Author: "Van Schoor, N.M." / Database: OAIster - Searchworks@Jio Institute Digital Library Search Results

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53 results on '"Van Schoor, N.M."'

1. Are higher antidepressant plasma concentrations associated with fall risk in older antidepressant users?

Author: Pronk, A.C., van Poelgeest, E.P., Seppala, L.J., Ploegmakers, K.J., Stricker, B.H., Swart, K.M.A., van Dijk, S.C., Oliai Araghi, S., de Groot, L.C.P.G.M., van Schoor, N.M., Mathôt, R.A.A., van der Velde, N., Pronk, A.C., van Poelgeest, E.P., Seppala, L.J., Ploegmakers, K.J., Stricker, B.H., Swart, K.M.A., van Dijk, S.C., Oliai Araghi, S., de Groot, L.C.P.G.M., van Schoor, N.M., Mathôt, R.A.A., and van der Velde, N.
Abstract: Antidepressants are well-established fall-risk increasing drugs (FRIDs) and therefore falls should be considered an important adverse drug event (ADE) of antidepressants. However, not all antidepressant users experience fall incidents and factors associated with increased fall risk among antidepressant users are incompletely understood. Our objective was to explore whether antidepressant plasma concentrations are associated with falls in older antidepressant users. Methods: For this study, we included antidepressant users of the multicenter B-PROOF study. Fall incidents were recorded prospectively using fall calendars. Antidepressant plasma concentrations were analyzed by Liquid chromatography-mass spectrometry (LC–MS) at baseline and at 2 years follow-up. The associations between the observed antidepressant concentration and fall risk were assessed using Cox proportional hazard and logistic regression models and adjusted for potential confounders. Results: In total 93 selective serotonin reuptake inhibitor (SSRI) and 41 antidepressant (TCA) users were identified. There was a significant association between baseline TCA plasma concentration and fall risk within users (HR 2.50, 95% CI 1.07–5.87, crude model). In the adjusted model, there were no significant associations between concentrations of SSRIs and fall risk. Conclusion: There might be an association between plasma concentrations of TCAs and the risk of falling in older users. However, these results needs to be interpreted with caution considering the small sample size and accompanying limitation of confinement to crude analyses. Therefore, these novel findings need to replicated in a larger cohort, preferably including adjustment for potential confounders and more frequent measures of plasma concentrations is needed.
Published: 2023

2. Update of the fracture risk prediction tool FRAX : a systematic review of potential cohorts and analysis plan

Author: Vandenput, L., Johansson, H., McCloskey, E.V., Liu, E., Åkesson, K.E., Anderson, F.A., Azagra, R., Bager, C.L., Beaudart, C., Bischoff-Ferrari, H.A., Biver, E., Bruyère, O., Cauley, J.A., Center, J.R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C.J., Cummings, S.R., da Silva, J.A.P., Dawson-Hughes, B., Diez-Perez, A., Dufour, A.B., Eisman, J.A., Elders, P.J.M., Ferrari, S., Fujita, Y., Fujiwara, S., Glüer, C.-C., Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R.J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M.K., Khosla, S., Kiel, D.P., Koh, W.-P., Koromani, F., Kotowicz, M.A., Kröger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., Mellström, D., Merlijn, T., Nordström, Annika, Nordström, Peter, O’Neill, T.W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E.S., Pasco, J.A., Rivadeneira, F., Schei, B., Schott, A.-M., Shiroma, E.J., Siggeirsdottir, K., Simonsick, E.M., Sornay-Rendu, E., Sund, R., Swart, K.M.A., Szulc, P., Tamaki, J., Torgerson, D.J., van Schoor, N.M., van Staa, T.P., Vila, J., Wareham, N.J., Wright, N.C., Yoshimura, N., Zillikens, M.C., Zwart, M., Harvey, N.C., Lorentzon, M., Leslie, W.D., Kanis, J.A., Vandenput, L., Johansson, H., McCloskey, E.V., Liu, E., Åkesson, K.E., Anderson, F.A., Azagra, R., Bager, C.L., Beaudart, C., Bischoff-Ferrari, H.A., Biver, E., Bruyère, O., Cauley, J.A., Center, J.R., Chapurlat, R., Christiansen, C., Cooper, C., Crandall, C.J., Cummings, S.R., da Silva, J.A.P., Dawson-Hughes, B., Diez-Perez, A., Dufour, A.B., Eisman, J.A., Elders, P.J.M., Ferrari, S., Fujita, Y., Fujiwara, S., Glüer, C.-C., Goldshtein, I., Goltzman, D., Gudnason, V., Hall, J., Hans, D., Hoff, M., Hollick, R.J., Huisman, M., Iki, M., Ish-Shalom, S., Jones, G., Karlsson, M.K., Khosla, S., Kiel, D.P., Koh, W.-P., Koromani, F., Kotowicz, M.A., Kröger, H., Kwok, T., Lamy, O., Langhammer, A., Larijani, B., Lippuner, K., Mellström, D., Merlijn, T., Nordström, Annika, Nordström, Peter, O’Neill, T.W., Obermayer-Pietsch, B., Ohlsson, C., Orwoll, E.S., Pasco, J.A., Rivadeneira, F., Schei, B., Schott, A.-M., Shiroma, E.J., Siggeirsdottir, K., Simonsick, E.M., Sornay-Rendu, E., Sund, R., Swart, K.M.A., Szulc, P., Tamaki, J., Torgerson, D.J., van Schoor, N.M., van Staa, T.P., Vila, J., Wareham, N.J., Wright, N.C., Yoshimura, N., Zillikens, M.C., Zwart, M., Harvey, N.C., Lorentzon, M., Leslie, W.D., and Kanis, J.A.
Abstract: Summary: We describe the collection of cohorts together with the analysis plan for an update of the fracture risk prediction tool FRAX with respect to current and novel risk factors. The resource comprises 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. Introduction: The availability of the fracture risk assessment tool FRAX® has substantially enhanced the targeting of treatment to those at high risk of fracture with FRAX now incorporated into more than 100 clinical osteoporosis guidelines worldwide. The aim of this study is to determine whether the current algorithms can be further optimised with respect to current and novel risk factors. Methods: A computerised literature search was performed in PubMed from inception until May 17, 2019, to identify eligible cohorts for updating the FRAX coefficients. Additionally, we searched the abstracts of conference proceedings of the American Society for Bone and Mineral Research, European Calcified Tissue Society and World Congress of Osteoporosis. Prospective cohort studies with data on baseline clinical risk factors and incident fractures were eligible. Results: Of the 836 records retrieved, 53 were selected for full-text assessment after screening on title and abstract. Twelve cohorts were deemed eligible and of these, 4 novel cohorts were identified. These cohorts, together with 60 previously identified cohorts, will provide the resource for constructing an updated version of FRAX comprising 2,138,428 participants with a follow-up of approximately 20 million person-years and 116,117 documented incident major osteoporotic fractures. For each known and candidate risk factor, multivariate hazard functions for hip fracture, major osteoporotic fracture and death will be tested using extended Poisson regression. Sex- and/or ethnicity-specific differences in the weights of the risk factors will be investigated. After meta-analyses of
Published: 2022
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3. Candidate genetic variants and antidepressant-related fall risk in middle-aged and older adults

Author: Pronk, A.C., Seppala, L.J., Trajanoska, K., Stringa, N., van de Loo, B., de Groot, L.C.P.G.M., Koskeridis, F., van Schoor, N.M., Markozannes, G., Ntzani, E., Uitterlinden, A.G., Rivadeneira, F., Stricker, B.H., van der Velde, N., Pronk, A.C., Seppala, L.J., Trajanoska, K., Stringa, N., van de Loo, B., de Groot, L.C.P.G.M., Koskeridis, F., van Schoor, N.M., Markozannes, G., Ntzani, E., Uitterlinden, A.G., Rivadeneira, F., Stricker, B.H., and van der Velde, N.
Abstract: Background Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users. Methods The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated. Results In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26–0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17–3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07–2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05–3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01–1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased r
Published: 2022

4. Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies

Author: van der Lee, S.J. (author), van Steenoven, Inger (author), van de Beek, Marleen (author), Tesi, N. (author), Jansen, Iris E. (author), van Schoor, N.M. (author), Reinders, M.J.T. (author), Huisman, Martijn (author), Scheltens, Philip (author), van der Lee, S.J. (author), van Steenoven, Inger (author), van de Beek, Marleen (author), Tesi, N. (author), Jansen, Iris E. (author), van Schoor, N.M. (author), Reinders, M.J.T. (author), Huisman, Martijn (author), and Scheltens, Philip (author)
Abstract: Background: Dementia with Lewy bodies (DLB) is a complex, progressive neurodegenerative disease with considerable phenotypic, pathological, and genetic heterogeneity. Objective: We tested if genetic variants in part explain the heterogeneity in DLB. Methods: We tested the effects of variants previously associated with DLB (near APOE, GBA, and SNCA) and polygenic risk scores for Alzheimer's disease (AD-PRS) and Parkinson's disease (PD-PRS). We studied 190 probable DLB patients from the Alzheimer's dementia cohort and compared them to 2,552 control subjects. The p-tau/Aβ1-42 ratio in cerebrospinal fluid was used as in vivo proxy to separate DLB cases into DLB with concomitant AD pathology (DLB-AD) or DLB without AD (DLB-pure). We studied the clinical measures age, Mini-Mental State Examination (MMSE), and the presence of core symptoms at diagnosis and disease duration. Results: We found that all studied genetic factors significantly associated with DLB risk (all-DLB). Second, we stratified the DLB patients by the presence of concomitant AD pathology and found that APOE ϵ4 and the AD-PRS associated specifically with DLB-AD, but less with DLB-pure. In addition, the GBA p.E365K variant showed strong associated with DLB-pure and less with DLB-AD. Last, we studied the clinical measures and found that APOE ϵ4 associated with reduced MMSE, higher odds to have fluctuations and a shorter disease duration. In addition, the GBA p.E365K variant reduced the age at onset by 5.7 years, but the other variants and the PRS did not associate with clinical features. Conclusion: These finding increase our understanding of the pathological and clinical heterogeneity in DLB., Pattern Recognition and Bioinformatics
Published: 2021
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5. 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

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

Author: Tesi, N. (author), Stringa, N. (author), Hadjigeorgiou, G. (author), Hulsman, M. (author), van Schoor, N.M. (author), Ruiz, A. (author), Jansen, I.E. (author), Holstege, H. (author), van der Lee, S.J. (author), Tesi, N. (author), Stringa, N. (author), Hadjigeorgiou, G. (author), Hulsman, M. (author), van Schoor, N.M. (author), Ruiz, A. (author), Jansen, I.E. (author), Holstege, H. (author), and van der Lee, S.J. (author)
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., Pattern Recognition and Bioinformatics
Published: 2021
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7. 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

8. Immune response and endocytosis pathways are associated with the resilience against Alzheimer’s disease

Author: Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Scheltens, Philip (author), van der Flier, Wiesje M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), Holstege, H. (author), Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Scheltens, Philip (author), van der Flier, Wiesje M. (author), Huisman, Martijn (author), Reinders, M.J.T. (author), and Holstege, H. (author)
Abstract: Developing Alzheimer’s disease (AD) is influenced by multiple genetic variants that are involved in five major AD-pathways. Per individual, these pathways may differentially contribute to the modification of the AD-risk. The pathways involved in the resilience against AD have thus far been poorly addressed. Here, we investigated to what extent each molecular mechanism associates with (i) the increased risk of AD and (ii) the resilience against AD until extreme old age, by comparing pathway-specific polygenic risk scores (pathway-PRS). We used 29 genetic variants associated with AD to develop pathway-PRS for five major pathways involved in AD. We developed an integrative framework that allows multiple genes to associate with a variant, and multiple pathways to associate with a gene. We studied pathway-PRS in the Amsterdam Dementia Cohort of well-phenotyped AD patients (N = 1895), Dutch population controls from the Longitudinal Aging Study Amsterdam (N = 1654) and our unique 100-plus Study cohort of cognitively healthy centenarians who avoided AD (N = 293). Last, we estimated the contribution of each pathway to the genetic risk of AD in the general population. All pathway-PRS significantly associated with increased AD-risk and (in the opposite direction) with resilience against AD (except for angiogenesis, p < 0.05). The pathway that contributed most to the overall modulation of AD-risk was β-amyloid metabolism (29.6%), which was driven mainly by APOE-variants. After excluding APOE variants, all pathway-PRS associated with increased AD-risk (except for angiogenesis, p < 0.05), while specifically immune response (p = 0.003) and endocytosis (p = 0.0003) associated with resilience against AD. Indeed, the variants in these latter two pathways became the main contributors to the overall modulation of genetic risk of AD (45.5% and 19.2%, respectively). The genetic variants associated with the resilience against AD indicate which pathways are involved with maintaine, Pattern Recognition and Bioinformatics, Intelligent Systems
Published: 2020
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9. Centenarian controls increase variant effect sizes by an average twofold in an extreme case–extreme control analysis of Alzheimer’s disease

Author: Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Meijers-Heijboer, Hanne (author), Reinders, M.J.T. (author), Holstege, H. (author), Tesi, N. (author), van der Lee, S.J. (author), Hulsman, M. (author), Jansen, Iris E. (author), Stringa, N. (author), van Schoor, N.M. (author), Meijers-Heijboer, Hanne (author), Reinders, M.J.T. (author), and Holstege, H. (author)
Abstract: The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3 ± 7.9 years), 1,664 age-matched controls (66.0 ± 6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4 ± 1.3 years). We estimated the effect size of 29 variants that were previously associated with AD in genome-wide association studies. Comparing extreme AD cases with centenarian controls increased the variant effect size relative to published effect sizes by on average 1.90-fold (SE = 0.29, p = 9.0 × 10−4). The effect size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-ε2 (2.2-fold), and APOE-ε4 (twofold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p < 0.05) in relatively small samples. The increase in effect sizes depended mainly on using centenarians as extreme controls: the average variant effect size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p = 6.8 × 10−1), suggesting that on average the tested genetic variants did not explain the extremity of the AD cases. Concluding, using centenarians as extreme controls in AD case–control studies boosts the variant effect size by on average twofold, allowing the replication of disease-association in relatively small samples., Pattern Recognition and Bioinformatics
Published: 2019
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10. Within-Person Pain Variability and Mental Health in Older Adults With Osteoarthritis: An Analysis Across 6 European Cohorts

Author: de Koning, Elisa J., Timmermans, E.J., van Schoor, N.M., Stubbs, Brendon, van den Kommer, Tessa N., Dennison, E.M., Limongi, Federica, Castell, Maria Victoria, Edwards, M.H., Queipo, Rocio, Cooper, Cyrus, Siviero, Paola, van der Pas, Suzan, Pedersen, N.L., Sánchez-Martínez, Mercedes, Deeg, D.J.H., Denkinger, Michael D., Nikolaus, T., Denkinger, M., Peter, R., Herbolsheimer, F., Maggi, S., Zambon, S., Limongi, F., Noale, M., Siviero, P., van der Pas, S., Schaap, L.A., Lips, P., Otero, Á., Castell, M.V., Sanchez-Martinez, M., Cooper, C., de Koning, Elisa J., Timmermans, E.J., van Schoor, N.M., Stubbs, Brendon, van den Kommer, Tessa N., Dennison, E.M., Limongi, Federica, Castell, Maria Victoria, Edwards, M.H., Queipo, Rocio, Cooper, Cyrus, Siviero, Paola, van der Pas, Suzan, Pedersen, N.L., Sánchez-Martínez, Mercedes, Deeg, D.J.H., Denkinger, Michael D., Nikolaus, T., Denkinger, M., Peter, R., Herbolsheimer, F., Maggi, S., Zambon, S., Limongi, F., Noale, M., Siviero, P., van der Pas, S., Schaap, L.A., Lips, P., Otero, Á., Castell, M.V., Sanchez-Martinez, M., and Cooper, C.
Abstract: Pain is a key symptom of Osteoarthritis (OA) and has been linked to poor mental health. Pain fluctuates over time within individuals, but a paucity of studies have considered day-to-day fluctuations of joint pain in relation to affective symptoms in older persons with OA. This study investigated the relationship of both pain severity and within-person pain variability with anxiety and depression symptoms in 832 older adults with OA who participated in the European Project on OSteoArthritis (EPOSA): a six-country cohort study. Affective symptoms were examined with the Hospital Anxiety and Depression Scale, pain severity was assessed with the WOMAC/AUSCAN, and intra-individual pain variability was measured using pain calendars assessed at baseline, 6 and 12-18 months. Age-stratified multiple linear regression analyses adjusted for relevant confounders showed that more pain was associated with more affective symptoms in older-old participants (74.1-85 years). Moreover, older-old participants experienced fewer symptoms of anxiety (ratio=.85, 95% CI: .77-.94), depression (ratio=.90, 95% CI: .82-.98) and total affective symptoms (ratio=.87, 95% CI: .79-.94) if their pain fluctuated more. No such association was evident in younger-old participants (65-74.0 years). These findings imply that stable pain levels are more detrimental to mental health than fluctuating pain levels in older persons. PERSPECTIVE: This study showed that more severe and stable joint pain levels were associated with anxiety and depressive symptoms in older persons with OA. These findings emphasize the importance of measuring pain in OA at multiple time-points, as joint pain fluctuations may be an indicator for the presence of affective symptoms.
Published: 2018
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11. Large meta-analysis of genome-wide association studies identifies five loci for lean body mass.

Author: Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., Kiel, D.P., Zillikens, M.C., Demissie, S., Hsu, Y.H., Yerges-Armstrong, L.M., Chou, W.C., Stolk, L., Livshits, G., Broer, L., Johnson, T., Koller, D.L., Kutalik, Z., Luan, J., Malkin, I., Ried, J.S., Smith, A.V., Thorleifsson, G., Vandenput, L., Hua Zhao, J., Zhang, W., Aghdassi, A., Åkesson, K., Amin, N., Baier, L.J., Barroso, I., Bennett, D.A., Bertram, L., Biffar, R., Bochud, M., Boehnke, M., Borecki, I.B., Buchman, A.S., Byberg, L., Campbell, H., Campos Obanda, N., Cauley, J.A., Cawthon, P.M., Cederberg, H., Chen, Z., Cho, N.H., Jin Choi, H., Claussnitzer, M., Collins, F., Cummings, S.R., De Jager, P.L., Demuth, I., Dhonukshe-Rutten, RAM, Diatchenko, L., Eiriksdottir, G., Enneman, A.W., Erdos, M., Eriksson, J.G., Eriksson, J., Estrada, K., Evans, D.S., Feitosa, M.F., Fu, M., Garcia, M., Gieger, C., Girke, T., Glazer, N.L., Grallert, H., Grewal, J., Han, B.G., Hanson, R.L., Hayward, C., Hofman, A., Hoffman, E.P., Homuth, G., Hsueh, W.C., Hubal, M.J., Hubbard, A., Huffman, K.M., Husted, L.B., Illig, T., Ingelsson, E., Ittermann, T., Jansson, J.O., Jordan, J.M., Jula, A., Karlsson, M., Khaw, K.T., Kilpeläinen, T.O., Klopp, N., Kloth, JSL, Koistinen, H.A., Kraus, W.E., Kritchevsky, S., Kuulasmaa, T., Kuusisto, J., Laakso, M., Lahti, J., Lang, T., Langdahl, B.L., Launer, L.J., Lee, J.Y., Lerch, M.M., Lewis, J.R., Lind, L., Lindgren, C., Liu, Y., Liu, T., Ljunggren, Ö., Lorentzon, M., Luben, R.N., Maixner, W., McGuigan, F.E., Medina-Gomez, C., Meitinger, T., Melhus, H., Mellström, D., Melov, S., Michaëlsson, K., Mitchell, B.D., Morris, A.P., Mosekilde, L., Newman, A., Nielson, C.M., O'Connell, J.R., Oostra, B.A., Orwoll, E.S., Palotie, A., Parker, S., Peacock, M., Perola, M., Peters, A., Polasek, O., Prince, R.L., Räikkönen, K., Ralston, S.H., Ripatti, S., Robbins, J.A., Rotter, J.I., Rudan, I., Salomaa, V., Satterfield, S., Schadt, E.E., Schipf, S., Scott, L., Sehmi, J., Shen, J., Soo Shin, C., Sigurdsson, G., Smith, S., Soranzo, N., Stančáková, A., Steinhagen-Thiessen, E., Streeten, E.A., Styrkarsdottir, U., Swart, KMA, Tan, S.T., Tarnopolsky, M.A., Thompson, P., Thomson, C.A., Thorsteinsdottir, U., Tikkanen, E., Tranah, G.J., Tuomilehto, J., van Schoor, N.M., Verma, A., Vollenweider, P., Völzke, H., Wactawski-Wende, J., Walker, M., Weedon, M.N., Welch, R., Wichmann, H.E., Widen, E., Williams, FMK, Wilson, J.F., Wright, N.C., Xie, W., Yu, L., Zhou, Y., Chambers, J.C., Döring, A., van Duijn, C.M., Econs, M.J., Gudnason, V., Kooner, J.S., Psaty, B.M., Spector, T.D., Stefansson, K., Rivadeneira, F., Uitterlinden, A.G., Wareham, N.J., Ossowski, V., Waterworth, D., Loos, RJF, Karasik, D., Harris, T.B., Ohlsson, C., and Kiel, D.P.
Abstract: Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 × 10(-8)) or suggestively genome wide (p < 2.3 × 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass.Lean body mass is a highly heritable trait and is associated with various health conditions. Here, Kiel and colleagues perform a meta-analysis of genome-wide association studies for whole body lean body mass and find five novel genetic loci to be significantly associated.
Published: 2017

12. Food sources of vitamin D and their association with 25-hydroxyvitamin D status in Dutch older adults

Author: Vaes, A.M.M., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., van Wijngaarden, J.P., Berendsen, A.A.M., Van Schoor, N.M., van der Velde, N., Uitterlinden, A., Lips, P., Dhonukshe-Rutten, R.A.M., de Groot, L.C.P.G.M., Vaes, A.M.M., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., van Wijngaarden, J.P., Berendsen, A.A.M., Van Schoor, N.M., van der Velde, N., Uitterlinden, A., Lips, P., Dhonukshe-Rutten, R.A.M., and de Groot, L.C.P.G.M.
Abstract: Various populations are at increased risk of developing a low vitamin D status, in particular older adults. Whereas sun exposure is considered the main source of vitamin D, especially during summer, dietary contributions should not be underestimated. This study aims to identify food sources of vitamin D that associate most strongly with serum vitamin D concentration. Data of 595 Dutch adults, aged 65 years, were analysed. Vitamin D intake was assessed with a food frequency questionnaire and 25- hydroxyvitamin D (25(OH)D) was determined in serum. Associations of total vitamin D intake and vitamin D intake from specific food groups with serum 25(OH)D status were examined by P-for trend analyses over tertiles of vitamin D intake, prevalence ratios (PRs), and spline regression. The prevalence of vitamin D deficiency was high, with 36% of the participants having a 25(OH)D status <50 nmol/L. Participants with adequate 25(OH)D concentrations were more likely to be men and more likely to be younger than participants with vitamin D deficiency. Total median vitamin D intake was 4.3mg/day, of which 4.0mg/day was provided by foods. Butter and margarine were the leading contributors to total vitamin D intake with 1.8mg/day, followed by the intake of fish and shellfish with 0.56mg/day. Participants with higher intakes of butter and margarine were 21% more likely to have a sufficient 25(OH) D status after adjustment for covariates (T1 vs. T3: PR 1.0 vs. 1.21 (95%CI: 1.03–1.42), P-for trend 0.02). None of the other food groups showed a significant association with the probability of having a sufficient 25(OH)D status. This study shows that vitamin D intake was positively associated with total serum 25 (OH)D concentration, with butter and margarine being the most important contributors to total vitamin D intake
Published: 2017
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13. Low vitamin D status is associated with more depressive symptoms in Dutch older adults

Author: Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., Sohl, E., in 't Veld, P.H., van Dijk, S.C., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Feskens, E.J.M., de Groot, C.P.G.M., Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., Sohl, E., in 't Veld, P.H., van Dijk, S.C., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Feskens, E.J.M., and de Groot, C.P.G.M.
Abstract: Purpose The existence of vitamin D receptors in the brain points to a possible role of vitamin D in brain function. We examined the association of vitamin D status and vitamin D-related genetic make-up with depressive symptoms amongst 2839 Dutch older adults aged =65 years. Methods 25-Hydroxyvitamin D (25(OH)D) was measured, and five ‘vitamin D-related genes’ were selected. Depressive symptoms were measured with the 15-point Geriatric Depression Scale. Results were expressed as the relative risk of the score of depressive symptoms by quartiles of 25(OH)D concentration or number of affected alleles, using the lowest quartile or minor allele group as reference. Results A clear cross-sectional and prospective association between serum 25(OH)D and depressive symptom score was observed. Fully adjusted models indicated a 22 % (RR 0.78, 95 % CI 0.68–0.89), 21 % (RR 0.79, 95 % CI 0.68–0.90), and 18 % (RR 0.82, 95 % CI 0.71–0.95) lower score of depressive symptoms in people in the second, third, and fourth 25(OH)D quartiles, when compared to people in the first quartile (P for trend
Published: 2016

14. A randomized controlled trial to examine the effect of 2-year vitamin B12 and folic acid supplementation on physical performance, strength, and falling: additional findings from the B-PROOF study

Author: Swart, K.M.A., Ham, A.C., van Wijngaarden, J.P., Enneman, A.W., van Dijk, S.C., Sohl, E., Brouwer, E.M., van der Zwaluw, N.L., Zillikens, M.C., Dhonukshe-Rutten, R.A.M., van der Velde, N., Brug, J., Uitterlinden, A.G., de Groot, C.P.G.M., Lips, P., van Schoor, N.M., Swart, K.M.A., Ham, A.C., van Wijngaarden, J.P., Enneman, A.W., van Dijk, S.C., Sohl, E., Brouwer, E.M., van der Zwaluw, N.L., Zillikens, M.C., Dhonukshe-Rutten, R.A.M., van der Velde, N., Brug, J., Uitterlinden, A.G., de Groot, C.P.G.M., Lips, P., and van Schoor, N.M.
Abstract: Elevated homocysteine concentrations are associated with a decline in physical function in elderly persons. Homocysteine-lowering therapy may slow down this decline. This study aimed to examine the effect of a 2-year intervention of vitamin B12 and folic acid supplementation on physical performance, handgrip strength, and risk of falling in elderly subjects in a double-blind, randomized placebo-controlled trial. Participants aged ≥65 years with elevated plasma homocysteine concentrations [12–50 µmol/L (n = 2919)] were randomly assigned to daily supplementation of 500 µg vitamin B12, 400 µg folic acid, and 600 IU vitamin D3, or to placebo with 600 IU vitamin D3. Physical performance (range 0–12) and handgrip strength (kg) were measured at baseline and after 2 years. Falls were reported prospectively on a research calendar. Intention-to-treat (primary) and per-protocol (secondary) analyses were performed. Physical performance level and handgrip strength significantly decreased during the follow-up period, but this decline did not differ between groups. Moreover, time to first fall was not significantly different (HR: 1.0, 95 % CI 0.9–1.2). Secondary analyses on a per-protocol base identified an interaction effect with age on physical performance. In addition, the treatment was associated with higher follow-up scores on the walking test (cumulative OR: 1.3, 95 % CI 1.1–1.5). Two-year supplementation of vitamin B12 and folic acid was neither effective in reducing the age-related decline in physical performance and handgrip strength, nor in the prevention of falling in elderly persons. Despite the overall null-effect, the results provide indications for a positive effect of the intervention on gait, as well as on physical performance among compliant persons >80 years. These effects should be further tested in future studies
Published: 2016

15. Correction: The influence of age and sex on genetic associations with adult body size and shape : a large-scale genome-wide interaction study.

Author: Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T.O., Lu, Y., Mägi, R., Mihailov, E., Pers, T.H., Rüeger, S., Teumer, A., Ehret, G.B., Ferreira, T., Heard-Costa, N.L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M.D., Prokopenko, I., Simino, J., Teslovich, T.M., Jansen, R., Westra, H.J., White, C.C., Absher, D., Ahluwalia, T.S., Ahmad, S., Albrecht, E., Alves, A.C., Bragg-Gresham, J.L., de Craen, A.J., Bis, J.C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y.C., Chiang, C.W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T.E., Geller, F., Goel, A., Gorski, M., Grammer, T.B., Gustafsson, S., Haitjema, S., Hottenga, J.J., Huffman, J.E., Jackson, A.U., Jacobs, K.B., Johansson, Å., Kaakinen, M., Kleber, M.E., Lahti, J., Mateo Leach, I., Lehne, B., Liu, Y., Lo, K.S., Lorentzon, M., Luan, J., Madden, P.A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K.L., Montasser, M.E., Müller, G., Müller-Nurasyid, M., Nolte, I.M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N.W., Renström, F., Rizzi, F., Rose, L.M., Ryan, K.A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A.V., Southam, L., Stančáková, A., Steinthorsdottir, V., Strawbridge, R.J., Sung, Y.J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J.P., Vandenput, L., van der Laan, S.W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J.V., Verweij, N., Vlachopoulou, E., Waite, L.L., Wang, S.R., Wang, Z., Wild, S.H., Willenborg, C., Wilson, J.F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L.M., Yu, L., Zhang, W., Zhao, J.H., Andersson, E.A., Bakker, S.J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L.L., Boyd, H.A., Bruinenberg, M., Buchman, A.S., Campbell, H., Chen, 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Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Montgomery, G.W., Morris, A.P., Narisu, N., Nelis, M., Ong, K.K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M.G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K.M., Rice, T.K., Rivolta, C., Salomaa, V., Sanders, A.R., Sarzynski, M.A., Scholtens, S., Scott, R.A., Scott, W.R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P.E., Smit, J.H., Sparsø, T.H., Stirrups, K., Stolk, R.P., Stringham, H.M., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tan, S.T., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P.J., Völker, U., Vohl, M.C., Vonk, J.M., Waldenberger, M., Walker, R.W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A.F., Zillikens, M.C., van Dijk, S.C., van Schoor, N.M., Asselbergs, F.W., de Bakker, P.I., Beckmann, J.S., Beilby, J., Bennett, D.A., Bergman, R.N., Bergmann, S., Böger, C.A., Boehm, B.O., Boerwinkle, E., 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G.R., Assimes, T.L., Barroso, I., Berndt, S.I., Boehnke, M., Deloukas, P., Fox, C.S., Groop, L.C., Hunter, D.J., Ingelsson, E., Kaplan, R.C., McCarthy, M.I., Mohlke, K.L., O'Connell, J.R., Schlessinger, D., Strachan, D.P., Stefansson, K., van Duijn, C.M., Hirschhorn, J.N., Lindgren, C.M., Heid, I.M., North, K.E., Borecki, I.B., Kutalik, Z., Loos, R.J., Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T.O., Lu, Y., Mägi, R., Mihailov, E., Pers, T.H., Rüeger, S., Teumer, A., Ehret, G.B., Ferreira, T., Heard-Costa, N.L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M.D., Prokopenko, I., Simino, J., Teslovich, T.M., Jansen, R., Westra, H.J., White, C.C., Absher, D., Ahluwalia, T.S., Ahmad, S., Albrecht, E., Alves, A.C., Bragg-Gresham, J.L., de Craen, A.J., Bis, J.C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y.C., Chiang, C.W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., 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Willenborg, C., Wilson, J.F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L.M., Yu, L., Zhang, W., Zhao, J.H., Andersson, E.A., Bakker, S.J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L.L., Boyd, H.A., Bruinenberg, M., Buchman, A.S., Campbell, H., Chen, Y.I., Chines, P.S., Claudi-Boehm, S., Cole, J., Collins, F.S., de Geus, E.J., de Groot, L.C., Dimitriou, M., Duan, J., Enroth, S., Eury, E., Farmaki, A.E., Forouhi, N.G., Friedrich, N., Gejman, P.V., Gigante, B., Glorioso, N., Go, A.S., Gottesman, O., Gräßler, J., Grallert, H., Grarup, N., Gu, Y.M., Broer, L., Ham, A.C., Hansen, T., Harris, T.B., Hartman, C.A., Hassinen, M., Hastie, N., Hattersley, A.T., Heath, A.C., Henders, A.K., Hernandez, D., Hillege, H., Holmen, O., Hovingh, K.G., Hui, J., Husemoen, L.L., Hutri-Kähönen, N., Hysi, P.G., Illig, T., De Jager, P.L., Jalilzadeh, S., Jørgensen, T., Jukema, J.W., Juonala, M., Kanoni, S., Karaleftheri, M., Khaw, K.T., Kinnunen, L., Kittner, S.J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N.T., Kratzer, W., Krüger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L.J., Leander, K., Lindström, J., Linneberg, A., Liu, Y.P., Lobbens, S., Luben, R., Lyssenko, V., Männistö, S., Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Montgomery, G.W., Morris, A.P., Narisu, N., Nelis, M., Ong, K.K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M.G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K.M., Rice, T.K., Rivolta, C., Salomaa, V., Sanders, A.R., Sarzynski, M.A., Scholtens, S., Scott, R.A., Scott, W.R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P.E., Smit, J.H., Sparsø, T.H., Stirrups, K., Stolk, R.P., Stringham, H.M., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tan, S.T., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P.J., Völker, U., Vohl, M.C., Vonk, J.M., Waldenberger, M., Walker, R.W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A.F., Zillikens, M.C., van Dijk, S.C., van Schoor, N.M., Asselbergs, F.W., de Bakker, P.I., Beckmann, J.S., Beilby, J., Bennett, D.A., Bergman, R.N., Bergmann, S., Böger, C.A., Boehm, B.O., Boerwinkle, E., Boomsma, D.I., Bornstein, S.R., Bottinger, E.P., Bouchard, C., Chambers, J.C., Chanock, S.J., Chasman, D.I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J.G., Evans, D.A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P.W., Froguel, P., Gansevoort, R.T., Gieger, C., Grönberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliövaara, M., Hengstenberg, C., Hicks, A.A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H.V., Hveem, K., James, A.L., Jordan, J.M., Jula, A., Kähönen, M., Kajantie, E., Kathiresan, S., Kiemeney, L.A., Kivimaki, M., Knekt, P.B., Koistinen, H.A., Kooner, J.S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N.G., Laakso, M., Lakka, T.A., Lehtimäki, T., Lettre, G., Levinson, D.F., Lind, L., Lokki, M.L., Mäntyselkä, P., Melbye, M., Metspalu, A., Mitchell, B.D., Moll, F.L., Murray, J.C., Musk, A.W., Nieminen, M.S., Njølstad, I., Ohlsson, C., Oldehinkel, A.J., Oostra, B.A., Palmer, L.J., Pankow, J.S., Pasterkamp, G., Pedersen, N.L., Pedersen, O., Penninx, B.W., Perola, M., Peters, A., Polaek, O., Pramstaller, P.P., Psaty, B.M., Qi, L., Quertermous, T., Raitakari, O.T., Rankinen, T., Rauramaa, R., Ridker, P.M., Rioux, J.D., Rivadeneira, F., Rotter, J.I., Rudan, I., den Ruijter, H.M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P.E., Shuldiner, A.R., Sinisalo, J., Snieder, H., Sørensen, T.I., Spector, T.D., Staessen, J.A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J.C., Tremoli, E., Tuomilehto, J., Uitterlinden, A.G., Uusitupa, M., Verbeek, A.L., Vermeulen, S.H., Viikari, J.S., Vitart, V., Völzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N.J., Watkins, H., Zeggini, E., arcOGEN, Consortium, CHARGE, Consortium, DIAGRAM, Consortium, GLGC, Consortium, Global-BPGen, Consortium, ICBP, Consortium, MAGIC, Consortium, Chakravarti, A., Clegg, D.J., Cupples, L.A., Gordon-Larsen, P., Jaquish, C.E., Rao, D.C., Abecasis, G.R., Assimes, T.L., Barroso, I., Berndt, S.I., Boehnke, M., Deloukas, P., Fox, C.S., Groop, L.C., Hunter, D.J., Ingelsson, E., Kaplan, R.C., McCarthy, M.I., Mohlke, K.L., O'Connell, J.R., Schlessinger, D., Strachan, D.P., Stefansson, K., van Duijn, C.M., Hirschhorn, J.N., Lindgren, C.M., Heid, I.M., North, K.E., Borecki, I.B., Kutalik, Z., and Loos, R.J.
Abstract: This corrects the article DOI: 10.1371/journal.pgen.1005378.
Published: 2016

16. Non-linear associations between serum 25-OH vitamin D and indices of arterial stiffness and arteriosclerosis in an older population

Author: van Dijk, S.C., Sohl, E., Oudshoorn, C., Enneman, A.W., Ham, A.C., Swart, K.M.A., van Wijngaarden, J.P., Brouwer, E.M., van der Zwaluw, N.L., Uitterlinden, A.G., de Groot, C.P.G.M., Dhonukshe-Rutten, R.A.M., Lips, P., van Schoor, N.M., Blom, H.J., Geleijnse, J.M., Feskens, E.J.M., van Dijk, S.C., Sohl, E., Oudshoorn, C., Enneman, A.W., Ham, A.C., Swart, K.M.A., van Wijngaarden, J.P., Brouwer, E.M., van der Zwaluw, N.L., Uitterlinden, A.G., de Groot, C.P.G.M., Dhonukshe-Rutten, R.A.M., Lips, P., van Schoor, N.M., Blom, H.J., Geleijnse, J.M., and Feskens, E.J.M.
Abstract: Background: several studies have been pointing towards a non-linear relationship between serum 25(OH)D and cardiovascular disease. Next to vitamin D deficiency, also higher levels of 25(OH)D have been reported to be associated with increased cardiovascular risk. We aimed to investigate the nature of the relationship between serum 25(OH)D and measures of arterial stiffness and arteriosclerosis in an elderly population. Design: cross-sectional. Setting/subjects: a subgroup of the B-PROOF study was included to determine associations between serum 25(OH)D and arterial stiffness and atherosclerosis (n = 567, 57% male, age 72.6 ± 5.6 years, mean serum 25(OH)D 54.6 ± 24.1 nmol/l). Methods: carotid intima media thickness (IMT) was assessed using ultrasonography and pulse wave velocity (PWV) was determined with applanation tonometry. Associations were tested using multivariable restricted cubic spline functions and stratified linear regression analysis. Results: the associations between serum 25(OH)D and carotid IMT or PWV were non-linear. Spline functions demonstrated a difference between 25(OH)D deficient and sufficient individuals. In serum 25(OH)D sufficient participants (=50 nmol/l; n = 287), a positive association with IMT and serum 25(OH)D was present (ß 1.24; 95%CI [0.002; 2.473]). PWV levels were slightly lower in vitamin D deficient individuals, but the association with 25(OH)D was not significant. Conclusion: our study demonstrates that associations of serum 25(OH)D and PWV and IMT in an elderly population are not linear. In particular from serum 25(OH)D levels of 50 nmol/l and up, there is a slight increase of IMT with increasing 25(OH)D levels.
Published: 2015

17. Cognitive performance: a cross-sectional study on serum vitamin D and its interplay with glucose homeostasis in Dutch older adults

Author: Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., in 't Veld, P.H., Wins, S., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Dijk, S.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Kessels, R.P.C., Steegenga, W.T., Feskens, E.J.M., de Groot, C.P.G.M., Brouwer-Brolsma, E.M., Dhonukshe-Rutten, R.A.M., van Wijngaarden, J.P., van der Zwaluw, N.L., in 't Veld, P.H., Wins, S., Swart, K.M.A., Enneman, A.W., Ham, A.C., van Dijk, S.C., van Schoor, N.M., van der Velde, N., Uitterlinden, A.G., Lips, P., Kessels, R.P.C., Steegenga, W.T., Feskens, E.J.M., and de Groot, C.P.G.M.
Abstract: Objectives First, the association between serum 25-hydroxyvitamin D (25[OH]D) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose homeostasis in the association with cognitive performance. Design, Setting, and Participants Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older. Measurements Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores. Results The overall median MMSE score was 29 (IQR 28–30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29–0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations. Conclusion Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance.
Published: 2015

18. Effect of vitamin B12 and folic acid supplementation on bone mineral density and quantitative ultrasound parameters in older people with an elevated plasma homocysteine level: B-PROOF, a randomized controlled trial

Author: Enneman, A.W., Swart, K.M.A., van Wijngaarden, J.P., van Dijk, S.C., Ham, A.C., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., Dhonukshe-Rutten, R.A.M., van der Cammen, T.J.M., de Groot, C.P.G.M., van Meurs, J.B.J., Lips, P., Uitterlinden, A.G., Zillikens, M.C., van Schoor, N.M., van der Velde, N., Enneman, A.W., Swart, K.M.A., van Wijngaarden, J.P., van Dijk, S.C., Ham, A.C., Brouwer-Brolsma, E.M., van der Zwaluw, N.L., Dhonukshe-Rutten, R.A.M., van der Cammen, T.J.M., de Groot, C.P.G.M., van Meurs, J.B.J., Lips, P., Uitterlinden, A.G., Zillikens, M.C., van Schoor, N.M., and van der Velde, N.
Abstract: High plasma homocysteine (Hcy) levels are associated with increased osteoporotic fracture incidence. However, the mechanism remains unclear. We investigated the effect of Hcy-lowering vitamin B12 and folic acid treatment on bone mineral density (BMD) and calcaneal quantitative ultrasound (QUS) parameters. This randomized, double-blind, placebo-controlled trial included participants aged =65 years with plasma Hcy levels between 12 and 50 µmol/L. The intervention comprised 2-year supplementation with either a combination of 500 µg B12, 400 µg folic acid, and 600 IU vitamin D or placebo with 600 IU vitamin D only. In total, 1111 participants underwent repeated dual-energy X-ray assessment and 1165 participants underwent QUS. Femoral neck (FN) BMD, lumbar spine (LS) BMD, calcaneal broadband ultrasound attenuation (BUA), and calcaneal speed of sound (SOS) were assessed. After 2 years, FN-BMD and BUA had significantly decreased, while LS-BMD significantly increased (all p <0.01) and SOS did not change in either treatment arm. No statistically significant differences between the intervention and placebo group were present for FN-BMD (p = 0.24), LS-BMD (p = 0.16), SOS (p = 0.67), and BUA (p = 0.96). However, exploratory subgroup analyses revealed a small positive effect of the intervention on BUA at follow-up among compliant persons >80 years (estimated marginal mean 64.4 dB/MHz for the intervention group and 61.0 dB/MHz for the placebo group, p = 0.04 for difference). In conclusion, this study showed no overall effect of treatment with vitamin B12 and folic acid on BMD or QUS parameters in elderly, mildly hyperhomocysteinemic persons, but suggests a small beneficial effect on BUA in persons >80 years who were compliant in taking the supplement.
Published: 2015

19. The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects

Author: Kok, D.E.G., Dhonukshe-Rutten, R.A.M., Lute, C., Heil, S.G., Uitterlinden, A.G., van der Velde, N., van Meurs, J.B.J., van Schoor, N.M., Hooiveld, G.J.E.J., de Groot, C.P.G.M., Kampman, E., Steegenga, W.T., Kok, D.E.G., Dhonukshe-Rutten, R.A.M., Lute, C., Heil, S.G., Uitterlinden, A.G., van der Velde, N., van Meurs, J.B.J., van Schoor, N.M., Hooiveld, G.J.E.J., de Groot, C.P.G.M., Kampman, E., and Steegenga, W.T.
Abstract: Folate and its synthetic form folic acid function as donor of one-carbon units and have been, together with other B-vitamins, implicated in programming of epigenetic processes such as DNA methylation during early development. To what extent regulation of DNA methylation can be altered via B-vitamins later in life, and how this relates to health and disease, is not exactly known. The aim of this study was to identify effects of long-term supplementation with folic acid and vitamin B 12 on genome-wide DNA methylation in elderly subjects. This project was part of a randomized, placebo-controlled trial on effects of supplemental intake of folic acid and vitamin B 12 on bone fracture incidence (B-vitamins for the PRevention Of Osteoporotic Fractures (B-PROOF) study). Participants with mildly elevated homocysteine levels, aged 65–75 years, were randomly assigned to take 400 µg folic acid and 500 µg vitamin B 12 per day or a placebo during an intervention period of 2 years. DNA was isolated from buffy coats, collected before and after intervention, and genome-wide DNA methylation was determined in 87 participants (n¿=¿44 folic acid/vitamin B 12 , n¿=¿43 placebo) using the Infinium HumanMethylation450 BeadChip. Results After intervention with folic acid and vitamin B 12 , 162 (versus 14 in the placebo group) of the 431,312 positions were differentially methylated as compared to baseline. Comparisons of the DNA methylation changes in the participants receiving folic acid and vitamin B 12 versus placebo revealed one single differentially methylated position (cg19380919) with a borderline statistical significance. However, based on the analyses of differentially methylated regions (DMRs) consisting of multiple positions, we identified 6 regions that differed statistically significantly between the intervention and placebo group. Pronounced changes were found for regions in the DIRAS3, ARMC8, and NODAL genes, implicated in carcinogenesis and early embryonic development. Further
Published: 2015

20. Defining the role of common variation in the genomic and biological architecture of adult human height.

Author: Genomics (eMEMERGEGE) Consortium, MIGen Consortium, PAGEGE Consortium, LifeLines Cohort Study, Electronic Medical, Records, McCarty, CA., Starren, J., Peissig, P., Berg, R., Rasmussen, L., Linneman, J., Miller, A., Choudary, V., Chen, L., Waudby, C., Kitchner, T., Reeser, J., Fost, N., Ritchie, M., Wilke, RA., Chisholm, RL., Avila, PC., Greenland, P., Hayes, M., Kho, A., Kibbe, WA., Lemke, AA., Lowe, WL., Smith, ME., Wolf, WA., Pacheco, JA., Thompson, WK., Humowiecki, J., Law, M., Chute, C., Kullo, I., Koenig, B., de Andrade, M., Bielinski, S., Pathak, J., Savova, G., Wu, J., Henriksen, J., Ding, K., Hart, L., Palbicki, J., Larson, EB., Newton, K., Ludman, E., Spangler, L., Hart, G., Carrell, D., Jarvik, G., Crane, P., Burke, W., Fullerton, SM., Trinidad, SB., Carlson, C., Hutchinson, F., McDavid, A., Roden, DM., Clayton, E., Haines, JL., Masys, DR., Churchill, LR., Cornfield, D., Crawford, D., Darbar, D., Denny, JC., Malin, BA., Ritchie, MD., Schildcrout, JS., Xu, H., Ramirez, AH., Basford, M., Pulley, J., Alizadeh, B., de Boer RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Kathiresan, S., Voight, BF., Purcell, S., Musunuru, K., Ardissino, D., Mannucci, PM., Anand, S., Engert, JC., Samani, NJ., Schunkert, H., Erdmann, J., Reilly, MP., Rader, DJ., Morgan, T., Spertus, JA., Stoll, M., Girelli, D., McKeown, PP., Patterson, CC., Siscovick, DS., O'Donnell, CJ., Elosua, R., Peltonen, L., Salomaa, V., Schwartz, SM., Melander, O., Altshuler, D., Merlini, PA., Berzuini, C., Bernardinelli, L., Peyvandi, F., Tubaro, M., Celli, P., Ferrario, M., Fetiveau, R., Marziliano, N., Casari, G., Galli, M., Ribichini, F., Rossi, M., Bernardi, F., Zonzin, P., Piazza, A., Yee, J., Friedlander, Y., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Meigs, JB., Williams, G., Nathan, DM., MacRae, CA., 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D., Bakker, S.J., Beilby, J., Bergman, R.N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D.I., Bornstein, S.R., Bovet, P., Brambilla, P., Brown, M.J., Campbell, H., Caulfield, M.J., Chakravarti, A., Collins, R., Collins, F.S., Crawford, D.C., Cupples, L.A., Danesh, J., de Faire, U., den Ruijter, H.M., Erbel, R., Eriksson, J.G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N.G., Forrester, T., Gansevoort, R.T., Gejman, P.V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D.W., Hall, A.S., Harris, T.B., Hattersley, A.T., Heath, A.C., Hicks, A.A., Hindorff, L.A., Hingorani, A.D., Hofman, A., Hovingh, G.K., Humphries, S.E., Hunt, S.C., Hypponen, E., Jacobs, K.B., Jarvelin, M.R., Jousilahti, P., Jula, A.M., Kaprio, J., Kastelein, J.J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S.M., Kiemeney, L.A., Kooner, J.S., Koskinen, S., Kovacs, P., Kraja, A.T., Kumari, M., Kuusisto, J., Lakka, T.A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P.A., Männistö, S., Manunta, P., Marette, A., Matise, T.C., McKnight, B., Meitinger, T., Moll, F.L., Montgomery, G.W., Morris, A.D., Morris, A.P., Murray, J.C., Nelis, M., Ohlsson, C., Oldehinkel, A.J., Ong, K.K., Ouwehand, W.H., Pasterkamp, G., Peters, A., Pramstaller, P.P., Price, J.F., Qi, L., Raitakari, O.T., Rankinen, T., Rao, D.C., Rice, T.K., Rudan, I., Samani, N.J., Saramies, J., Sarzynski, M.A., Schwarz, P.E., Sebert, S., Sever, P., Shuldiner, A.R., Sinisalo, J., Steinthorsdottir, V., Stolk, R.P., Tardif, J.C., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M.C., Amouyel, P., Asselbergs, F.W., Assimes, T.L., Bochud, M., Boehm, B.O., Bottinger, E.P., Bouchard, C., Cauchi, S., Chambers, J.C., Chanock, S.J., Cooper, R.S., de Bakker, P.I., Dedoussis, G., Ferrucci, L., Franks, P.W., Froguel, P., Groop, L.C., Haiman, C.A., Hamsten, A., Hayes, M.G., Hui, J., Hunter, D.J., Hveem, K., Jukema, J.W., Kaplan, R.C., Kivimaki, M., Kuh, D., Laakso, M., Liu, 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Abstract: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
Published: 2014

21. Peak expiratory flow rate shows a gender-specific association with vitamin D deficiency

Author: van Schoor, N.M., de Jongh, R.T., Daniels, J.M.A., Heijmans, M.W., Deeg, D.J.H., Lips, P.T.A.M., van Schoor, N.M., de Jongh, R.T., Daniels, J.M.A., Heijmans, M.W., Deeg, D.J.H., and Lips, P.T.A.M.
Abstract: Context: To our knowledge, no previous studies examined the longitudinal relationship between vitamin D status and pulmonary function in a population-based sample of older persons. Objective: Our objective was to examine the cross-sectional as well as the longitudinal relationship between vitamin D status and peak expiratory flow rate (PEFR) in a representative sample of the Dutch older population. Design, Setting, and Participants: Participants included men and women in the Longitudinal Aging Study Amsterdam, an ongoing cohort study in older people. Main Outcome Measure: PEFR was measured using the mini-Wright peak flow meter. Results: Men with serum 25-hydroxyvitamin D (25-OHD) levels below 10 ng/ml (25 nmol/liter) had a significantly lower PEFR in the cross-sectional analyses, and men with serum 25-OHD levels below 20 ng/ml (50 nmol/liter) had a significantly lower PEFR in the longitudinal analyses as compared with men with serum 25-OHD levels above 30 ng/ml (75 nmol/liter) (cross-sectional: β = -47.0, P = 0.01 for serum 25-OHD<10 ng/ml; longitudinal: β = -45.0, P<0.01 for serum 25-OHD<10 ng/ml; and β = -20.2, P = 0.03 for serum 25-OHD = 10-20 ng/ml in the fully adjusted models). Physical performance (β = -32.5, P = 0.08 for serum 25-OHD<10 ng/ml) and grip strength (β = -40.0, P = 0.03 for serum 25-OHD <10 ng/ml) partly mediated the cross-sectional associations but not the longitudinal associations. In women, statistically significant associations between 25-OHD and PEFR were observed in the cross-sectional analyses after adjustment for age and season of blood collection but not in the fully adjusted models or in the longitudinal analyses. Conclusions: A strong relationship between serum 25-OHD and PEFR was observed in older men, both in the cross-sectional as well as longitudinal analyses, but not in older women. The association in men could partly be explained by physical performance and muscle strength. Copyright © 2012 by The Endocrine Society.
Published: 2012
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22. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Author: van Wijngaarden, J., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M., Enneman, A., van Dijk, S.C., Brouwer-Brolsma, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P.T.A.M., de Groot, L.C.P.G.M., van Wijngaarden, J., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M., Enneman, A., van Dijk, S.C., Brouwer-Brolsma, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P.T.A.M., and de Groot, L.C.P.G.M.
Abstract: Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B
Published: 2011
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23. European Project on Osteoarthritis (EPOSA): methodological challenges in harmonization of existing data from five European population-based cohorts on aging

Author: Schaap, L.A., Peeters, G.M., Dennison, E.M., Zambon, S., Nikolaus, T., Sanchez-Martinez, M., Musacchio, E., van Schoor, N.M., Deeg, D.J.H., Schaap, L.A., Peeters, G.M., Dennison, E.M., Zambon, S., Nikolaus, T., Sanchez-Martinez, M., Musacchio, E., van Schoor, N.M., and Deeg, D.J.H.
Published: 2011
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24. Sunlight exposure or vitamin D supplementation for vitamin D-deficient non-western immigrants: a randomized clinical trial

Author: Wicherts, I.S., Boeke, A.J.P., van der Meer, I.M., van Schoor, N.M., Knol, D.L., Lips, P.T.A.M., Wicherts, I.S., Boeke, A.J.P., van der Meer, I.M., van Schoor, N.M., Knol, D.L., and Lips, P.T.A.M.
Abstract: Summary: Vitamin D deficiency is very common in non-western immigrants. In this randomized clinical trial, vitamin D 800 IU/day or 100,000 IU/3 months were compared with advised sunlight exposure. Vitamin D supplementation was more effective than advised sunlight exposure in improving vitamin D status and lowering parathyroid hormone levels. Introduction: Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D]<25 nmol/l) is common among non-western immigrants. It can be treated with vitamin D supplementation or sunlight exposure. Methods: To determine whether the effect of vitamin D
Published: 2011
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25. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Author: van Wijngaarden, J., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M., Enneman, A., van Dijk, S.C., Brouwer-Brolsma, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P.T.A.M., de Groot, L.C.P.G.M., van Wijngaarden, J., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M., Enneman, A., van Dijk, S.C., Brouwer-Brolsma, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P.T.A.M., and de Groot, L.C.P.G.M.
Abstract: Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B
Published: 2011
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26. Sunlight exposure or vitamin D supplementation for vitamin D-deficient non-western immigrants: a randomized clinical trial

Author: Wicherts, I.S., Boeke, A.J.P., van der Meer, I.M., van Schoor, N.M., Knol, D.L., Lips, P.T.A.M., Wicherts, I.S., Boeke, A.J.P., van der Meer, I.M., van Schoor, N.M., Knol, D.L., and Lips, P.T.A.M.
Abstract: Summary: Vitamin D deficiency is very common in non-western immigrants. In this randomized clinical trial, vitamin D 800 IU/day or 100,000 IU/3 months were compared with advised sunlight exposure. Vitamin D supplementation was more effective than advised sunlight exposure in improving vitamin D status and lowering parathyroid hormone levels. Introduction: Vitamin D deficiency (25-hydroxyvitamin D [25(OH)D]<25 nmol/l) is common among non-western immigrants. It can be treated with vitamin D supplementation or sunlight exposure. Methods: To determine whether the effect of vitamin D
Published: 2011
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27. European Project on Osteoarthritis (EPOSA): methodological challenges in harmonization of existing data from five European population-based cohorts on aging

Author: Schaap, L.A., Peeters, G.M., Dennison, E.M., Zambon, S., Nikolaus, T., Sanchez-Martinez, M., Musacchio, E., van Schoor, N.M., Deeg, D.J.H., Schaap, L.A., Peeters, G.M., Dennison, E.M., Zambon, S., Nikolaus, T., Sanchez-Martinez, M., Musacchio, E., van Schoor, N.M., and Deeg, D.J.H.
Published: 2011
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28. Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Author: van Wijngaarden, J.P., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M.A., Enneman, A.W., van Dijk, S.C., Brouwer, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P., de Groot, C.P.G.M., van Wijngaarden, J.P., Dhonukshe-Rutten, R.A.M., van Schoor, N.M., van der Velde, N., Swart, K.M.A., Enneman, A.W., van Dijk, S.C., Brouwer, E.M., Zillikens, M.C., van Meurs, J.B.J., Brug, J., Uitterlinden, A.G., Lips, P., and de Groot, C.P.G.M.
Abstract: Background Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12 and folate status are associated with an increased fracture risk. As vitamin B12 and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration (= 12 µmol/L). One group receives daily a tablet with 500 µg vitamin B12 and 400 µg folic acid and the other group receives a placebo tablet. In both tablets 15 µg (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health i.e. bone mineral density and bone turnover markers, physical performance and physical activity including falls, nutritional intake and status, cognitive function, depression, genetics and quality of life. This large multi-center project is carried out by a consortium from the Erasmus MC (Rotterdam, the Netherlands), VUmc (Amsterdam, the Netherlands) and Wageningen University, (Wageningen, the Netherlands), the latter acting as coordinator. Discussion To our best knowledge, the B-PROOF study is the first intervention study in which the effect of vitamin B12 and folic acid supplementation on osteoporotic fractures is studied in a general elderly population. We expect the first longitudinal results of the B-PROOF intervention in the second semeste
Published: 2011

29. Validation of the LASA fall risk profile for recurrent falling in older recent fallers

Author: Peeters, G.M.E.E., Pluijm, S.M., van Schoor, N.M., Elders, P.J.M., Bouter, L.M., Lips, P.T.A.M., Peeters, G.M.E.E., Pluijm, S.M., van Schoor, N.M., Elders, P.J.M., Bouter, L.M., and Lips, P.T.A.M.
Abstract: Objectives: The fall risk profile developed in the Longitudinal Aging Study Amsterdam (LASA) identifies community-dwelling elderly at high risk for recurrent falling. This study assessed the predictive validity of this profile in older persons seeking care after a fall. Study Design and Setting: The LASA fall risk profile was completed for 408 persons of 65 years and older who consulted the emergency department or general practitioner after a fall. Falls were prospectively reported with a calendar during 1 year. Recurrent falling was defined as ≥2 falls within a period of 6 months. Results: During 1 year of followup, 76 (18.6%) participants became recurrent fallers. The area under the receiver operating characteristic curve was 0.65 (95% confidence interval [95% CI]: 0.58-0.72). At a cutoff value of 8, the sensitivity was 56.6% (CI: 51.8-61.4), the specificity was 71.4% (CI: 67.0-75.8), the positive predictive value was 34.1% (CI: 29.5-38.7), and the negative predictive value was 85.6% (CI: 82.2-89.0). Conclusion: The discriminative ability of the LASA fall risk profile was moderate. The predictive validity of the LASA fall risk profile to identify recurrent fallers is limited among older persons who consulted the emergency department or general practitioner after a fall. © 2010 Elsevier Inc. All rights reserved.
Published: 2010
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30. Validation of the IOF quality of life questionnaire for patients with wrist fracture

Author: Lips, P.T.A.M., Jameson, K., Bianchi, M.L., Goemaere, S., Boonen, S., Reeve, J., Stepan, J., Johnell, O., van Schoor, N.M., Dennison, E., Kanis, J.A., Cooper, C., Lips, P.T.A.M., Jameson, K., Bianchi, M.L., Goemaere, S., Boonen, S., Reeve, J., Stepan, J., Johnell, O., van Schoor, N.M., Dennison, E., Kanis, J.A., and Cooper, C.
Abstract: Introduction: Wrist fracture causes pain and decreased physical, social and emotional function. The International Osteoporosis Foundation has developed a specific questionnaire to assess quality of life in patients with wrist fracture. This questionnaire, including 12 questions, was validated in a multicentre study and compared with an osteoporosis-specific questionnaire (Qualeffo-41) and a generic questionnaire (EQ-5D). Methods: The study included 105 patients with a recent wrist fracture and 74 sex- and age-matched control subjects. The questionnaire was administered as soon as possible after the fracture, at 6 weeks, 3 months, 6 months and 1 year after the fracture. Test-retest reproducibility, internal consistency and sensitivity to change were assessed. Results and discussion: The results showed adequate repeatability and internal consistency of the International Osteoporosis Foundation (IOF) wrist fracture questionnaire. The discriminatory capacity between patients and control subjects was very high, with significant odds ratios for each question and domain. The IOF-wrist fracture questionnaire domain scores showed significant improvement after 3 and 6 months and some improvement from 6 months up to 1 year. The sensitivity to change was much higher for the IOF-wrist fracture total score than for Qualeffo-41 and EQ-5D. Conclusion: In conclusion, the IOF-wrist fracture questionnaire appears to be a reliable and responsive quality of life questionnaire. © 2009 International Osteoporosis Foundation and National Osteoporosis Foundation.
Published: 2010
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31. Is there a U-shaped association between physical activity and falling in older persons?

Author: Peeters, G.M.E.E., van Schoor, N.M., Pluijm, S.M., Deeg, D.J.H., Lips, P.T.A.M., Peeters, G.M.E.E., van Schoor, N.M., Pluijm, S.M., Deeg, D.J.H., and Lips, P.T.A.M.
Abstract: Summary: This study tests whether the relationship between physical activity and (recurrent) falling is U-shaped. Among 1,337 community-dwelling older persons, no evidence for a nonlinear association was found. If all older persons increase their physical activity level with 100 units, 4% may be prevented to become recurrent fallers. Introduction: Previous studies suggest a U-shaped relationship between physical activity and falling. This study tests this hypothesis and examines whether this relationship is modified by level of physical functioning. Methods: Community-dwelling persons (65+) from the Longitudinal Aging Study Amsterdam (LASA) were prospectively followed on falls for 3 years after baseline assessment in 1995/1996 (n=1,337). Outcome measures were time to first fall and time to recurrent falling. The LASA Physical Activity Questionnaire was used to calculate physical activity in minutes per day weighted for intensity (range 0-2000). Physical functioning was measured with physical performance tests and self reported functional limitations. Confounders were age, sex, body mass index, chronic diseases, psychotropic medication, cognitive functioning, depressive symptoms, and fear of falling. Results: No evidence for a nonlinear association was found (p for physical activity
Published: 2010
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32. Distinguishing four components underlying physical activity: a new approach to using physical activity questionnaire data in old age

Author: Verweij, L.M., van Schoor, N.M., Dekker, J., Visser, M., Verweij, L.M., van Schoor, N.M., Dekker, J., and Visser, M.
Abstract: Background. It is evident that physical activity has many benefits, but it often remains unclear which types of activity are optimal for health and functioning in old age. The aim of this methodological study was to propose a method for distinguishing four components underlying self reported physical activity of older adults: intensity, muscle strength, turning actions and mechanical strain. Methods. Physical activity was assessed by the validated LAPAQ questionnaire among 1699 older adults of the Longitudinal Aging Study Amsterdam. Based on expert consultation and literature review, the four component scores for several individual daily and sports activities were developed. Factor analysis was performed to confirm whether the developed components indeed measured different constructs of physical activity. Results. Based on the factor analyses, three components were distinguished: 1. intensity and muscle strength loaded on the same factor, 2. mechanical strain and 3. turning actions. Analyses in gender, age and activity level subgroups consistently distinguished three factors. Conclusion. Future research using these components may contribute to our understanding of how specific daily and sports activities may have a different influence on health and physical functioning in old age. © 2010 Verweij et al; licensee BioMed Central Ltd.
Published: 2010
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33. Distinguishing four components underlying physical activity: a new approach to using physical activity questionnaire data in old age

Author: Verweij, L.M., van Schoor, N.M., Dekker, J., Visser, M., Verweij, L.M., van Schoor, N.M., Dekker, J., and Visser, M.
Abstract: Background. It is evident that physical activity has many benefits, but it often remains unclear which types of activity are optimal for health and functioning in old age. The aim of this methodological study was to propose a method for distinguishing four components underlying self reported physical activity of older adults: intensity, muscle strength, turning actions and mechanical strain. Methods. Physical activity was assessed by the validated LAPAQ questionnaire among 1699 older adults of the Longitudinal Aging Study Amsterdam. Based on expert consultation and literature review, the four component scores for several individual daily and sports activities were developed. Factor analysis was performed to confirm whether the developed components indeed measured different constructs of physical activity. Results. Based on the factor analyses, three components were distinguished: 1. intensity and muscle strength loaded on the same factor, 2. mechanical strain and 3. turning actions. Analyses in gender, age and activity level subgroups consistently distinguished three factors. Conclusion. Future research using these components may contribute to our understanding of how specific daily and sports activities may have a different influence on health and physical functioning in old age. © 2010 Verweij et al; licensee BioMed Central Ltd.
Published: 2010
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34. Is there a U-shaped association between physical activity and falling in older persons?

Author: Peeters, G.M.E.E., van Schoor, N.M., Pluijm, S.M., Deeg, D.J.H., Lips, P.T.A.M., Peeters, G.M.E.E., van Schoor, N.M., Pluijm, S.M., Deeg, D.J.H., and Lips, P.T.A.M.
Abstract: Summary: This study tests whether the relationship between physical activity and (recurrent) falling is U-shaped. Among 1,337 community-dwelling older persons, no evidence for a nonlinear association was found. If all older persons increase their physical activity level with 100 units, 4% may be prevented to become recurrent fallers. Introduction: Previous studies suggest a U-shaped relationship between physical activity and falling. This study tests this hypothesis and examines whether this relationship is modified by level of physical functioning. Methods: Community-dwelling persons (65+) from the Longitudinal Aging Study Amsterdam (LASA) were prospectively followed on falls for 3 years after baseline assessment in 1995/1996 (n=1,337). Outcome measures were time to first fall and time to recurrent falling. The LASA Physical Activity Questionnaire was used to calculate physical activity in minutes per day weighted for intensity (range 0-2000). Physical functioning was measured with physical performance tests and self reported functional limitations. Confounders were age, sex, body mass index, chronic diseases, psychotropic medication, cognitive functioning, depressive symptoms, and fear of falling. Results: No evidence for a nonlinear association was found (p for physical activity
Published: 2010
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35. Validation of the LASA fall risk profile for recurrent falling in older recent fallers

Author: Peeters, G.M.E.E., Pluijm, S.M., van Schoor, N.M., Elders, P.J.M., Bouter, L.M., Lips, P.T.A.M., Peeters, G.M.E.E., Pluijm, S.M., van Schoor, N.M., Elders, P.J.M., Bouter, L.M., and Lips, P.T.A.M.
Abstract: Objectives: The fall risk profile developed in the Longitudinal Aging Study Amsterdam (LASA) identifies community-dwelling elderly at high risk for recurrent falling. This study assessed the predictive validity of this profile in older persons seeking care after a fall. Study Design and Setting: The LASA fall risk profile was completed for 408 persons of 65 years and older who consulted the emergency department or general practitioner after a fall. Falls were prospectively reported with a calendar during 1 year. Recurrent falling was defined as ≥2 falls within a period of 6 months. Results: During 1 year of followup, 76 (18.6%) participants became recurrent fallers. The area under the receiver operating characteristic curve was 0.65 (95% confidence interval [95% CI]: 0.58-0.72). At a cutoff value of 8, the sensitivity was 56.6% (CI: 51.8-61.4), the specificity was 71.4% (CI: 67.0-75.8), the positive predictive value was 34.1% (CI: 29.5-38.7), and the negative predictive value was 85.6% (CI: 82.2-89.0). Conclusion: The discriminative ability of the LASA fall risk profile was moderate. The predictive validity of the LASA fall risk profile to identify recurrent fallers is limited among older persons who consulted the emergency department or general practitioner after a fall. © 2010 Elsevier Inc. All rights reserved.
Published: 2010
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36. Validation of the IOF quality of life questionnaire for patients with wrist fracture

Author: Lips, P.T.A.M., Jameson, K., Bianchi, M.L., Goemaere, S., Boonen, S., Reeve, J., Stepan, J., Johnell, O., van Schoor, N.M., Dennison, E., Kanis, J.A., Cooper, C., Lips, P.T.A.M., Jameson, K., Bianchi, M.L., Goemaere, S., Boonen, S., Reeve, J., Stepan, J., Johnell, O., van Schoor, N.M., Dennison, E., Kanis, J.A., and Cooper, C.
Abstract: Introduction: Wrist fracture causes pain and decreased physical, social and emotional function. The International Osteoporosis Foundation has developed a specific questionnaire to assess quality of life in patients with wrist fracture. This questionnaire, including 12 questions, was validated in a multicentre study and compared with an osteoporosis-specific questionnaire (Qualeffo-41) and a generic questionnaire (EQ-5D). Methods: The study included 105 patients with a recent wrist fracture and 74 sex- and age-matched control subjects. The questionnaire was administered as soon as possible after the fracture, at 6 weeks, 3 months, 6 months and 1 year after the fracture. Test-retest reproducibility, internal consistency and sensitivity to change were assessed. Results and discussion: The results showed adequate repeatability and internal consistency of the International Osteoporosis Foundation (IOF) wrist fracture questionnaire. The discriminatory capacity between patients and control subjects was very high, with significant odds ratios for each question and domain. The IOF-wrist fracture questionnaire domain scores showed significant improvement after 3 and 6 months and some improvement from 6 months up to 1 year. The sensitivity to change was much higher for the IOF-wrist fracture total score than for Qualeffo-41 and EQ-5D. Conclusion: In conclusion, the IOF-wrist fracture questionnaire appears to be a reliable and responsive quality of life questionnaire. © 2009 International Osteoporosis Foundation and National Osteoporosis Foundation.
Published: 2010
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37. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation

Author: Estrada, K., Krawczak, M., Schreiber, S, van Duijn, K., Stolk, L., van Meurs, J.B.J., Liu, F., Penninx, B.W.J.H., Smit, J.H., Vogelzangs, N., Hottenga, J.J., Willemsen, G., de Geus, E.J.C., Lorentzon, M., von Eller-Eberstein, H., Lips, P.T.A.M., van Schoor, N.M., Pop, V., de Keijzer, J., Hofman, A., Aulchenko, Y.S., Oostra, B.A., Ohlsson, C., Boomsma, D.I., Uitterlinden, A.G., van Duijn, C.M., Rivadeneira, F.F., Kayser, M., Estrada, K., Krawczak, M., Schreiber, S, van Duijn, K., Stolk, L., van Meurs, J.B.J., Liu, F., Penninx, B.W.J.H., Smit, J.H., Vogelzangs, N., Hottenga, J.J., Willemsen, G., de Geus, E.J.C., Lorentzon, M., von Eller-Eberstein, H., Lips, P.T.A.M., van Schoor, N.M., Pop, V., de Keijzer, J., Hofman, A., Aulchenko, Y.S., Oostra, B.A., Ohlsson, C., Boomsma, D.I., Uitterlinden, A.G., van Duijn, C.M., Rivadeneira, F.F., and Kayser, M.
Abstract: Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P
Published: 2009
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38. A genome-wide association study of northwestern Europeans involves the C-type natriuretic peptide signaling pathway in the etiology of human height variation

Author: Estrada, K., Krawczak, M., Schreiber, S, van Duijn, K., Stolk, L., van Meurs, J.B.J., Liu, F., Penninx, B.W.J.H., Smit, J.H., Vogelzangs, N., Hottenga, J.J., Willemsen, G., de Geus, E.J.C., Lorentzon, M., von Eller-Eberstein, H., Lips, P.T.A.M., van Schoor, N.M., Pop, V., de Keijzer, J., Hofman, A., Aulchenko, Y.S., Oostra, B.A., Ohlsson, C., Boomsma, D.I., Uitterlinden, A.G., van Duijn, C.M., Rivadeneira, F.F., Kayser, M., Estrada, K., Krawczak, M., Schreiber, S, van Duijn, K., Stolk, L., van Meurs, J.B.J., Liu, F., Penninx, B.W.J.H., Smit, J.H., Vogelzangs, N., Hottenga, J.J., Willemsen, G., de Geus, E.J.C., Lorentzon, M., von Eller-Eberstein, H., Lips, P.T.A.M., van Schoor, N.M., Pop, V., de Keijzer, J., Hofman, A., Aulchenko, Y.S., Oostra, B.A., Ohlsson, C., Boomsma, D.I., Uitterlinden, A.G., van Duijn, C.M., Rivadeneira, F.F., and Kayser, M.
Abstract: Northwestern Europeans are among the tallest of human populations. The increase in body height in these people appears to have reached a plateau, suggesting the ubiquitous presence of an optimal environment in which genetic factors may have exerted a particularly strong influence on human growth. Therefore, we performed a genome-wide association study (GWAS) of body height using 2.2 million markers in 10 074 individuals from three Dutch and one German population-based cohorts. Upon genotyping, the 12 most significantly height-associated single nucleotide polymorphisms (SNPs) from this GWAS in 6912 additional individuals of Dutch and Swedish origin, a genetic variant (rs6717918) on chromosome 2q37.1 was found to be associated with height at a genome-wide significance level (P
Published: 2009
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39. Maximum potential preventive effect of hip protectors

Author: van Schoor, N.M., Smit, J.H., Bouter, L.M., Veenings, B., Asma, G.B., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Bouter, L.M., Veenings, B., Asma, G.B., and Lips, P.T.A.M.
Abstract: OBJECTIVES: To estimate the maximum potential preventive effect of hip protectors in older persons living in the community or homes for the elderly. DESIGN: Observational cohort study. SETTING: Emergency departments in the Netherlands. PARTICIPANTS: Hip fracture patients aged 70 and older who visited the emergency departments of five hospitals in the Netherlands (n=520). MEASUREMENTS: Using the risk score of the Dutch Guidelines for Osteoporosis, how many patients had a high risk for fractures was retrospectively assessed. In addition, the circumstances of the hip fracture were assessed (n=299). Four factors were specified that might influence the maximum potential preventive effect of hip protectors: (1) hip fracture occurred in persons having a low risk, (2) hip fracture was not the consequence of a fall, (3) hip fracture occurred during circumstances that preclude the use of hip protectors, and (4) hip fracture occurred during the night. RESULTS: When providing hip protectors to women at high risk of fractures, 48.2% of all hip fractures could have been prevented. CONCLUSION: Many hip fractures occur in persons with a low risk for hip fracture or under circumstances that preclude the use of hip protectors. It was estimated that the maximum potential preventive effect of hip protectors is approximately 50% in older women living in the community or homes for the elderly. The actual preventive effect will be lower and depends on the acceptance and effectiveness of hip protectors and adherence to wearing them. © 2007, The American Geriatrics Society.
Published: 2007
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40. Relationship between cortisol and physical performance in older persons

Author: Peeters, G.M.E.E., van Schoor, N.M., Visser, M., Knol, D.L., Eeckhoff, E.M.W., Lips, P.T.A.M., Peeters, G.M.E.E., van Schoor, N.M., Visser, M., Knol, D.L., Eeckhoff, E.M.W., and Lips, P.T.A.M.
Abstract: Objective: Hypercortisolism is associated with muscle weakness. This study examines the relationship between cortisol and physical performance in older persons. Design/patients: The study was conducted within the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a population-based sample of healthy older persons in the Netherlands. Data from the second (1995/1996) and fourth (2001/2002) cycle were used pertaining to 1172 (65-88 years) and 884 (65-94 years) men and women, respectively. Measurements: Physical performance was measured by adding up scores on the chair stands, tandem stand and walk test (range 0-12). In the second cycle serum total and calculated free cortisol were assessed; in the fourth cycle evening salivary cortisol was assessed. Regression analysis (stratified for sex, adjusted for age, body mass index, alcohol use, physical activity and region) was performed to examine the cross-sectional relationship between cortisol and physical performance. Results: Women with higher calculated free cortisol scored less well on physical performance (b = -0.28 per SD higher cortisol, P = 0.016), which was mainly explained by poorer performance on the tandem stand (OR = 1.32 for a lower score per SD higher cortisol, P = 0.003). Men with higher salivary cortisol scored less well on physical performance (b = -0.90 in the highest vs. the lowest quartile, P = 0.008), which was mainly explained by poorer performance on the chair stands and walk test (OR = 1.88, P = 0.020 and OR = 1.81, P = 0.027, respectively, in the highest vs. the lowest quartile). Conclusion: Physical performance is negatively associated with high cortisol levels in older persons. © 2007 The Authors.
Published: 2007
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41. Maximum potential preventive effect of hip protectors

Author: van Schoor, N.M., Smit, J.H., Bouter, L.M., Veenings, B., Asma, G.B., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Bouter, L.M., Veenings, B., Asma, G.B., and Lips, P.T.A.M.
Abstract: OBJECTIVES: To estimate the maximum potential preventive effect of hip protectors in older persons living in the community or homes for the elderly. DESIGN: Observational cohort study. SETTING: Emergency departments in the Netherlands. PARTICIPANTS: Hip fracture patients aged 70 and older who visited the emergency departments of five hospitals in the Netherlands (n=520). MEASUREMENTS: Using the risk score of the Dutch Guidelines for Osteoporosis, how many patients had a high risk for fractures was retrospectively assessed. In addition, the circumstances of the hip fracture were assessed (n=299). Four factors were specified that might influence the maximum potential preventive effect of hip protectors: (1) hip fracture occurred in persons having a low risk, (2) hip fracture was not the consequence of a fall, (3) hip fracture occurred during circumstances that preclude the use of hip protectors, and (4) hip fracture occurred during the night. RESULTS: When providing hip protectors to women at high risk of fractures, 48.2% of all hip fractures could have been prevented. CONCLUSION: Many hip fractures occur in persons with a low risk for hip fracture or under circumstances that preclude the use of hip protectors. It was estimated that the maximum potential preventive effect of hip protectors is approximately 50% in older women living in the community or homes for the elderly. The actual preventive effect will be lower and depends on the acceptance and effectiveness of hip protectors and adherence to wearing them. © 2007, The American Geriatrics Society.
Published: 2007
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42. Relationship between cortisol and physical performance in older persons

Author: Peeters, G.M.E.E., van Schoor, N.M., Visser, M., Knol, D.L., Eeckhoff, E.M.W., Lips, P.T.A.M., Peeters, G.M.E.E., van Schoor, N.M., Visser, M., Knol, D.L., Eeckhoff, E.M.W., and Lips, P.T.A.M.
Abstract: Objective: Hypercortisolism is associated with muscle weakness. This study examines the relationship between cortisol and physical performance in older persons. Design/patients: The study was conducted within the Longitudinal Aging Study Amsterdam (LASA), an ongoing cohort study in a population-based sample of healthy older persons in the Netherlands. Data from the second (1995/1996) and fourth (2001/2002) cycle were used pertaining to 1172 (65-88 years) and 884 (65-94 years) men and women, respectively. Measurements: Physical performance was measured by adding up scores on the chair stands, tandem stand and walk test (range 0-12). In the second cycle serum total and calculated free cortisol were assessed; in the fourth cycle evening salivary cortisol was assessed. Regression analysis (stratified for sex, adjusted for age, body mass index, alcohol use, physical activity and region) was performed to examine the cross-sectional relationship between cortisol and physical performance. Results: Women with higher calculated free cortisol scored less well on physical performance (b = -0.28 per SD higher cortisol, P = 0.016), which was mainly explained by poorer performance on the tandem stand (OR = 1.32 for a lower score per SD higher cortisol, P = 0.003). Men with higher salivary cortisol scored less well on physical performance (b = -0.90 in the highest vs. the lowest quartile, P = 0.008), which was mainly explained by poorer performance on the chair stands and walk test (OR = 1.88, P = 0.020 and OR = 1.81, P = 0.027, respectively, in the highest vs. the lowest quartile). Conclusion: Physical performance is negatively associated with high cortisol levels in older persons. © 2007 The Authors.
Published: 2007
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43. The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women

Author: Schaap, L.A., Pluijm, S.M., Smit, J.H., van Schoor, N.M., Visser, M., Gooren, L.J.G., Lips, P.T.A.M., Schaap, L.A., Pluijm, S.M., Smit, J.H., van Schoor, N.M., Visser, M., Gooren, L.J.G., and Lips, P.T.A.M.
Abstract: Objective: The objective of this study was to examine whether low levels of oestradiol and testosterone are associated with impaired mobility, low muscle strength and the incidence of falls in a population-based sample of older men and women. Design: Cross-sectional population-based study, based on data of the Longitudinal Ageing Study Amsterdam (LASA), including 623 men and 663 women, aged 65-88 years. Measurements: Serum levels of oestradiol, testosterone, albumin and sex hormone-binding globulin (SHBG) were measured. Physical performance, functional limitations and muscle strength were assessed, and a follow-up on falls was performed prospectively within 3 years. Results: After adjustment for age, level of education, alcohol use, physical activity, chronic disease and body mass index (BMI), men in the highest quartile of the oestradiol/SHBG ratio had significantly higher physical performance scores than men in the lowest quartile (β = 0.103). Serum levels of total testosterone were positively associated with muscle strength (β = 0.085). Calculated bioavailable testosterone levels were positively associated with physical performance and muscle strength (β = 0.128 and 0.109 respectively). No associations of oestradiol levels with mobility were seen in women. Levels of oestradiol and testosterone were not associated with falls. Conclusions: It can be concluded that low levels of sex hormones were associated with impaired mobility and low muscle strength in men, but not in women. Levels of sex hormones were not associated with the incidence of falls neither in men, nor in women. © 2005 Blackwell Publishing Ltd.
Published: 2005
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44. Cost-effectiveness of hip protectors in frail institutionalized elderly

Author: van Schoor, N.M., de Bruyne, M.C., van der Roer, N., Lommerse, E., van Tulder, M., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., de Bruyne, M.C., van der Roer, N., Lommerse, E., van Tulder, M., Bouter, L.M., and Lips, P.T.A.M.
Abstract: A randomized controlled trial was performed to examine the cost-effectiveness of external hip protectors in the prevention of hip fractures. Since the hip protectors were not effective in preventing hip fractures in our study, the main objective became to examine whether the use of hip protectors results in lower average costs per participant in the hip protector group as compared with the control group. In addition, the average costs of a hip fracture and subsequent rehabilitation in frail, institutionalized elderly were calculated. Residents from apartment houses for the elderly, homes for the elderly and nursing homes with a high risk for hip fractures were randomized to the hip protector group (n = 276) or control group (n = 285). Costs were calculated for the hip fracture and subsequent rehabilitation until 1 year after the fracture. Six months after each hip fracture, a nurse was interviewed and after 12 months, a questionnaire was sent to the general practitioner or nursing home physician to determine the utilization of health care resources. Differences in costs between the groups were analyzed using non-parametric bootstrapping. Eighteen hip fractures occurred in the intervention group and 20 hip fractures (in 19 persons) in the control group (log rank P-value = 0.86). The average costs per participant, including the costs of the intervention, were €913 in the intervention group and 502 in the control group (cost difference of €-411; 95% confidence interval: -723; 57). The average costs of a hip fracture and subsequent rehabilitation were €8100 (95% CI: 6716-10,010). The use of hip protectors was not associated with lower costs. In addition, the average costs of a hip fracture and subsequent rehabilitation in the first year after the fracture were estimated at €8100 in institutionalized elderly. © International Osteoporosis Foundation and National Osteoporosis Foundation 2004.
Published: 2004
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45. Cost-effectiveness of hip protectors in frail institutionalized elderly

Author: van Schoor, N.M., de Bruyne, M.C., van der Roer, N., Lommerse, E., van Tulder, M., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., de Bruyne, M.C., van der Roer, N., Lommerse, E., van Tulder, M., Bouter, L.M., and Lips, P.T.A.M.
Abstract: A randomized controlled trial was performed to examine the cost-effectiveness of external hip protectors in the prevention of hip fractures. Since the hip protectors were not effective in preventing hip fractures in our study, the main objective became to examine whether the use of hip protectors results in lower average costs per participant in the hip protector group as compared with the control group. In addition, the average costs of a hip fracture and subsequent rehabilitation in frail, institutionalized elderly were calculated. Residents from apartment houses for the elderly, homes for the elderly and nursing homes with a high risk for hip fractures were randomized to the hip protector group (n = 276) or control group (n = 285). Costs were calculated for the hip fracture and subsequent rehabilitation until 1 year after the fracture. Six months after each hip fracture, a nurse was interviewed and after 12 months, a questionnaire was sent to the general practitioner or nursing home physician to determine the utilization of health care resources. Differences in costs between the groups were analyzed using non-parametric bootstrapping. Eighteen hip fractures occurred in the intervention group and 20 hip fractures (in 19 persons) in the control group (log rank P-value = 0.86). The average costs per participant, including the costs of the intervention, were €913 in the intervention group and 502 in the control group (cost difference of €-411; 95% confidence interval: -723; 57). The average costs of a hip fracture and subsequent rehabilitation were €8100 (95% CI: 6716-10,010). The use of hip protectors was not associated with lower costs. In addition, the average costs of a hip fracture and subsequent rehabilitation in the first year after the fracture were estimated at €8100 in institutionalized elderly. © International Osteoporosis Foundation and National Osteoporosis Foundation 2004.
Published: 2004
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46. External hip protectors and risk of hip fracture - Reply

Author: van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., and Lips, P.T.A.M.
Published: 2003
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47. Prevention of hip fractures by external hip protectors - A randomized controlled trial

Author: van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., and Lips, P.T.A.M.
Abstract: Context: Several randomized controlled trials have been performed to examine the effectiveness of external hip protectors in reducing the incidence of hip fractures, but the results are controversial. Objective: To examine the effectiveness of hip protectors in reducing the incidence of hip fractures in an elderly high-risk population. Design, Setting, and Participants: Randomized controlled trial of elderly persons aged 70 years or older, who have low bone density, and are at high risk for falls. Participants lived in apartment houses for the elderly, homes for the elderly, and nursing homes in Amsterdam and surrounding areas in the Netherlands. They were enrolled in the study between March 1999 and March 2001; the mean follow-up was 69.6 weeks. Of the 830 persons who were screened, 561 persons were enrolled. Intervention: External hip protector. Both groups received written information on bone health and risk factors for falls. Main Outcome Measure: Time to first hip fracture. Survival analysis was used to include all participants for the time they participated. Results: In the intervention group, 18 hip fractures occurred vs 20 in the control group. Four hip fractures in the intervention group occurred while an individual was wearing a hip protector. At least 4 hip fractures in the intervention group occurred late at night or early in the morning. Both in univariate analysis (log-rank P=.86) and in multivariate analysis (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.55-2.03), no statistically significant difference between the intervention group and control group was found with regard to time to first hip fracture. In addition, the per protocol analysis in compliant participants did not show a statistically significant difference between the groups (HR, 0.77; 95% CI, 0.25-2.38). Conclusion: The hip protector studied was not effective in preventing hip fractures.
Published: 2003
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48. The Amsterdam Hip Protector Study: Compliance and determinants of compliance

Author: van Schoor, N.M., Asma, G., Smit, J.H., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., Asma, G., Smit, J.H., Bouter, L.M., and Lips, P.T.A.M.
Abstract: Hip protectors appear to be effective in reducing the incidence of hip fractures. However, compliance is often poor. Therefore, the objective of this study was to examine the compliance and determinants of compliance with external hip protectors. A prospective study was performed in residents from apartment houses for the elderly, homes for the elderly and nursing homes with a high risk for hip fracture (n = 276). The study was performed within the framework of the Amsterdam Hip Protector Study, a randomized controlled trial examining the effect of external hip protectors on the incidence of hip fractures. Compliance was assessed by unannounced visits at 1, 6 and 12 months after inclusion in the study. During the visits, a member of the research team checked whether the participant was wearing the hip protector and, if so, whether it was worn correctly. Furthermore, data on potential determinants of compliance were collected by interviewing the participants or their nurses. Compliance was 60.8% after 1 month (n = 217), 44.7% after 6 months (n = 246), and 37.0% after 12 months (n = 230). Of those wearing the hip protector, 86.7%, 91.7% and 96.5% of the participants were wearing the hip protector correctly after 1, 6 and 12 months respectively; and 14.8%, 16.1% and 8.8% respectively reported wearing the hip protector at night. Compliance after 12 months was predicted by the compliance after 1 month (RR = 2.04; 90% CI: 1.05-3.96). Furthermore, people who experienced one or more falls in the half year before baseline had a lower probability of being compliant at 6 months (RR = 0.72; 90% CI: 0.52-0.99). In conclusion, compliance is a very important issue in hip protector research and implementation. Although, the compliance percentages were moderately high during the unannounced visits in this study, not everyone was wearing the protector correctly and most participants did not wear the hip protector during the night. © International Osteoporosis Foundation and National
Published: 2003
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49. Prevention of hip fractures by external hip protectors - A randomized controlled trial

Author: van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., and Lips, P.T.A.M.
Abstract: Context: Several randomized controlled trials have been performed to examine the effectiveness of external hip protectors in reducing the incidence of hip fractures, but the results are controversial. Objective: To examine the effectiveness of hip protectors in reducing the incidence of hip fractures in an elderly high-risk population. Design, Setting, and Participants: Randomized controlled trial of elderly persons aged 70 years or older, who have low bone density, and are at high risk for falls. Participants lived in apartment houses for the elderly, homes for the elderly, and nursing homes in Amsterdam and surrounding areas in the Netherlands. They were enrolled in the study between March 1999 and March 2001; the mean follow-up was 69.6 weeks. Of the 830 persons who were screened, 561 persons were enrolled. Intervention: External hip protector. Both groups received written information on bone health and risk factors for falls. Main Outcome Measure: Time to first hip fracture. Survival analysis was used to include all participants for the time they participated. Results: In the intervention group, 18 hip fractures occurred vs 20 in the control group. Four hip fractures in the intervention group occurred while an individual was wearing a hip protector. At least 4 hip fractures in the intervention group occurred late at night or early in the morning. Both in univariate analysis (log-rank P=.86) and in multivariate analysis (hazard ratio [HR], 1.05; 95% confidence interval [CI], 0.55-2.03), no statistically significant difference between the intervention group and control group was found with regard to time to first hip fracture. In addition, the per protocol analysis in compliant participants did not show a statistically significant difference between the groups (HR, 0.77; 95% CI, 0.25-2.38). Conclusion: The hip protector studied was not effective in preventing hip fractures.
Published: 2003
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50. External hip protectors and risk of hip fracture - Reply

Author: van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., Lips, P.T.A.M., van Schoor, N.M., Smit, J.H., Twisk, J.W.R., Bouter, L.M., and Lips, P.T.A.M.
Published: 2003
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