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140 results on '"Milewicz, D"'

6. The molecular genetics of Marfan syndrome and related disorders

Author

Robinson, P N, Arteaga-Solis, E, Baldock, C, Collod-Béroud, G, Booms, P, De Paepe, A, Dietz, H C, Guo, G, Handford, P A, Judge, D P, Kielty, C M, Loeys, B, Milewicz, D M, Ney, A, Ramirez, F, Reinhardt, D P, Tiedemann, K, Whiteman, P, and Godfrey, M

Published
2006

7. MYLK pathogenic variants aortic disease presentation, pregnancy risk, and characterization of pathogenic missense variants

Author

Wallace, S. E., Regalado, E. S., Gong, L., Janda, A. L., Guo, D. -C., Russo, C. F., Kulmacz, R. J., Hanna, N., Jondeau, G., Boileau, C., Arnaud, P., Lee, K., Leal, S. M., Hannuksela, M., Carlberg, B., Johnston, T., Antolik, C., Hostetler, E. M., Colombo, Roberto, Milewicz, D. M., Colombo R. (ORCID:0000-0003-0482-7542), Wallace, S. E., Regalado, E. S., Gong, L., Janda, A. L., Guo, D. -C., Russo, C. F., Kulmacz, R. J., Hanna, N., Jondeau, G., Boileau, C., Arnaud, P., Lee, K., Leal, S. M., Hannuksela, M., Carlberg, B., Johnston, T., Antolik, C., Hostetler, E. M., Colombo, Roberto, Milewicz, D. M., and Colombo R. (ORCID:0000-0003-0482-7542)

Abstract

Purpose: Heritable thoracic aortic disease can result from null variants in MYLK, which encodes myosin light-chain kinase (MLCK). Data on which MYLK missense variants are pathogenic and information to guide aortic disease management are limited. Methods: Clinical data from 60 cases with MYLK pathogenic variants were analyzed (five null and two missense variants), and the effect of missense variants on kinase activity was assessed. Results: Twenty-three individuals (39%) experienced an aortic event (defined as aneurysm repair or dissection); the majority of these events (87%) were aortic dissections. Aortic diameters were minimally enlarged at the time of dissection in many cases. Time-to-aortic-event curves showed that missense pathogenic variant (PV) carriers have earlier-onset aortic events than null PV carriers. An MYLK missense variant segregated with aortic disease over five generations but decreases MYLK kinase acitivity marginally. Functional Assays fail to identify all pathogenic variants in MYLK. Conclusion: These data further define the aortic phenotype associated with MYLK pathogenic variants. Given minimal aortic enlargement before dissection, an alternative approach to guide the timing of aortic repair is proposed based on the probability of a dissection at a given age.

Published
2019

8. Association of Apolipoprotein E With Intracerebral Hemorrhage Risk by Race/Ethnicity A Meta-analysis

Author

Marini, S, Crawford, K, Morotti, A, Lee, MJ, Pezzini, A, Moomaw, CJ, Flaherty, ML, Montaner, J, Roquer, J, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano-Tarraga, C, Slowik, A, Jagiella, JM, Pera, J, Urbanik, A, Pichler, A, Hansen, BM, McCauley, JL, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Testai, FD, Kittner, SJ, Schmidt, H, Enzinger, C, Deary, LJ, Rannikmae, K, Samarasekera, N, Salman, RA-S, Sudlow, CL, Klijn, CJM, van Nieuwenhuizen, KM, Fernandez-Cadenas, I, Delgado, P, Nonving, B, Lindgren, A, Goldstein, JN, Viswanathan, A, Greenberg, SM, Falcone, GJ, Biffi, A, Langefeld, CD, Woo, D, Rosand, J, Anderson, CD, Smoller, S, Sorkin, J, Wang, X, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Cotlarcius, L, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lennnnens, R, Ahmadi, K, Opherk, C, Duering, M, Dichgans, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr-Nabavi, A, Romero, J, Anderson, C, Falcone, G, Brouwers, B, Rost, N, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pare, G, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jem, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Hansen, B, Norrving, B, Smith, G, Martin, JJ, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Hunter, J, Attia, J, Farrall, M, Giese, A-K, Fomage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Marini, S, Crawford, K, Morotti, A, Lee, MJ, Pezzini, A, Moomaw, CJ, Flaherty, ML, Montaner, J, Roquer, J, Jimenez-Conde, J, Giralt-Steinhauer, E, Elosua, R, Cuadrado-Godia, E, Soriano-Tarraga, C, Slowik, A, Jagiella, JM, Pera, J, Urbanik, A, Pichler, A, Hansen, BM, McCauley, JL, Tirschwell, DL, Selim, M, Brown, DL, Silliman, SL, Worrall, BB, Meschia, JF, Kidwell, CS, Testai, FD, Kittner, SJ, Schmidt, H, Enzinger, C, Deary, LJ, Rannikmae, K, Samarasekera, N, Salman, RA-S, Sudlow, CL, Klijn, CJM, van Nieuwenhuizen, KM, Fernandez-Cadenas, I, Delgado, P, Nonving, B, Lindgren, A, Goldstein, JN, Viswanathan, A, Greenberg, SM, Falcone, GJ, Biffi, A, Langefeld, CD, Woo, D, Rosand, J, Anderson, CD, Smoller, S, Sorkin, J, Wang, X, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Cotlarcius, L, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lennnnens, R, Ahmadi, K, Opherk, C, Duering, M, Dichgans, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr-Nabavi, A, Romero, J, Anderson, C, Falcone, G, Brouwers, B, Rost, N, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pare, G, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jem, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Hansen, B, Norrving, B, Smith, G, Martin, JJ, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Hunter, J, Attia, J, Farrall, M, Giese, A-K, Fomage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K

Published
2019

12. Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

Author

Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, Sheth, K, Pulit, SL, Weng, L-C, McArdle, PF, Trinquart, L, Choi, SH, Mitchell, BD, Rosand, J, de Bakker, PIW, Benjamin, EJ, Ellinor, PT, Kittner, SJ, Lubitz, SA, Anderson, CD, Christophersen, IE, Rienstra, M, Roselli, C, Yin, X, Geelhoed, B, Barnard, J, Lin, H, Arking, DE, Smith, A, Albert, CM, Chaffin, M, Tucker, NR, Li, M, Klarin, D, Bihlmeyer, NA, Low, S-K, Weeke, PE, Mueller-Nurasyid, M, Smith, JG, Brody, JA, Niemeijer, MN, Doerr, M, Trompet, S, Huffman, J, Gustafsson, S, Schurmann, C, Kleber, ME, Lyytikainen, L-P, Seppala, I, Malik, R, Horimoto, ARVR, Perez, M, Sinisalo, J, Aeschbacher, S, Theriault, S, Yao, J, Radmanesh, F, Weiss, S, Teumer, A, Clauss, S, Deo, R, Rader, DJ, Shah, S, Sun, A, Hopewell, JC, Debette, S, Chauhan, G, Yang, Q, Worrall, BB, Pare, G, Kamatani, Y, Hagemeijer, YP, Verweij, N, Siland, JE, Kubo, M, Smith, JD, Van Wagoner, DR, Bis, JC, Perz, S, Psaty, BM, Ridker, PM, Magnani, JW, Harris, TB, Launer, LJ, Shoemaker, MB, Padmanabhan, S, Haessler, J, Bartz, TM, Waldenberger, M, Lichtner, P, Arendt, M, Krieger, JE, Kahonen, M, Risch, L, Mansur, AJ, Peters, A, Smith, BH, Lind, L, Scott, SA, Lu, Y, Bottinger, EB, Hernesniemi, J, Lindgren, CM, Wong, JA, Huang, J, Eskola, M, Morris, AP, Ford, I, Reiner, AP, Delgado, G, Chen, LY, Chen, Y-DI, Sandhu, RK, Boerwinkle, E, Eisele, L, Lannfelt, L, Rost, N, Taylor, KD, Campbell, A, Magnusson, PK, Porteous, D, Hocking, LJ, Vlachopoulou, E, Pedersen, NL, Nikus, K, Orho-Melander, M, Hamsten, A, Heeringa, J, Denny, JC, Kriebel, J, Darbar, D, Newton-Cheh, C, Shaffer, C, Macfarlane, PW, Heilmann, S, Almgren, P, Huang, PL, Sotoodehnia, N, Soliman, EZ, Uitterlinden, AG, Hofman, A, Franco, OH, Voelker, U, Joeckel, K-H, Sinner, MF, Lin, HJ, Guo, X, Dichgans, M, Ingelsson, E, Kooperberg, C, Melander, O, Loos, RJF, Laurikka, J, Conen, D, van der Harst, P, Lokki, M-L, Kathiresan, S, Pereira, A, Jukema, JW, Hayward, C, Rotter, J, Maerz, W, Lehtimaki, T, Stricker, BH, Chung, MK, Felix, SB, Gudnason, V, Alonso, A, Roden, DM, Kaeaeb, S, Chasman, D, Heckbert, SR, Tanaka, T, Lunetta, KL, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Seshadri, S, de Bakker, P, Rexrode, K, Chen, I, Luke, M, Sale, M, Lee, T-H, Chang, K-C, Elkind, M, Goldstein, L, James, ML, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez-Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, KJ, Levi, C, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Lemmens, R, Ahmadi, K, Opherk, C, Duering, M, Gonik, M, Staals, J, Burri, P, Sadr-Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller-Myhsok, B, Meschia, J, Brott, T, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Chan, Y-FY, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Le, KE, Lee, WL, Tan, EK, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Bevan, S, Sheu, W, Chiou, HY, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Jose Martin, J, Thijs, V, Klijn, K, van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, A, Padovani, A, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Sudlow, C, Rannikmae, K, Silliman, S, McDonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, McArdle, P, Chang, Y-C, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, A-K, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez-Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, J-M, and Sheth, K

Abstract

OBJECTIVE: We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. METHODS: We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. RESULTS: We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10-4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10-48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). CONCLUSIONS: Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

Published
2018

13. Report of a Delphi exercise to inform the design of a research programme on screening for thoracic aortic disease.

Author

Abbasciano, R. G., Barwell, J., Sayers, R., Bown, M., Milewicz, D., Cooper, G., Mariscalco, G., Wheeldon, N., Fowler, C., Owens, G., Murphy, G. J., on behalf of the Aortic Dissection Awareness Day UK 2019 Working Group, Cooper, Graham, Fowler, Catherine, Callaway, Mark, Chelliah, Rajesh, Deshpande, Aparna, Khoo, Jeffrey, McCann, Gerry, and Rao, Praveen

Subjects
CLINICAL trial registries, EXPERIMENTAL design, AORTIC dissection, MAGNETIC resonance imaging, EXERCISE
Abstract

Objectives: To inform the design of a clinical trial of a targeted screening programme for relatives of individuals affected by thoracic aortic disease, we performed a consensus exercise as to the acceptability of screening, the optimal sequence and choice of tests, long-term patient management, and choice of trial design.Methods: Working with the Aortic Dissection Awareness UK & Ireland patient association, we performed a Delphi exercise with clinical experts, patients, and carers, consisting of three rounds of consultation followed by a final multi-stakeholder face-to-face workshop.Results: Thirty-five experts and 84 members of the public took part in the surveys, with 164 patients and clinicians attending the final workshop. There was substantial agreement on the need for a targeted screening pathway that would employ a combined approach (imaging + genetic testing). The target population would include the first- and second-degree adult (> 15 years) relatives, with no upper age limit of affected patients. Disagreement persisted about the screening process, sequence, personnel, the imaging method to adopt, computed tomography (CT) scan vs magnetic resonance imaging (MRI), and the specifics of a potential trial, including willingness to undergo randomisation, and measures of effectiveness and acceptability.Conclusion: A Delphi process, initiated by patients, identified areas of uncertainty with respect to behaviour, process, and the design of a targeted screening programme for thoracic aortic disease that requires further research prior to any future trial. [ABSTRACT FROM AUTHOR]

Published
2020
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14. Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Author

Traylor, M, Zhang, Cr, Adib Samii, P, Devan, Wj, Parsons, Oe, Lanfranconi, S, Gregory, S, Cloonan, L, Falcone, Gj, Radmanesh, F, Fitzpatrick, K, Kanakis, A, Barrick, Tr, Moynihan, B, Lewis, Cm, Boncoraglio, Gb, Lemmens, R, Thijs, V, Sudlow, C, Wardlaw, J, Rothwell, Pm, Meschia, Jf, Worrall, Bb, Levi, C, Bevan, S, Furie, Kl, Dichgans, M, Rosand, J, Markus, Hs, Rost, N, Smoller, S, Sorkin, J, Wang, X, Selim, M, Pikula, A, Wolf, P, Debette, S, Seshadri, S, de Bakker, P, Chasman, D, Rexrode, K, Chen, I, Rotter, J, Luke, M, Sale, M, Lee, Th, Chang, Kc, Elkind, M, Goldstein, L, James, Ml, Breteler, M, O'Donnell, C, Leys, D, Carty, C, Kidwell, C, Olesen, J, Sharma, P, Rich, S, Tatlisumak, T, Happola, O, Bijlenga, P, Soriano, C, Giralt, E, Roquer, J, Jimenez Conde, J, Cotlarcius, I, Hardy, J, Korostynski, M, Boncoraglio, G, Ballabio, E, Parati, E, Mateusz, A, Urbanik, A, Dziedzic, T, Jagiella, J, Gasowski, J, Wnuk, M, Olszanecki, R, Pera, J, Slowik, A, Juchniewicz, Kj, Nyquist, P, Cendes, I, Cabral, N, Franca, P, Goncalves, A, Keller, L, Crisby, M, Kostulas, K, Ahmadi, K, Opherk, C, Duering, M, Malik, R, Gonik, M, Staals, J, Melander, O, Burri, P, Sadr Nabavi, A, Romero, J, Biffi, A, Anderson, C, Falcone, G, Brouwers, B, Du, R, Kourkoulis, C, Battey, T, Lubitz, S, Mueller Myhsok, B, Meschia, J, Brott, T, Pare, G, Pichler, A, Enzinger, C, Schmidt, H, Schmidt, R, Seiler, S, Blanton, S, Yamada, Y, Bersano, A, Rundek, T, Sacco, R, Yvonne Chan, Yf, Gschwendtner, A, Deng, Z, Barr, T, Gwinn, K, Corriveau, R, Singleton, A, Waddy, S, Launer, L, Chen, C, Ke, Le, Lee, Wl, Tan, Ek, Olugbodi, A, Rothwell, P, Schilling, S, Mok, V, Lebedeva, E, Jern, C, Jood, K, Olsson, S, Kim, H, Lee, C, Kilarski, L, Markus, H, Peycke, J, Sheu, W, Chiou, Hy, Chern, J, Giraldo, E, Taqi, M, Jain, V, Lam, O, Howard, G, Woo, D, Kittner, S, Mitchell, B, Cole, J, O'Connell, J, Milewicz, D, Illoh, K, Worrall, B, Stine, C, Karaszewski, B, Werring, D, Sofat, R, Smalley, J, Lindgren, A, Hansen, B, Norrving, B, Smith, G, Martín, Jj, Klijn, K, Van't Hof, F, Algra, A, Macleod, M, Perry, R, Arnett, D, Pezzini, Alessandro, Padovani, Alessandro, Cramer, S, Fisher, M, Saleheen, D, Broderick, J, Kissela, B, Doney, A, Rannikmae, K, Silliman, S, Mcdonough, C, Walters, M, Pedersen, A, Nakagawa, K, Chang, C, Dobbins, M, Mcardle, P, Chang, Yc, Brown, R, Brown, D, Holliday, E, Kalaria, R, Maguire, J, Attia, J, Farrall, M, Giese, Ak, Fornage, M, Majersik, J, Cushman, M, Keene, K, Bennett, S, Tirschwell, D, Psaty, B, Reiner, A, Longstreth, W, Spence, D, Montaner, J, Fernandez Cadenas, I, Langefeld, C, Bushnell, C, Heitsch, L, Lee, Jm, and Sheth, K.

Subjects
Cerebral Small Vessel Diseases, Genetic Predisposition to Disease, Genetic Testing, Humans, Polymorphism, Single Nucleotide, Risk Factors, Stroke, White Matter, Genome-Wide Association Study, Neurology (clinical), Single Nucleotide, C420 Human Genetics, Article, C431 Medical Genetics, C400 Genetics, Polymorphism, C440 Molecular Genetics
Abstract

Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Published
2016
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15. A mutation in theLMOD1actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

Author

Wan, Y.B.A., primary, Simpson, M.A., additional, Aragon-Martin, J.A., additional, Osborn, D.P.S., additional, Regalado, E., additional, Guo, D.C., additional, Boileau, C., additional, Jondeau, G., additional, Benarroch, L., additional, Isekame, Y., additional, Bharj, J., additional, Sneddon, J., additional, Fisher, E., additional, Dean, J., additional, Tome Esteban, M.T., additional, Saggar, A., additional, Milewicz, D., additional, Jahangiri, M., additional, Behr, E. R., additional, Smith, A., additional, and Child, A. H., additional

Published
2017
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18. Parental somatic and germ-line mosaicism for a FBN2 mutation and analysis of FBN2 transcript levels in dermal fibroblasts

Author

Putnam, E. A., Park, E. S., Aalfs, C. M., Hennekam, R. C., Milewicz, D. M., and Other departments

Abstract

Congenital contractural arachnodactyly (CCA) is an autosomal dominant disorder that is phenotypically related to the Marfan syndrome. CCA has recently been shown to result from mutations in the FBN2 gene, which encodes an elastin-associated microfibrillar protein called fibrillin-2. Two siblings are reported here with classic manifestations of CCA with unaffected parents. Analysis of the FBN2 cDNA from dermal fibroblasts from one of the affected siblings revealed a heterozygous exon splicing error deleting nt 3722-3844 of the FBN2 mRNA. This cDNA deletion resulted in selective removal of one of the 43 calcium-binding EGF-like domains of the fibrillin-2 protein. Analysis of the FBN2 gene in the affected siblings' DNA indicated that the splicing error resulted from an A-to-G transition 15 nt upstream from the 3' splice site of the intron. The genomic mutation resulting in the splicing error alters a putative branch point sequence important for lariat formation, an intermediate structure of normal splicing. The mutation was detectable in DNA from the father's hair bulbs and buccal cells but not his white blood cell DNA, indicating that the father was a somatic mosaic. Analysis of transcript levels by use of dermal fibroblasts from the proband demonstrated that the FBN2 allele containing the exon deletion was expressed at a higher level than the allele inherited from the mother. These results indicate that FBN2 exon splicing errors are a cause of CCA, furthering the understanding of the molecular basis of this disorder. In addition, the demonstration of gonadal mosaicism in the FBN2 gene is important for accurate genetic counseling of families with sporadic cases of CCA. Finally, the preferential expression of the mutated FBN2 allele in dermal fibroblasts may have implications for understanding the pathogenesis and rarity of CCA

Published
1997

19. A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

Author

Munot, P., primary, Saunders, D. E., additional, Milewicz, D. M., additional, Regalado, E. S., additional, Ostergaard, J. R., additional, Braun, K. P., additional, Kerr, T., additional, Lichtenbelt, K. D., additional, Philip, S., additional, Rittey, C., additional, Jacques, T. S., additional, Cox, T. C., additional, and Ganesan, V., additional

Published
2012
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20. The revised Ghent nosology for the Marfan syndrome

Author

Loeys, B. L., primary, Dietz, H. C., additional, Braverman, A. C., additional, Callewaert, B. L., additional, De Backer, J., additional, Devereux, R. B., additional, Hilhorst-Hofstee, Y., additional, Jondeau, G., additional, Faivre, L., additional, Milewicz, D. M., additional, Pyeritz, R. E., additional, Sponseller, P. D., additional, Wordsworth, P., additional, and De Paepe, A. M., additional

Published
2010
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21. Abnormal fibrillin metabolism in bovine Marfan syndrome

Author

Potter, K. A., Hoffman, Y., Sakai, L. Y., Peter H. Byers, Besser, T. E., and Milewicz, D. M.

Subjects
musculoskeletal diseases, Male, congenital, hereditary, and neonatal diseases and abnormalities, integumentary system, Microfilament Proteins, Cattle Diseases, Fluorescent Antibody Technique, Fibroblasts, Fibrillins, Marfan Syndrome, Animals, Cattle, Female, cardiovascular diseases, skin and connective tissue diseases, Research Article, Skin
Abstract

Bovine Marfan syndrome is a disorder that closely resembles human Marfan syndrome in its clinical signs and pathological lesions. The similarities between the human and bovine diseases suggest that similar metabolic defects could be responsible. Although indirect immunofluorescent assays for fibrillin in skin biopsies did not distinguish affected cattle from control animals, cultures of skin fibroblasts of affected animals were distinguished from normal, unrelated control animals and normal half-siblings on the basis of fibrillin staining. After 72 to 96 hours in culture, stained with anti-fibrillin monoclonal antibody 201, hyperconfluent fibroblast cultures of affected cattle had less immunoreactive fibrillin than control cultures, and the staining pattern was granular rather than fibrillar. Under similar culture conditions, normal bovine aortic smooth muscle cells produced large amounts of immunoreactive fibrillin, but smooth muscle cells from a single affected cow showed markedly less fibrillin staining. In pulse-chase metabolic labeling experiments with [35S]cysteine, dermal fibroblasts from 6 affected calves, incorporated far less fibrillin into the extracellular matrix than control cells. These findings are similar to those reported in human Marfan syndrome, and they suggest that the bovine Marfan syndrome, like the human disorder, is caused by a mutation in fibrillin, leading to defective microfibrillar synthesis.

Published
1993

22. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor1 and angiotensin II

Author

Pannu, H., primary, Tran-Fadulu, V., additional, Papke, C. L., additional, Scherer, S., additional, Liu, Y., additional, Presley, C., additional, Guo, D., additional, Estrera, A. L., additional, Safi, H. J., additional, Brasier, A. R., additional, Vick, G. W., additional, Marian, A.J., additional, Raman, C.S., additional, Buja, L. M., additional, and Milewicz, D. M., additional

Published
2007
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23. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II

Author

Pannu, H., primary, Tran-Fadulu, V., additional, Papke, C. L., additional, Scherer, S., additional, Liu, Y., additional, Presley, C., additional, Guo, D., additional, Estrera, A. L., additional, Safi, H. J., additional, Brasier, A. R., additional, Vick, G. W., additional, Marian, A.J., additional, Raman, C.S., additional, Buja, L. M., additional, and Milewicz, D. M., additional

Published
2007
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28. Marfan Database (second edition): software and database for the analysis of mutations in the human FBN1 gene

Author

Collod-Beroud, G., primary, Beroud, C., additional, Ades, L., additional, Black, C., additional, Boxer, M., additional, Brock, D. J., additional, Godfrey, M., additional, Hayward, C., additional, Karttunen, L., additional, Milewicz, D., additional, Peltonen, L., additional, Richards, R. I., additional, Wang, M., additional, Junien, C., additional, and Boileau, C., additional

Published
1997
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33. A Novel Mutation in Human PAX9Causes Molar Oligodontia.

Author

Frazier-Bowers, S. A., Guo, D. C., Cavender, A., Xue, L., Evans, B., King, T., Milewicz, D., and D'Souza, R. N.

Subjects
GENETIC mutation, MOLAR abnormalities, TEETH abnormalities, DENTITION, DNA, GENETICS
Abstract

Experimental and animal studies, as well as genetic mutations in man, have indicated that the development of dentition is under the control of several genes. So far, mutations in MSX1 and PAX9 have been associated with dominantly inherited forms of human tooth agenesis that mainly involve posterior teeth. We identified a large kindred with several individuals affected with molar oligodontia that was transmitted as an isolated autosomaldominant trait. Two-point linkage analysis using DNA from the family and polymorphic marker D14S288 in chromosome 14q12 produced a maximum lod score of 2.29 at θ = 0.1. Direct sequencing of exons 2 to 4 of PAX9 revealed a cytosine insertion mutation at nucleotide 793, leading to a premature termination of translation at aa 315. Our results support the conclusion that molar oligodontia is due to allelic heterogeneity in PAX9, and these data further corroborate the role of PAX9 as an important regulator of molar development. [ABSTRACT FROM AUTHOR]

Published
2002
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36. Sterols in blood of normal and Smith-Lemli-Opitz subjects.

Author

Ruan, B, Wilson, W K, Pang, J, Gerst, N, Pinkerton, F D, Tsai, J, Kelley, R I, Whitby, F G, Milewicz, D M, Garbern, J, and Schroepfer, G J

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a hereditary disorder in which a defective gene encoding 7-dehydrocholesterol reductase causes the accumulation of noncholesterol sterols, such as 7- and 8-dehydrocholesterol. Using rigorous analytical methods in conjunction with a large collection of authentic standards, we unequivocally identified numerous noncholesterol sterols in 6 normal and 17 SLOS blood samples. Plasma or erythrocytes were saponified under oxygen-free conditions, followed by multiple chromatographic separations. Individual sterols were identified and quantitated by high performance liquid chromatography (HPLC), Ag(+)-HPLC, gas chromatography (GC), GC-mass spectrometry, and nuclear magnetic resonance. As a percentage of total sterol content, the major C(27) sterols observed in the SLOS blood samples were cholesterol (12;-98%), 7-dehydrocholesterol (0.4;-44%), 8-dehydrocholesterol (0.5;-22%), and cholesta-5,7,9(11)-trien-3beta-ol (0.02;-5%), whereas the normal blood samples contained <0.03% each of the three noncholesterol sterols. SLOS and normal blood contained similar amounts of lathosterol (0.05;-0.6%) and cholestanol (0.1;-0.4%) and approximately 0.003;-0.1% each of the Delta(8), Delta(8(14)), Delta(5,8(14)), Delta(5,24), Delta(6,8), Delta(6,8(14)), and Delta(7,24) sterols.The results are consistent with the hypothesis that the Delta(8(14)) sterol is an intermediate of cholesterol synthesis and indicate the existence of undescribed aberrant pathways that may explain the formation of the Delta(5,7,9(11)) sterol. 19-Norcholesta-5,7,9-trien-3beta-ol was absent in both SLOS and normal blood, although it was routinely observed as a GC artifact in fractions containing 8-dehydrocholesterol. The overall findings advance the understanding of SLOS and provide a methodological model for studying other metabolic disorders of cholesterol synthesis.

Published
2001

38. Carboxy-terminal conversion of profibrillin to fibrillin at a basic site by PACE/furin-like activity required for incorporation in the matrix.

Author

Raghunath, M, Putnam, E A, Ritty, T, Hamstra, D, Park, E S, Tschödrich-Rotter, M, Peters, R, Rehemtulla, A, and Milewicz, D M

Abstract

Fibrillin-1, the main component of 10-12 nm microfibrils of the extracellular matrix, is synthesized as profibrillin and proteolytically processed to fibrillin. The putative cleavage site has been mapped to the carboxy-terminal domain of profibrillin-1, between amino acids arginine 2731 and serine 2732, by a spontaneous mutation in this recognition site that prevents profibrillin conversion. This site contains a basic amino acid recognition sequence (R-G-R-K-R-R) for proprotein convertases of the furin/PACE family. In this study, we use a mini-profibrillin protein to confirm the cleavage in the carboxy-terminal domain by both fibroblasts and recombinantly expressed furin/PACE, PACE4, PC1/3 and PC2. Site-directed mutagenesis of amino acids in the consensus recognition motif prevented conversion, thereby identifying the scissile bond and characterizing the basic amino acids required for cleavage. Using a PACE/furin inhibitor, we show that wild-type profibrillin is not incorporated into the extracellular matrix until it is converted to fibrillin. Therefore, profibrillin-1 is the first extracellular matrix protein to be shown to be a substrate for subtilisin-like proteases, and the conversion of profibrillin to fibrillin controls microfibrillogenesis through exclusion of uncleaved profibrillin.

Published
1999

39. Processing of the fibrillin-1 carboxyl-terminal domain.

Author

Ritty, T M, Broekelmann, T, Tisdale, C, Milewicz, D M, and Mecham, R P

Abstract

To investigate the processing and general properties of the fibrillin-1 carboxyl-terminal domain, three protein expression constructs have been developed as follows: one without the domain, one with the domain, and one with a mutation near the putative proteolytic processing site. The constructs have been expressed in two eukaryotic model systems, baculoviral and CHO-K1. Post-translational modifications that normally occur in fibrillin-1, including glycosylation, signal peptide cleavage, and carboxyl-terminal processing, occur in the three constructs in both cell systems. Amino-terminal sequencing of secreted protein revealed leader sequence processing at two sites, a primary site between Gly-24/Ala-25 and a secondary site of Ala-27/Asn-28. Processing of the carboxyl-terminal domain could be observed by migration differences in SDS-polyacrylamide gel electrophoresis and was evident in both mammalian and insect cells. Immunological identification by Western blotting confirmed the loss of the expected region. The failure of both cell systems to process the mutant construct shows that the multi-basic sequence is the site of proteolytic processing. Cleavage of the fibrillin-1 carboxyl-terminal domain occurred intracellularly in CHO-K1 cells in an early secretory pathway compartment as demonstrated by studies with secretion blocking agents. This finding, taken with the multi-basic nature of the cleavage site and observed calcium sensitivity of cleavage, suggests that the processing enzyme is a secretory pathway resident furin-like protease.

Published
1999

40. Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5

Author

Tsipouras, P., Del Mastro, R., Sarfarazi, M., Lee, B., Vitale, E., Child, A. H., Godfrey, M., Devereux, R. B., Hewett, D., Steinmann, B., Viljoen, D., Sykes, B. C., Kilpatrick, M., Ramirez, F., Farndon, P. A., Boxer, M., Brock, D. J. H., Caroline Hayward, Keston, M., Milewicz, D. M., Byers, P. H., Superti-Furga, A., Ramesar, R. S., Davee, M. A., Weaver, D. D., Wainer, S., and Kramer-Fox, R.

42. International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

Author

Michelena, H.I., Corte, A. della, Evangelista, A., Maleszewski, J.J., Edwards, W.D., Roman, M.J., Devereux, R.B., Fernandez, B., Asch, F.M., Barker, A.J., Sierra-Galan, L.M., Kerchove, L. de, Fernandes, S.M., Fedak, P.W.M., Girdauskas, E., Delgado, V., Abbara, S., Lansac, E., Prakash, S.K., Bissell, M.M., Popescu, B.A., Hope, M.D., Sitges, M., Thourani, V.H., Pibarot, P., Chandrasekaran, K., Lancellotti, P., Borger, M.A., Forrest, J.K., Webb, J., Milewicz, D.M., Makkar, R., Leon, M.B., Sanders, S.P., Markl, M., Ferrari, V.A., Roberts, W.C., Song, J.K., Blanke, P., White, C.S., Siu, S., Svensson, L.G., Braverman, A.C., Bavaria, J., Sundt, T.M., Khoury, G. el, Paulis, R. de, Enriquez-Sarano, M., Bax, J.J., Otto, C.M., Schafers, H.J., Endorsed Heart Valve Soc HVS, European Assoc Cardiovasc Imaging, Soc Thoracic Surg STS, Amer Assoc Thoracic Surg AATS, Soc Cardiovasc Magnetic Resonance, Soc Cardiovasc Computed Tomography, North Amer Soc Cardiovasc Imaging, Int Bicuspid Aortic Valve Consorti, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service de chirurgie cardiovasculaire et thoracique, Michelena, H. I., Della Corte, A., Evangelista, A., Maleszewski, J. J., Edwards, W. D., Roman, M. J., Devereux, R. B., Fernandez, B., Asch, F. M., Barker, A. J., Sierra-Galan, L. M., De Kerchove, L., Fernandes, S. M., Fedak, P. W. M., Girdauskas, E., Delgado, V., Abbara, S., Lansac, E., Prakash, S. K., Bissell, M. M., Popescu, B. A., Hope, M. D., Sitges, M., Thourani, V. H., Pibarot, P., Chandrasekaran, K., Lancellotti, P., Borger, M. A., Forrest, J. K., Webb, J., Milewicz, D. M., Makkar, R., Leon, M. B., Sanders, S. P., Markl, M., Ferrari, V. A., Roberts, W. C., Song, J. -K., Blanke, P., White, C. S., Siu, S., Svensson, L. G., Braverman, A. C., Bavaria, J., Sundt, T. M., El Khoury, G., De Paulis, R., Enriquez-Sarano, M., Bax, J. J., Otto, C. M., Schafers, H. -J., Michelena, Hector I, Corte, Alessandro Della, Evangelista, Arturo, Maleszewski, Joseph J, Edwards, William D, Roman, Mary J, Devereux, Richard B, Fernández, Borja, Asch, Federico M, Barker, Alex J, Sierra-Galan, Lilia M, De Kerchove, Laurent, Fernandes, Susan M, Fedak, Paul W M, Girdauskas, Evalda, Delgado, Victoria, Abbara, Suhny, Lansac, Emmanuel, Prakash, Siddharth K, Bissell, Malenka M, Popescu, Bogdan A, Hope, Michael D, Sitges, Marta, Thourani, Vinod H, Pibarot, Phillippe, Chandrasekaran, Krishnaswamy, Lancellotti, Patrizio, Borger, Michael A, Forrest, John K, Webb, John, Milewicz, Dianna M, Makkaar, Raj, Leon, Martin B, Sanders, Stephen P, Markl, Michael, Ferrari, Victor A, Roberts, William C, Song, Jae-Kwan, Blanke, Philipp, White, Charles S, Siu, Samuel, Svensson, Lars G, Braverman, Alan C, Bavaria, Joseph, Sundt, Thoralf M, El Khoury, Gebrine, De Paulis, Ruggero, Enriquez-Sarano, Maurice, Bax, Jeroen J, Otto, Catherine M, and Schäfers, Hans-Joachim

Subjects
Statement (logic), Predictive Value of Test, Computed tomography, 030204 cardiovascular system & hematology, Congenital Aortic Valve Insufficiency, 0302 clinical medicine, Bicuspid aortic valve, Bicuspid Aortic Valve Disease, 030212 general & internal medicine, Nomenclature, Aorta, medicine.diagnostic_test, General Medicine, Anatomy, Prognosis, Classification, Phenotype, Aortic Valve, cardiovascular system, Cardiology and Cardiovascular Medicine, Key Words, Human, Pulmonary and Respiratory Medicine, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Consensus, Prognosi, education, Aortic Diseases, Consensu, Aortography, 03 medical and health sciences, Bicuspid valve, Predictive Value of Tests, Terminology as Topic, Aortopathy, medicine, Humans, Radiology, Nuclear Medicine and imaging, cardiovascular diseases, Special Report, Cardiac Imaging Technique, business.industry, General surgery, Systematized Nomenclature of Medicine, Forme fruste, nomencla-ture, Aortic Valve Stenosis, Aortic Disease, medicine.disease, Aortic Valve Stenosi, Cardiac Imaging Techniques, Cusp (anatomy), Surgery, business
Abstract

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes. © 2021 Jointly between the RSNA, the European Association for Cardio-Thoracic Surgery, The Society of Thoracic Surgeons, and the American Association for Thoracic Surgery. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. All rights reserved. Keywords: Bicuspid Aortic Valve, Aortopathy, Nomenclature, Classification.

Published
2021

43. Surgical repair of bicuspid aortopathy at small diameters: Clinical and institutional factors

Author

Alexander P. Nissen, Van Thi Thanh Truong, Bader A. Alhafez, Jyothy J. Puthumana, Anthony L. Estrera, Simon C. Body, Siddharth K. Prakash, Eduardo Bossone, Rodolfo Citro, Simon Body, J. Daniel Muehlschlegel, Jasmine T. Shahram, Thy B. Nguyen, Vicenza Stefano Nistri, Dan Gilon, Ronen Durst, Carlo de Vincentiis, Francesca R. Pluchinotta, Thoralf M. Sundt, Hector I. Michelena, Giuseppe Limongelli, Patrick M. McCarthy, S. Chris Malaisrie, Aakash Bavishi, Malenka M. Bissell, Gordon S. Huggins, Victor Dayan, Francois Dagenais, Alessandro Della Corte, Evaldas Girdsaukas, Bo Yang, Kim Eagle, Dianna M. Milewicz, Tom C. Nguyen, Harleen K. Sandhu, Hazim J. Safi, Josh C. Denny, Arturo Evangelista, Laura Galian-Gay, Kim A. Eagle, Williams Ravekes, Harry C. Dietz, Kathryn W. Holmes, Jennifer Habashi, Scott A. LeMaire, Joseph S. Coselli, Shaine A. Morris, Cheryl L. Maslen, Howard K. Song, G. Michael Silberbach, Reed E. Pyeritz, Joseph E. Bavaria, Karianna Milewski, Richard B. Devereux, Jonathan W. Weinsaft, Mary J. Roman, Ralph V. Shohet, Nazli McDonnell, Federico M. Asch, H. Eser Tolunay, Patrice Desvigne-Nickens, Hung Tseng, Barbara L. Kroner, Nissen, A. P., Truong, V. T. T., Alhafez, B. A., Puthumana, J. J., Estrera, A. L., Body, S. C., Prakash, S. K., Bossone, E., Citro, R., Body, S., Muehlschlegel, J. D., Shahram, J. T., Nguyen, T. B., Stefano Nistri, V., Gilon, D., Durst, R., de Vincentiis, C., Pluchinotta, F. R., Sundt, T. M., Michelena, H. I., Limongelli, G., Mccarthy, P. M., Malaisrie, S. C., Bavishi, A., Bissell, M. M., Huggins, G. S., Dayan, V., Dagenais, F., Corte, A. D., Girdsaukas, E., Yang, B., Eagle, K., Milewicz, D. M., Nguyen, T. C., Sandhu, H. K., Safi, H. J., Denny, J. C., Evangelista, A., Galian-Gay, L., Eagle, K. A., Ravekes, W., Dietz, H. C., Holmes, K. W., Habashi, J., Lemaire, S. A., Coselli, J. S., Morris, S. A., Maslen, C. L., Song, H. K., Silberbach, G. M., Pyeritz, R. E., Bavaria, J. E., Milewski, K., Devereux, R. B., Weinsaft, J. W., Roman, M. J., Shohet, R. V., Mcdonnell, N., Asch, F. M., Tolunay, H. E., Desvigne-Nickens, P., Tseng, H., and Kroner, B. L.

Subjects
Registrie, Male, Time Factors, thoracic aortic aneurysm, Heart Valve Diseases, Patient characteristics, ascending aortic intervention, thoracic aortic dissection, 030204 cardiovascular system & hematology, 0302 clinical medicine, Bicuspid aortic valve, Aortic valve replacement, Bicuspid Aortic Valve Disease, Risk Factors, Registries, Heart Valve Prosthesis Implantation, Middle Aged, Dissection, Heart Valve Disease, Treatment Outcome, Elective Surgical Procedures, Aortic Valve, cardiovascular system, Cardiology, Female, Cardiology and Cardiovascular Medicine, Vascular Surgical Procedures, Human, Pulmonary and Respiratory Medicine, United State, Adult, medicine.medical_specialty, bicuspid aortic valve, Time Factor, Aortic Valve Insufficiency, Clinical Decision-Making, Thoracic aortic aneurysm, Risk Assessment, 03 medical and health sciences, Internal medicine, medicine, Humans, Limited evidence, Risk factor, Aged, Surgical repair, Cross-Sectional Studie, Elective Surgical Procedure, Aortic Aneurysm, Thoracic, business.industry, Risk Factor, Patient Selection, Aortic Valve Stenosis, medicine.disease, Aortic Valve Stenosi, United States, Cross-Sectional Studies, 030228 respiratory system, Surgery, business
Abstract

Objective: Bicuspid aortic valve is a common risk factor for thoracic aortic aneurysm and dissection. Guidelines for elective ascending aortic intervention (AAI) in bicuspid aortic valve are derived from limited evidence, and the extent of practice variation due to patient and provider characteristics is unknown. Using data from 2 large cardiovascular registries, we investigated factors that influence decisions for AAI. Methods: All bicuspid aortic valve cases with known aortic diameters and surgical status were included. We used multivariable logistic regression to profile predictors of isolated aortic valve replacement (AVR) or AVR+AAI, stratified by patient characteristics, surgical indications, and institution. Results: We studied 2861 subjects at 18 institutions from 1996 to 2015. The median aortic diameter of patients who underwent AVR+AAI varied widely across institutions (39-52 mm). Aortic diameters were

Published
2019

45. Reduced penetrance and variable expressivity of familial thoracic aortic aneurysms/dissections.

Author

Milewicz, Dianna M., Hua Chen, Park, Eun-Sook, Petty, Elizabeth M., Zaghi, Hedayatollah, Pai, G. Shashidhar, Willing, Marcia, Patel, Vasant, Milewicz, D M, Chen, H, Park, E S, Petty, E M, Zaghi, H, Shashidhar, G, Willing, M, and Patel, V

Subjects
*AORTIC aneurysms
Abstract

Autosomal dominant inheritance of thoracic aortic aneurysms and dissections occurs in subjects with Marfan syndrome, which results from mutations in the FBN1 gene on chromosome 15. A second chromosomal locus on 3p24-25 has been identified for a Marfan-like condition with thoracic aortic aneurysms. We describe here 6 families with multiple members with thoracic aortic aneurysms and dissections in the absence of the ocular and skeletal complications of Marfan syndrome. Medical records and autopsy reports on affected subjects in families with multiple members with thoracic aortic aneurysms and dissections were reviewed. Subjects in these families at risk for developing aortic disease underwent echocardiography to evaluate the aorta. The pattern of inheritance of thoracic aortic aneurysms and dissections was autosomal dominant in these families. Most affected subjects presented with aortic root dilatation or acute type I dissection, but the age of onset of disease was variable and there was decreased penetrance of the disorder. In 2 of the families, the syndrome was not linked to FBN1 or 3p24-25. Familial thoracic aortic aneurysm and dissection is an autosomal dominant condition with marked variability in the age of onset of aortic disease and decreased penetrance, making identification of affected subjects difficult. This condition is not due to mutations in the FBN1 gene or the unidentified gene on 3p24-25. [ABSTRACT FROM AUTHOR]

Published
1998
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46. Chronobiology of Acute Aortic Dissection in the Marfan Syndrome (from the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions and the International Registry of Acute Aortic Dissection)

Author

Dan Montgomery, Arturo Evangelista, Michael Silberbach, Harry C. Dietz, Scott A. LeMaire, Dianna M. Milewicz, Roberto Manfredini, Eduardo Bossone, Udo Sechtem, Hasan K. Siddiqi, Eric M. Isselbacher, Kim A. Eagle, Reed E. Pyeritz, Steven N. Luminais, Christoph A. Nienaber, Mary J. Roman, Siddiqi, Hk, Luminais, Sn, Montgomery, D, Bossone, E, Dietz, H, Evangelista, A, Isselbacher, E, Lemaire, S, Manfredini, R, Milewicz, D, Nienaber, Ca, Roman, M, Sechtem, U, Silberbach, M, Eagle, Ka, and Pyeritz, Re

Subjects
musculoskeletal diseases, Marfan syndrome, circadian rhythm, Adult, Male, medicine.medical_specialty, Population, Socio-culturale, 030204 cardiovascular system & hematology, Marfan Syndrome, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Registries, education, Aortic dissection, Chronobiology Phenomena, Chronobiology, education.field_of_study, Aortic Aneurysm, Thoracic, business.industry, Subject Age, Irad, Middle Aged, medicine.disease, Connective tissue disease, Aortic Dissection, Cardiology, aneurysm, chronobiology, circadian rhythm, season, aneurysm, Marfan syndrome, Female, National registry, Seasons, Cardiology and Cardiovascular Medicine, business, chronobiology, season
Abstract

Marfan syndrome (MFS) is an autosomal dominant connective tissue disease associated with acute aortic dissection (AAD). We used 2 large registries that include patients with MFS to investigate possible trends in the chronobiology of AAD in MFS. We queried the International Registry of Acute Aortic Dissection (IRAD) and the Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) registry to extract data on all patients with MFS who had suffered an AAD. The group included 257 patients with MFS who suffered an AAD from 1980 to 2012. The chi-square tests were used for statistical testing. Mean subject age at time of AAD was 38 years, and 61% of subjects were men. AAD was more likely in the winter/spring season (November to April) than the other half of the year (57% vs 43%, p = 0.05). Dissections were significantly more likely to occur during the daytime hours, with 65% of dissections occurring from 6 a.m. to 6 p.m. (p = 0.001). Men were more likely to dissect during the daytime hours (6 a.m. to 6 p.m.) than women (74% vs 51%, p = 0.01). These insights offer a glimpse of the times of greatest vulnerability for patients with MFS who suffer from this catastrophic event. In conclusion, the chronobiology of AAD in MFS reflects that of AAD in the general population.

Published
2016

47. A roadmap to investigate the genetic basis of bicuspid aortic valve and its complications: Insights from the international BAVCon (bicuspid aortic valve consortium)

Author

Siddharth K, Prakash, Yohan, Bossé, Jochen D, Muehlschlegel, Hector I, Michelena, Giuseppe, Limongelli, Alessandro, Della Corte, Francesca R, Pluchinotta, Maria Giovanna, Russo, Artur, Evangelista, D Woodrow, Benson, Simon C, Body, Dianna M, Milewicz, Prakash, S. K., Bossé, Y, Muehlschlegel, J. D., Michelena, H. I., Limongelli, Giuseppe, DELLA CORTE, Alessandro, Pluchinotta, F. R., Russo, Maria Giovanna, Evangelista, A, Benson, D. W., Body, S. C., and Milewicz, D. M.

Subjects
Biomedical Research, Bicuspid Aortic Valve Disease, bicuspid, Aortic Valve, Mutation, Heart Valve Diseases, Animals, Humans, consortium, roadmap, valve, Genetic Association Studies, Article
Abstract

Bicuspid aortic valve (BAV) is the most common adult congenital heart defect and is found in 0.5% to 2.0% of the general population. The term "BAV" refers to a heterogeneous group of disorders characterized by diverse aortic valve malformations with associated aortopathy, congenital heart defects, and genetic syndromes. Even after decades of investigation, the genetic determinants of BAV and its complications remain largely undefined. Just as BAV phenotypes are highly variable, the genetic etiologies of BAV are equally diverse and vary from complex inheritance in families to sporadic cases without any evidence of inheritance. In this paper, the authors discuss current concepts in BAV genetics and propose a roadmap for unraveling unanswered questions about BAV through the integrated analysis of genetic and clinical data. © 2014 by the American College of Cardiology Foundation.

Published
2014

48. Bicuspid aortic valve identifying knowledge gaps and rising to the challenge from the international bicuspid aortic valve consortium (BAVCON)

Author

Yohan Bossé, Nandan S. Anavekar, Siddharth K. Prakash, Maurice Enriquez-Sarano, Hector I. Michelena, Alessandro Della Corte, Eric M. Isselbacher, Malenka M. Bissell, Simon C. Body, Dianna M. Milewicz, Eduardo Bossone, Giuseppe Limongelli, Thoralf M. Sundt, D. Woodrow Benson, Artur Evangelista, Patrizio Lancellotti, Patrick Mathieu, Philippe Pibarot, Michelena, H. I., Prakash, S. K., Corte, A. D., Bissell, M. M., Anavekar, N., Mathieu, P., Bosse, Y., Limongelli, G., Bossone, E., Benson, D. W., Lancellotti, P., Isselbacher, E. M., Enriquez-Sarano, M., Sundt III, T. M., Pibarot, P., Evangelista, A., Milewicz, D. M., Body, S. C., Michelena, Hi, Prakash, Sk, Della Corte, A, Bissell, Mm, Anavekar, N, Mathieu, P, Bosse, Y, Limongelli, G, Bossone, E, Benson, Dw, Lancellotti, P, Isselbacher, Em, Enriquez-Sarano, M, Sundt, Tm, Pibarot, P, Evangelista, A, Milewicz, Dm, and Body, Sc

Subjects
Aortic valve, Diagnostic Imaging, medicine.medical_specialty, Health Knowledge, Attitudes, Practice, Heart Valve Diseases, Article, Bicuspid aortic valve, Bicuspid Aortic Valve Disease, Physiology (medical), Internal medicine, Medicine, Cardiac Surgical Procedure, Humans, Cardiac Surgical Procedures, High prevalence, business.industry, aortic valve stenosi, medicine.disease, heart defects, congenital, aortic aneurysm, thoracic, Stenosis, Heart Valve Disease, Clinical research, medicine.anatomical_structure, Aortic valve stenosis, Heart failure, Aortic Valve, Cardiology, aortic valve, bicuspid, Presentation (obstetrics), Cardiology and Cardiovascular Medicine, business
Abstract

> Everything should be kept as simple as possible, but no simpler. > > —Albert Einstein1 Since its estimated first description >500 years ago by Leonardo da Vinci,2 the bicuspid aortic valve (BAV) has progressively built a reputation; initially, as a curious valvular phenotype with a tendency to develop obstruction and insufficiency. In more contemporary times, however, the BAV is recognized as underlying almost 50% of isolated severe aortic stenosis cases requiring surgery,3 and has been extensively associated with ominous outcomes such as bacterial endocarditis and aortic dissection.4 These associations, coupled with the high prevalence of BAV in humans,5 have prompted investigative efforts into the condition, which although insightful, have generated more questions than answers. This review describes our current knowledge of BAV, but, more importantly, it highlights knowledge gaps and areas where basic and clinical research is warranted. Our review has 2 sections. The first section outlines the multifaceted challenge of BAV, our current understanding of the condition, and barriers that may hamper the advancement of the science. The second section proposes a roadmap to discovery based on current imaging, molecular biology, and genetic tools, recognizing their advantages and limitations. ### A Condition Characterized by Variable Clinical Presentation The clinical presentation and consequences of BAV in humans are exceedingly heterogeneous, with few clinical or molecular markers to predict associated complications.4,6 BAV can be diagnosed at any stage during a lifetime, from newborns7 to the elderly,8 and in the setting of variable clinical circumstances. Some are benign circumstances such as auscultatory abnormalities or incidental echocardiographic findings in otherwise healthy patients8; other circumstances are morbid, such as early severe aortic valve dysfunction, premature congestive heart failure, and thoracic aortic aneurysms (TAAs).8,9 Life-threatening circumstances include bacterial endocarditis and acute aortic dissection.8–11 These complications may present …

Published
2014

49. Aortic and arterial manifestations and clinical features in TGFB3 -related heritable thoracic aortic disease: results from the Montalcino Aortic Consortium.

Author

Lim MS, Guo DC, Velasco Torrez W, Lai A, Schweber J, Garg N, Fleischer J, Boileau C, De Backer J, Evangelista A, Jondeau G, Le Goff C, Milleron O, Muiño-Mosquera L, Morris S, Ouzounian M, Cervi E, Marcadier J, Caffarelli A, Shalhub S, Pyeritz R, Yetman A, Milewicz D, and Braverman AC

Abstract

Background: Pathogenic variants in TGFB3 may lead to a syndromic genetic aortopathy. Heritable thoracic aortic disease (HTAD) and arterial events may occur in TGFB3 -related disease but there are limited outcomes data on vascular events in this condition., Methods: Clinical data, phenotypical features and aortic outcomes in individuals with pathogenic/likely pathogenic (P/LP) TGFB3 variants enrolled in the Montalcino Aortic Consortium registry were reviewed., Results: 34 individuals (56% male, median age 42 years, IQR 17-49, range 3-74 years) with P/LP TGFB3 variants were studied. Craniofacial, cutaneous and musculoskeletal features seen in Loeys-Dietz syndrome were variably present. Extra-aortic cardiovascular features included arterial tortuosity (25%), extra-aortic arterial aneurysms (6%) and mitral valve prolapse (21%).Aortic dilation (Z-Score>2) was present in 10 individuals (29%) and aortic dissection occurred in 2 (6%). Type A aortic dissection occurred in two patients (aged between 55 years and 60 years), and one of these patients experienced a type B aortic dissection 6 years later. Seven adults (median age 62 years, range 32-69 years) with aortic root dilation (41-49 mm) are being followed. No patients have undergone prophylactic aortic surgery. Twenty-five per cent of children have aortic dilation. Sixty-eight per cent of the entire cohort remains free of aortic disease. No deaths have occurred., Conclusions: TGFB3 -related HTAD is characterised by late-onset and less penetrant thoracic aortic and arterial disease compared with other transforming growth factor β HTAD. Based on our data, a larger aortic size threshold for prophylactic aortic surgery is appropriate in patients with TGFB3 -related HTAD compared with HTAD due to TGFBR1 or TGFBR2 variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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50. Differentiation between descending thoracic aortic diseases using machine learning and plasma proteomic signatures.

Author

Momenzadeh A, Kreimer S, Guo D, Ayres M, Berman D, Chyu KY, Shah PK, Milewicz D, Azizzadeh A, Meyer JG, and Parker S

Abstract

Background: Descending thoracic aortic aneurysms and dissections can go undetected until severe and catastrophic, and few clinical indices exist to screen for aneurysms or predict risk of dissection., Methods: This study generated a plasma proteomic dataset from 75 patients with descending type B dissection (Type B) and 62 patients with descending thoracic aortic aneurysm (DTAA). Standard statistical approaches were compared to supervised machine learning (ML) algorithms to distinguish Type B from DTAA cases. Quantitatively similar proteins were clustered based on linkage distance from hierarchical clustering and ML models were trained with uncorrelated protein lists across various linkage distances with hyperparameter optimization using fivefold cross validation. Permutation importance (PI) was used for ranking the most important predictor proteins of ML classification between disease states and the proteins among the top 10 PI protein groups were submitted for pathway analysis., Results: Of the 1,549 peptides and 198 proteins used in this study, no peptides and only one protein, hemopexin (HPX), were significantly different at an adjusted p < 0.01 between Type B and DTAA cases. The highest performing model on the training set (Support Vector Classifier) and its corresponding linkage distance (0.5) were used for evaluation of the test set, yielding a precision-recall area under the curve of 0.7 to classify between Type B from DTAA cases. The five proteins with the highest PI scores were immunoglobulin heavy variable 6-1 (IGHV6-1), lecithin-cholesterol acyltransferase (LCAT), coagulation factor 12 (F12), HPX, and immunoglobulin heavy variable 4-4 (IGHV4-4). All proteins from the top 10 most important groups generated the following significantly enriched pathways in the plasma of Type B versus DTAA patients: complement activation, humoral immune response, and blood coagulation., Conclusions: We conclude that ML may be useful in differentiating the plasma proteome of highly similar disease states that would otherwise not be distinguishable using statistics, and, in such cases, ML may enable prioritizing important proteins for model prediction., (© 2024. The Author(s).)

Published
2024
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