Skip to main content
×
×
Home

Genetic risk scores and family history as predictors of schizophrenia in Nordic registers

  • Y. Lu (a1), J. G. Pouget (a2), O. A. Andreassen (a3), S. Djurovic (a4) (a5), T. Esko (a6), C. M. Hultman (a1), A. Metspalu (a6), L. Milani (a6), T. Werge (a7) (a8) (a9) and P. F. Sullivan (a1) (a10)...
Abstract
Background

Family history is a long-standing and readily obtainable risk factor for schizophrenia (SCZ). Low-cost genotyping technologies have enabled large genetic studies of SCZ, and the results suggest the utility of genetic risk scores (GRS, direct assessments of inherited common variant risk). Few studies have evaluated family history and GRS simultaneously to ask whether one can explain away the other.

Methods

We studied 5959 SCZ cases and 8717 controls from four Nordic countries. All subjects had family history data from national registers and genome-wide genotypes that were processed through the quality control procedures used by the Psychiatric Genomics Consortium. Using external training data, GRS were estimated for SCZ, bipolar disorder (BIP), major depression, autism, educational attainment, and body mass index. Multivariable modeling was used to estimate effect sizes.

Results

Using harmonized genomic and national register data from Denmark, Estonia, Norway, and Sweden, we confirmed that family history of SCZ and GRS for SCZ and BIP were risk factors for SCZ. In a joint model, the effects of GRS for SCZ and BIP were essentially unchanged, and the effect of family history was attenuated but remained significant. The predictive capacity of a model including GRS and family history neared the minimum for clinical utility.

Conclusions

Combining national register data with measured genetic risk factors represents an important investigative approach for psychotic disorders. Our findings suggest the potential clinical utility of combining GRS and family history for early prediction and diagnostic improvements.

Copyright
Corresponding author
Author for correspondence: P. F. Sullivan, E-mail: patrick.sullivan@ki.se
References
Hide All
Agerbo, E, Sullivan, PF, Vilhjalmsson, BJ, Pedersen, CB, Mors, O, Borglum, AD, Hougaard, DM, Hollegaard, MV, Meier, S, Mattheisen, M, Ripke, S, Wray, NR, Mortensen, PB (2015) Polygenic risk score, parental socioeconomic status, family history of psychiatric disorders, and the risk for schizophrenia: a Danish population-based study and meta-analysis. JAMA Psychiatry 72, 635641.
Athanasiu, L, Mattingsdal, M, Kahler, AK, Brown, A, Gustafsson, O, Agartz, I, Giegling, I, Muglia, P, Cichon, S, Rietschel, M, Pietilainen, OPH, Peltonen, L, Bramon, E, Collier, D, Clair, DS, Sigurdsson, E, Petursson, H, Rujescu, D, Melle, I, Steen, VM, Djurovic, S, Andreassen, OA (2010) Gene variants associated with schizophrenia in a Norwegian genome-wide study are replicated in a large European cohort. Journal of Psychiatric Research 44, 748753.
Belsky, DW, Moffitt, TE, Caspi, A (2013 a). Genetics in population health science: strategies and opportunities. American Journal of Public Health 103 (Suppl. 1), S73S83.
Belsky, DW, Sears, MR, Hancox, RJ, Harrington, H, Houts, R, Moffitt, TE, Sugden, K, Williams, B, Poulton, R, Caspi, A (2013 b). Polygenic risk and the development and course of asthma: an analysis of data from a four-decade longitudinal study. Lancet Respiratory Medicine 1, 453461.
Bigdeli, TB, Ripke, S, Bacanu, SA, Lee, SH, Wray, NR, Gejman, PV, Rietschel, M, Cichon, S, St Clair, D, Corvin, A, Kirov, G, Mcquillin, A, Gurling, H, Rujescu, D, Andreassen, OA, Werge, T, Blackwood, DH, Pato, CN, Pato, MT, Malhotra, AK, O'donovan, MC, Kendler, KS, Fanous, AH, Schizophrenia Working Group of the Psychiatric Genomics C (2016) Genome-wide association study reveals greater polygenic loading for schizophrenia in cases with a family history of illness. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics 171B, 276289.
Chang, CC, Chow, CC, Tellier, LC, Vattikuti, S, Purcell, SM, Lee, JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4, 7.
Chong, HY, Teoh, SL, Wu, DB, Kotirum, S, Chiou, CF, Chaiyakunapruk, N (2016) Global economic burden of schizophrenia: a systematic review. Neuropsychiatric Disease and Treatment 12, 357373.
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nature Genetics 45, 984994.
Do, CB, Hinds, DA, Francke, U, Eriksson, N (2012) Comparison of family history and SNPs for predicting risk of complex disease. PLoS Genetics 8, e1002973.
Gronberg, H, Adolfsson, J, Aly, M, Nordstrom, T, Wiklund, P, Brandberg, Y, Thompson, J, Wiklund, F, Lindberg, J, Clements, M, Egevad, L, Eklund, M (2015) Prostate cancer screening in men aged 50–69 years (STHLM3): a prospective population-based diagnostic study. The Lancet Oncology 16, 16671676.
Howie, BN, Donnelly, P, Marchini, J (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5, e1000529.
International Schizophrenia Consortium (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460, 748752.
Janssens, AC, Moonesinghe, R, Yang, Q, Steyerberg, EW, Van Duijn, CM, Khoury, MJ (2007) The impact of genotype frequencies on the clinical validity of genomic profiling for predicting common chronic diseases. Genetics in Medicine 9, 528535.
Lee, SH, Decandia, TR, Ripke, S, Yang, J, Schizophrenia Psychiatric Genome-Wide Association Study C, International Schizophrenia C, Molecular Genetics of Schizophrenia C, Sullivan, PF, Goddard, ME, Keller, MC, Visscher, PM, Wray, NR (2012 a). Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nature Genetics 44, 247250.
Lee, SH, Goddard, ME, Wray, NR, Visscher, PM (2012 b). A better coefficient of determination for genetic profile analysis. Genetic Epidemiology 36, 214224.
Lichtenstein, P, Bjork, C, Hultman, CM, Scolnick, EM, Sklar, P, Sullivan, PF (2006) Recurrence risks for schizophrenia in a Swedish national cohort. Psychological Medicine 36, 14171426.
Lichtenstein, P, Yip, B, Bjork, C, Pawitan, Y, Cannon, TD, Sullivan, PF, Hultman, CM (2009) Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 373, 234239.
Locke, AE, Kahali, B, Berndt, SI, Justice, AE, Pers, TH, Day, FR, Powell, C, Vedantam, S, Buchkovich, ML, Yang, J, Croteau-Chonka, DC, Esko, T, Fall, T, Ferreira, T, Gustafsson, S, Kutalik, Z, Luan, J, Magi, R, Randall, JC, Winkler, TW, Wood, AR, Workalemahu, T, Faul, JD, Smith, JA, Hua Zhao, J, Zhao, W, Chen, J, Fehrmann, R, Hedman, AK, Karjalainen, J, Schmidt, EM, Absher, D, Amin, N, Anderson, D, Beekman, M, Bolton, JL, Bragg-Gresham, JL, Buyske, S, Demirkan, A, Deng, G, Ehret, GB, Feenstra, B, Feitosa, MF, Fischer, K, Goel, A, Gong, J, Jackson, AU, Kanoni, S, Kleber, ME, Kristiansson, K, Lim, U, Lotay, V, Mangino, M, Mateo Leach, I, Medina-Gomez, C, Medland, SE, Nalls, MA, Palmer, CD, Pasko, D, Pechlivanis, S, Peters, MJ, Prokopenko, I, Shungin, D, Stancakova, A, Strawbridge, RJ, Ju Sung, Y, Tanaka, T, Teumer, A, Trompet, S, Van Der Laan, SW, Van Setten, J, Van Vliet-Ostaptchouk, JV, Wang, Z, Yengo, L, Zhang, W, Isaacs, A, Albrecht, E, Arnlov, J, Arscott, GM, Attwood, AP, Bandinelli, S, Barrett, A, Bas, IN, Bellis, C, Bennett, AJ, Berne, C, Blagieva, R, Bluher, M, Bohringer, S, Bonnycastle, LL, Bottcher, Y, Boyd, HA, Bruinenberg, M, Caspersen, IH, Ida Chen, YD, Clarke, R, Daw, EW, De Craen, AJ, Delgado, G, Dimitriou, M, Doney, ASF, Eklund, N, Estrada, K, Eury, E, Folkersen, L, Fraser, RM, Garcia, ME, Geller, F, Giedraitis, V, Gigante, B, Go, AS, Golay, A, Goodall, AH, Gordon, SD, Gorski, M, Grabe, HJ, Grallert, H, Grammer, TB, Grassler, J, Gronberg, H, Groves, CJ, Gusto, G, Haessler, J, Hall, P, Haller, T, Hallmans, G, Hartman, CA, Hassinen, M, Hayward, C, Heard-Costa, NL, Helmer, Q, Hengstenberg, C, Holmen, O, Hottenga, JJ, James, AL, Jeff, JM, Johansson, A, Jolley, J, Juliusdottir, T, Kinnunen, L, Koenig, W, Koskenvuo, M, Kratzer, W, Laitinen, J, Lamina, C, Leander, K, Lee, NR, Lichtner, P, Lind, L, Lindstrom, J, Lo, KS, Lobbens, S, Lorbeer, R, Lu, Y, Mach, F, Magnusson, PKE, Mahajan, A, McArdle, WL, McLachlan, S, Menni, C, Merger, S, Mihailov, E, Milani, L, Moayyeri, A, Monda, KL, Morken, MA, Mulas, A, Muller, G, Muller-Nurasyid, M, Musk, AW, Nagaraja, R, Nothen, MM, Nolte, IM, Pilz, S, Rayner, NW, Renstrom, F, Rettig, R, Ried, JS, Ripke, S, Robertson, NR, Rose, LM, Sanna, S, Scharnagl, H, Scholtens, S, Schumacher, FR, Scott, WR, Seufferlein, T, Shi, J, Smith, AV, Smolonska, J, Stanton, AV, Steinthorsdottir, V, Stirrups, K, Stringham, HM, Sundstrom, J, Swertz, MA, Swift, AJ, Syvanen, AC, Tan, ST, Tayo, BO, Thorand, B, Thorleifsson, G, Tyrer, JP, Uh, HW, Vandenput, L, Verhulst, FC, Vermeulen, SH, Verweij, N, Vonk, JM, Waite, LL, Warren, HR, Waterworth, D, Weedon, MN, Wilkens, LR, Willenborg, C, Wilsgaard, T, Wojczynski, MK, Wong, A, Wright, AF, Zhang, Q, Brennan, EP, Choi, M, Dastani, Z, Drong, AW, Eriksson, P, Franco-Cereceda, A, Gadin, JR, Gharavi, AG, Goddard, ME, Handsaker, RE, Huang, J, Karpe, F, Kathiresan, S, Keildson, S, Kiryluk, K, Kubo, M, Lee, JY, Liang, L, Lifton, RP, Ma, B, McCarroll, SA, McKnight, AJ, Min, JL, Moffatt, MF, Montgomery, GW, Murabito, JM, Nicholson, G, Nyholt, DR, Okada, Y, Perry, JRB, Dorajoo, R, Reinmaa, E, Salem, RM, Sandholm, N, Scott, RA, Stolk, L, Takahashi, A, Tanaka, T, van'tHooft, FM, Vinkhuyzen, AAE, Westra, HJ, Zheng, W, Zondervan, KT, Heath, AC, Arveiler, D, Bakker, SJL, Beilby, J, Bergman, RN, Blangero, J, Bovet, P, Campbell, H, Caulfield, MJ, Cesana, G, Chakravarti, A, Chasman, DI, Chines, PS, Collins, FS, Crawford, DC, Cupples, LA, Cusi, D, Danesh, J, deFaire, U, denRuijter, HM, Dominiczak, AF, Erbel, R, Erdmann, J, Eriksson, JG, Farrall, M, Felix, SB, Ferrannini, E, Ferrieres, J, Ford, I, Forouhi, NG, Forrester, T, Franco, OH, Gansevoort, RT, Gejman, PV, Gieger, C, Gottesman, O, Gudnason, V, Gyllensten, U, Hall, AS, Harris, TB, Hattersley, AT, Hicks, AA, Hindorff, LA, Hingorani, AD, Hofman, A, Homuth, G, Hovingh, GK, Humphries, SE, Hunt, SC, Hypponen, E, Illig, T, Jacobs, KB, Jarvelin, MR, Jockel, KH, Johansen, B, Jousilahti, P, Jukema, JW, Jula, AM, Kaprio, J, Kastelein, JJP, Keinanen-Kiukaanniemi, SM, Kiemeney, LA, Knekt, P, Kooner, JS, Kooperberg, C, Kovacs, P, Kraja, AT, Kumari, M, Kuusisto, J, Lakka, TA, Langenberg, C, Marchand, LL, Lehtimaki, T, Lyssenko, V, Mannisto, S, Marette, A, Matise, TC, McKenzie, CA, McKnight, B, Moll, FL, Morris, AD, Morris, AP, Murray, JC, Nelis, M, Ohlsson, C, Oldehinkel, AJ, Ong, KK, Madden, PAF, Pasterkamp, G, Peden, JF, Peters, A, Postma, DS, Pramstaller, PP, Price, JF, Qi, L, Raitakari, OT, Rankinen, T, Rao, DC, Rice, TK, Ridker, PM, Rioux, JD, Ritchie, MD, Rudan, I, Salomaa, V, Samani, NJ, Saramies, J, Sarzynski, MA, Schunkert, H, Schwarz, PEH, Sever, P, Shuldiner, AR, Sinisalo, J, Stolk, RP, Strauch, K, Tonjes, A, Tregouet, DA, Tremblay, A, Tremoli, E, Virtamo, J, Vohl, MC, Volker, U, Waeber, G, Willemsen, G, Witteman, JC, Zillikens, MC, Adair, LS, Amouyel, P, Asselbergs, FW, Assimes, TL, Bochud, M, Boehm, BO, Boerwinkle, E, Bornstein, SR, Bottinger, EP, Bouchard, C, Cauchi, S, Chambers, JC, Chanock, SJ, Cooper, RS, deBakker, PIW, Dedoussis, G, Ferrucci, L, Franks, PW, Froguel, P, Groop, LC, Haiman, CA, Hamsten, A, Hui, J, Hunter, DJ, Hveem, K, Kaplan, RC, Kivimaki, M, Kuh, D, Laakso, M, Liu, Y, Martin, NG, Marz, W, Melbye, M, Metspalu, A, Moebus, S, Munroe, PB, Njolstad, I, Oostra, BA, Palmer, CNA, Pedersen, NL, Perola, M, Perusse, L, Peters, U, Power, C, Quertermous, T, Rauramaa, R, Rivadeneira, F, Saaristo, TE, Saleheen, D, Sattar, N, Schadt, EE, Schlessinger, D, Slagboom, PE, Snieder, H, Spector, TD, Thorsteinsdottir, U, Stumvoll, M, Tuomilehto, J, Uitterlinden, AG, Uusitupa, M, vanderHarst, P, Walker, M, Wallaschofski, H, Wareham, NJ, Watkins, H, Weir, DR, Wichmann, HE, Wilson, JF, Zanen, P, Borecki, IB, Deloukas, P, Fox, CS, Heid, IM, O'Connell, JR, Strachan, DP, Stefansson, K, vanDuijn, CM, Abecasis, GR, Franke, L, Frayling, TM, McCarthy, MI, Visscher, PM, Scherag, A, Willer, CJ, Boehnke, M, Mohlke, KL, Lindgren, CM, Beckmann, JS, Barroso, I, North, KE, Ingelsson, E, Hirschhorn, JN, Loos, RJF, Speliotes, EK (2015) Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197206.
March, D, Susser, E (2006) Invited commentary: taking the search for causes of schizophrenia to a different level. American Journal of Epidemiology 163, 979981.
Mcgrath, JJ, Mortensen, PB, Visscher, PM, Wray, NR (2013) Where GWAS and epidemiology meet: opportunities for the simultaneous study of genetic and environmental risk factors in schizophrenia. Schizophrenia Bulletin 39, 955959.
Metspalu, A, Kohler, F, Laschinski, G, Ganten, D, Roots, I (2004) The Estonian genome project in the context of European genome research. Deutsche medizinische Wochenschrift 129 (Suppl. 1), S25S28.
Mortensen, PB, Pedersen, CB, Westergaard, T, Wohlfahrt, J, Ewald, H, Mors, O, Andersen, PK, Melbye, M (1999) Effects of family history and place and season of birth on the risk of schizophrenia. New England Journal of Medicine 340, 603608.
Nagelkerke, NJD (1991) A note on a general definition of the coefficient of determination. Biometrika 78, 691692.
Okbay, A, Beauchamp, JP, Fontana, MA, Lee, JJ, Pers, TH, Rietveld, CA, Turley, P, Chen, GB, Emilsson, V, Meddens, SF, Oskarsson, S, Pickrell, JK, Thom, K, Timshel, P, De Vlaming, R, Abdellaoui, A, Ahluwalia, TS, Bacelis, J, Baumbach, C, Bjornsdottir, G, Brandsma, JH, Pina Concas, M, Derringer, J, Furlotte, NA, Galesloot, TE, Girotto, G, Gupta, R, Hall, LM, Harris, SE, Hofer, E, Horikoshi, M, Huffman, JE, Kaasik, K, Kalafati, IP, Karlsson, R, Kong, A, Lahti, J, Van Der Lee, SJ, Deleeuw, C, Lind, PA, Lindgren, KO, Liu, T, Mangino, M, Marten, J, Mihailov, E, Miller, MB, Van Der Most, PJ, Oldmeadow, C, Payton, A, Pervjakova, N, Peyrot, WJ, Qian, Y, Raitakari, O, Rueedi, R, Salvi, E, Schmidt, B, Schraut, KE, Shi, J, Smith, AV, Poot, RA, St Pourcain, B, Teumer, A, Thorleifsson, G, Verweij, N, Vuckovic, D, Wellmann, J, Westra, HJ, Yang, J, Zhao, W, Zhu, Z, Alizadeh, BZ, Amin, N, Bakshi, A, Baumeister, SE, Biino, G, Bonnelykke, K, Boyle, PA, Campbell, H, Cappuccio, FP, Davies, G, De Neve, JE, Deloukas, P, Demuth, I, Ding, J, Eibich, P, Eisele, L, Eklund, N, Evans, DM, Faul, JD, Feitosa, MF, Forstner, AJ, Gandin, I, Gunnarsson, B, Halldorsson, BV, Harris, TB, Heath, AC, Hocking, LJ, Holliday, EG, Homuth, G, Horan, MA et al. (2016) Genome-wide association study identifies 74 loci associated with educational attainment. Nature 533, 539542.
Polderman, TJ, Benyamin, B, De Leeuw, CA, Sullivan, PF, Van Bochoven, A, Visscher, PM, Posthuma, D (2015) Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nature Genetics 47, 702709.
Ripke, S, O'dushlaine, C, Chambert, K, Moran, JL, Kähler, A, Akterin, S, Bergen, S, Collins, AL, Crowley, J, Fromer, M, Kim, Y, Lee, SH, Magnusson, PK, Sanchez, N, Stahl, EA, Williams, S, Wray, N, Xia, K, Bettella, F, Børglum, AD, Bulik-Sullivan, BK, Cormican, P, Craddock, N, De Leeuw, C, Durmishi, N, Gill, M, Golimbet, V, Hamshere, ML, Holmans, P, Hougaard, DM, Kendler, KS, Lin, K, Morris, DW, Mors, O, Mortensen, PB, Neale, B, O'neill, FA, Owen, MJ, Pejovic Milovancevic, M, Posthuma, D, Powell, J, Richards, AL, Riley, BP, Ruderfer, D, Rujescu, D, Sigurdsson, E, Silagadze, T, Smit, AB, Stefansson, H, Steinberg, S, Suvisaari, J, Tosato, S, Walters, JT, Verhage, M, Multicenter Genetic Studies of Schizophrenia Consortium, Psychosis Endophenotypes Consortium, Wellcome Trust Case-Control Consortium2, Bramon, E, Corvin, AP, O'donovan, MC, Stefansson, K, Scolnick, E, Purcell, S, Mccarroll, S, Sklar, P, Hultman, C, Sullivan, PF (2013) Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nature Genetics 45, 11501159.
Schizophrenia Psychiatric Genome-Wide Association Study Consortium (2011) Genome-wide association study identifies five new schizophrenia loci. Nature Genetics 43, 969976.
Schizophrenia Working Group of the Psychiatric Genomics C (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421427.
Scott, LJ, Mohlke, KL, Bonnycastle, LL, Willer, CJ, Li, Y, Duren, WL, Erdos, MR, Stringham, HM, Chines, PS, Jackson, AU, Prokunina-Olsson, L, Ding, CJ, Swift, AJ, Narisu, N, Hu, T, Pruim, R, Xiao, R, Li, XY, Conneely, KN, Riebow, NL, Sprau, AG, Tong, M, White, PP, Hetrick, KN, Barnhart, MW, Bark, CW, Goldstein, JL, Watkins, L, Xiang, F, Saramies, J, Buchanan, TA, Watanabe, RM, Valle, TT, Kinnunen, L, Abecasis, GR, Pugh, EW, Doheny, KF, Bergman, RN, Tuomilehto, J, Collins, FS, Boehnke, M (2007) A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science 316, 13411345.
Sullivan, PF, Agrawal, A, Bulik, C, Andreassen, OA, Borglum, A, Breen, G, Cichon, S, Edenberg, H, Faraone, SV, Gelernter, J, Mathews, CA, Nievergelt, CM, Smoller, J, O'donovan, M (2017) Psychiatric genomics: an update and an Agenda. bioRxiv.
Sullivan, PF, Kendler, KS, Neale, MC (2003) Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Archives of General Psychiatry 60, 11871192.
Van Os, J, Krabbendam, L, Myin-Germeys, I, Delespaul, P (2005) The schizophrenia envirome. Current Opinion in Psychiatry 18, 141145.
Willer, CJ, Li, Y, Abecasis, GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26, 21902191.
Wray, NR, Gottesman, II (2012) Using summary data from the Danish national registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Frontiers in Genetics 3, 118.
Wray, NR, Yang, J, Goddard, ME, Visscher, PM (2010) The genetic interpretation of area under the ROC curve in genomic profiling. PLoS Genetics 6, e1000864.
Yang, J, Visscher, PM, Wray, NR (2010) Sporadic cases are the norm for complex disease. European Journal of Human Genetics 18, 10391043.
Zheng, J, Erzurumluoglu, AM, Elsworth, BL, Kemp, JP, Howe, L, Haycock, PC, Hemani, G, Tansey, K, Laurin, C, Early, G, Lifecourse Epidemiology Eczema C, Pourcain, BS, Warrington, NM, Finucane, HK, Price, AL, Bulik-Sullivan, BK, Anttila, V, Paternoster, L, Gaunt, TR, Evans, DM, Neale, BM (2016) LD hub: a centralized database and web interface to perform LD score regression that maximizes the potential of summary level GWAS data for SNP heritability and genetic correlation analysis. Bioinformatics 33, 272–279.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Psychological Medicine
  • ISSN: 0033-2917
  • EISSN: 1469-8978
  • URL: /core/journals/psychological-medicine
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Type Description Title
WORD
Supplementary materials

Lu et al supplementary material
Lu et al supplementary material 1

 Word (1.6 MB)
1.6 MB

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed