Book reviews, Philosophy and religion
Published
2001

46. Perception and belief

Author

Smith, A.D.

Subjects
Perception (Philosophy) -- Analysis, Belief and doubt -- Beliefs, opinions and attitudes, Philosophy and religion
Abstract

The role of belief in perception is discussed. Issues include the way in which 'collateral' beliefs can override perceptual belief and Fred Dretske's conception of 'non-epistemic perception.'

Published
2001

49. 710P Phase II trial of lenvatinib (LEN) + pembrolizumab (PEMBRO) for progressive disease after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell (mcc) renal cell carcinoma (RCC): Results by independent imaging review and subgroup analyses

Author

Lee, C-H., primary, Shah, A.Y., additional, Hsieh, J.J., additional, Rao, A., additional, Pinto, A., additional, Bilen, M.A., additional, Cohn, A.L., additional, Di Simone, C., additional, Shaffer, D.R., additional, Girones Sarrio, R., additional, Gunnestad Ribe, S., additional, Wu, J., additional, Schmidt, E., additional, Kubiak, P., additional, Okpara, C.E., additional, Smith, A.D., additional, and Motzer, R.J., additional

Published
2020
Full Text
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50. LBA44 Lenvatinib (len) plus pembrolizumab (pembro) for advanced melanoma (MEL) that progressed on a PD-1 or PD-L1 inhibitor: Initial results of LEAP-004

Author

Fernandez, A.M. Arance, primary, O'Day, S.J., additional, Merino, L. de la Cruz, additional, Petrella, T., additional, Jamal, R., additional, Ny, L., additional, Carneiro, A., additional, Berrocal, A., additional, Márquez-Rodas, I., additional, Spreafico, A., additional, Victoria Atkinson, V., additional, Costa Svedman, F., additional, Smith, A.D., additional, Chen, K., additional, Diede, S.J., additional, Krepler, C., additional, and Long, G.V., additional

Published
2020
Full Text
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