Abstract
A conventional potato breeding strategy uses targeted outcrossing, followed by phenotypic recurrent selection over a series of generations to identify improved cultivars. This paper reviews recent research in Australia aimed at improving the efficiency of such breeding. To develop marker-assisted selection (MAS) for traits of interest, our initial targets were qualitative disease resistances for potato cyst nematode (Globodera rostochiensis Ro1), Potato virus Y and Potato virus X. We undertook a cost analysis comparison between MAS and conventional screening, confirming that MAS would be cost-effective within a breeding programme. Then, as the majority of target traits are quantitative in nature, we also looked at methods to address these traits, including progeny testing and a quantitative genetic analysis technique to develop estimated breeding values (EBVs). We found the markers were useful for detecting the disease resistance characters, while the EBVs improved the analysis of the complex traits. Using a combination of MAS, EBVs and conventional screening methods, we then designed a breeding scheme for rapid selection of cultivars with multiple desirable traits, reducing the breeding cycle from over 10 to 4 years. We then explored the factors that will affect the application of genomic selection in potato and investigated strategies to incorporate genomic selection in potato breeding, as we found that it would accelerate genetic gain as the breeding cycle can be reduced to 1 year. Improvements in computational power are also flowing on to research capabilities such as sequencing, high-throughput phenotyping and data analysis, which will accelerate germplasm improvement and breeding. High-throughput phenotyping facilities are being developed that include automated glasshouse systems equipped with imaging sensors and in-field high-throughput phenotyping systems with sensors mounted on ground- or aerial-based vehicles. Using these technological improvements in phenotypic and genotypic analysis will reduce the breeding cycle in a cost-effective manner and means that we can now breed differently.
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References
Anderson J, Howard H (1981) Effectiveness of selection in the early stages of potato breeding programmes. Potato Res 24:289–299
Barone A (2004) Molecular marker-assisted selection for potato breeding. Am J Potato Res 81:111–117
Biryukova V, Zhuravlev A, Abrosimova S, Kostina L, Khromova L, Shmyglya I, Morozova N, Kirsanova S (2008) Use of molecular markers of potato golden nematode resistance genes H1 and GRO1. Russ Agric Sci 34:365–368
Bonierbale MW, Plaisted RL, Tanksley SD (1988) RFLP maps based on a common set of clones reveal modes of chromosomal evolution in potato and tomato. Genetics 120:1095–1103
Bradshaw JE (2007) Potato-breeding strategy. In: Vreugdenhil D, Bradshaw J, Gebhardt C, Govers F, MacKerron DKL, Taylor MA, Ross HA (eds) Potato biology and biotechnology: advances and perspectives. Elsevier, Amsterdam, pp 157–177
Bradshaw JE (2017) Review and analysis of limitations in ways to improve conventional potato breeding. Potato Res 60:171–193
Bradshaw JE, Mackay GR (1994) Breeding strategies for clonally propagated potatoes. In: Bradshaw JE, Mackay GR (eds) Potato genetics. Cab International, Wallingford, pp 467–497
Bradshaw JE, Dale MFB, Mackay GR (2003) Use of mid-parent values and progeny tests to increase the efficiency of potato breeding for combined processing quality and disease and pest resistance. Theor Appl Genet 107:36–42
Bradshaw JE, Hackett CA, Pande B, Waugh R, Bryan GJ (2008) QTL mapping of yield, agronomic and quality traits in tetraploid potato (Solanum tuberosum subsp. tuberosum). Theor Appl Genet 116:193–211
Bradshaw JE, Dale MFB, Mackay GR (2009) Improving the yield, processing quality and disease and pest resistance of potatoes by genotypic recurrent selection. Euphytica 170:215–227
Brigneti G, Garcia-Mas J, Baulcombe DC (1997) Molecular mapping of the potato virus Y resistance gene Ry sto in potato. Theor Appl Genet 94:198–203
Brown J, Caligari PDS, Mackay GR, Swan GEL (1984) The efficiency of seedling selection by visual preference in a potato breeding programme. J Agric Sci 103:339–346
Brown J, Caligari PDS, Mackay GR, Swan GEL (1987) The efficiency of visual selection in early generations of a potato breeding programme. Ann Appl Biol 110:357–363
Brown J, Caligari PDS, Dale MFB, Swan GEL, Mackay GR (1988) The use of cross prediction methods in a practical potato breeding programme. Theor Appl Genet 76:33–38
Brown CR, Corsini D, Pavek J, Thomas PE (1997) Heritability of field resistance to potato leafroll virus in cultivated potato. Plant Breed 116:585–588
Caligari PDS, Mackay GR, Stewart HE, Wastie RL (1984) A seedling progeny test for resistance to potato foliage blight (Phytophthora infestans (Mont.) de Bary). Potato Res 27:43–50
Caruana BM, Pembleton LW, Constable F, Rodoni B, Slater T, Cogan N (2017) GBS-transcriptomics for diversity and application of breeding traits in potato. 20th Triennial Conference of the European Association for Potato Research, 9–14 July 2017, Versailles, France
Chen X, Salamini F, Gebhardt C (2001) A potato molecular-function map for carbohydrate metabolism and transport. Theor Appl Genet 102:284–295
Collard BC, Mackill DJ (2008) Marker-assisted selection: an approach for precision plant breeding in the twenty-first century. Philos Trans R Soc Lond B 363:557–572
Collard B, Jahufer M, Brouwer J, Pang E (2005) An introduction to markers, quantitative trait loci (QTL) mapping and marker-assisted selection for crop improvement: the basic concepts. Euphytica 142:169–196
Crossa J, Gdl C, Pérez P, Gianola D, Burgueño J, Araus JL, Makumbi D, Singh RP, Dreisigacker S, Yan J, Arief V, Banziger M, Braun H-J (2010) Prediction of genetic values of quantitative traits in plant breeding using pedigree and molecular markers. Genetics 186:713–724
D’hoop B, Paulo M, Kowitwanich K, Sengers M, Visser R, van Eck H, van Eeuwijk F (2010) Population structure and linkage disequilibrium unravelled in tetraploid potato. Theor Appl Genet 121:1151–1170
Daetwyler HD, Hickey JM, Henshall JM, Dominik S, Gredler B, van der Werf JHJ, Hayes BJ (2010) Accuracy of estimated genomic breeding values for wool and meat traits in a multi-breed sheep population. Anim Prod Sci 50:1004–1010
Dalla Rizza M, Vilaró F, Torres D, Maeso D (2006) Detection of PVY extreme resistance genes in potato germplasm from the Uruguayan breeding program. Am J Potato Res 83:297–304
De Koeyer D, Chen H, Gustafson V (2011) Molecular breeding for potato improvement. In: Bradeen J, Kole C (eds) Genetics, genomics and breeding of potato. Science Publishers, Enfield, pp 41–67
Endelman J, Carley CS (2017) Combining marker and pedigree information for genome-wide prediction in potato. 20th Triennial Conference of the European Association for Potato Research, 9–14 July 2017, Versailles, France
Falconer DS, Mackay TFC (1996) Introduction to quantitative genetics, 4. Pearson, Prentice Hall, Harlow
Finkers-Tomczak A, Bakker E, de Boer J, van der Vossen E, Achenbach U, Golas T, Suryaningrat S, Smant G, Bakker J, Goverse A (2011) Comparative sequence analysis of the potato cyst nematode resistance locus H1 reveals a major lack of co-linearity between three haplotypes in potato (Solanum tuberosum ssp.). Theor Appl Genet 122:595–608
Fischer RA, Edmeades GO (2010) Breeding and cereal yield progress. Crop Sci 50:S-85-S-98
Flis B, Wasilewicz-Flis I (1998) Progeny tests to identify diploid potato clones homozygous at loci controlling resistance to PLRV. Potato Res 41:219–228
Flis B, Hennig J, Strzelczyk-Zyta D, Gebhardt C, Marczewski W (2005) The Ry-f sto gene from Solanum stoloniferum for extreme resistant to Potato virus Y maps to potato chromosome XII and is diagnosed by PCR marker GP122718 in PVY resistant potato cultivars. Mol Breed 15:95–101
Furbank RT (2009) Plant phenomics: from gene to form and function. Funct Plant Biol 36:v–vi
Furbank RT, Tester M (2011) Phenomics—technologies to relieve the phenotyping bottleneck. Trends Plant Sci 16:635–644
Gebhardt C (2013) Bridging the gap between genome analysis and precision breeding in potato. Trends Genet 29:248–256
Gebhardt C, Valkonen JPT (2001) Organization of genes controlling disease resistance in the potato genome. Annu Rev Phytopathol 39:79–102
Gebhardt C, Ritter E, Debener T, Schachtschabel U, Walkemeier B, Uhrig H, Salamini F (1989) RFLP analysis and linkage mapping in Solanum tuberosum. Theor Appl Genet 78:65–75
Gebhardt C, Ritter E, Barone A, Debener T, Walkemeier B, Schachtschabel U, Kaufmann H, Thompson RD, Bonierbale MW, Ganal MW, Tanksley SD, Salamini F (1991) RFLP maps of potato and their alignment with the homoeologous tomato genome. Theor Appl Genet 83:49–57
Gebhardt C, Lörz H, Wenzel G (2005) Potato genetics: molecular maps and more. Molecular marker systems in plant breeding and crop improvement. Springer, Berlin, pp 215–227
Gebhardt C, Bellin D, Henselewski H, Lehmann W, Schwarzfischer J, Valkonen J (2006) Marker-assisted combination of major genes for pathogen resistance in potato. Theor Appl Genet 112:1458–1464
Gebhardt C, Urbany C, Li L, Stich B, Paulo J, Draffehn A, Ballvora A (2011) Molecular diagnostics for complex pest and disease resistance and tuber quality traits: concept, achievements and perspectives. Potato Res 54:313–318
Gopal J, Gaur PC, Rana MS (1992) Early generation selection for agronomic characters in a potato breeding programme. Theor Appl Genet 84:709–713
Grattapaglia D, Vilela Resende MD, Resende MR, Sansaloni CP, Petroli CD, Missiaggia AA, Takahashi EK, Zamprogno KC, Kilian A (2011) Genomic selection for growth traits in Eucalyptus: accuracy within and across breeding populations. BMC Proc 5:1–2
Grube RC, Radwanski ER, Jahn M (2000) Comparative genetics of disease resistance within the solanaceae. Genetics 155:873–887
Haverkort AJ, Boonekamp PM, Hutten R, Jacobsen E, Lotz LAP, Kessel GJT, Vossen JH, Visser RGF (2016) Durable late blight resistance in potato through dynamic varieties obtained by cisgenesis: scientific and societal advances in the DuRPh project. Potato Res 59:35–66
Hawkes JG (1990) The potato; evolution, biodiversity and genetic resources. Belhaven Press, London
Henderson CR (1984) Applications of linear models in animal breeding. University of Guelph, Guelph
Hijmans RJ, Spooner DM (2001) Geographic distribution of wild potato species. Am J Bot 88:2101–2112
Houle D, Govindaraju DR, Omholt S (2010) Phenomics: the next challenge. Nat Rev Genet 11:855–866
Hutchison CA (2007) DNA sequencing: bench to bedside and beyond. Nucleic Acids Res 35:6227–6237
Jansky S (2009) Breeding, genetics and cultivar development. In: Singh J, Kaur L (eds) Advances in potato chemistry and technology. Academic Press, New York, pp 27–62
Jansky SH, Spooner DM (2018) The evolution of potato breeding. In: Plant breeding reviews. Wiley, pp 169–214
Kaku M (2011) Physics of the future: the inventions that will transform our lives. Penguin Books, Camberwell
Kanyuka K, Bendahmane A, van der Voort JNAMR, van der Vossen EAG, Baulcombe DC (1999) Mapping of intra-locus duplications and introgressed DNA: aids to map-based cloning of genes from complex genomes illustrated by physical analysis of the Rx locus in tetraploid potato. Theor Appl Genet 98:679–689
Kasai K, Morikawa Y, Sorri VA, Valkonen JP, Gebhardt C, Watanabe KN (2000) Development of SCAR markers to the PVY resistance gene Ry adg based on a common feature of plant disease resistance genes. Genome 43:1–8
Kim C, Guo H, Kong W, Chandnani R, Shuang L-S, Paterson AH (2016) Application of genotyping by sequencing technology to a variety of crop breeding programs. Plant Sci 242:14–22
Kloosterman B, Abelenda JA, Gomez MMC, Oortwijn M, de Boer JM, Kowitwanich K, Horvath BM, van Eck HJ, Smaczniak C, Prat S, Visser RGF, Bachem CWB (2013) Naturally occurring allele diversity allows potato cultivation in northern latitudes. Nature 495:246–250
Leister D, Ballvora A, Salamini F, Gebhardt C (1996) A PCR-based approach for isolating pathogen resistance genes from potato with potential for wide application in plants. Nat Genet 14:421–429
Lin Z, Hayes BJ, Daetwyler HD (2014) Genomic selection in crops, trees and forages: a review. Crop Pasture Sci 65:1177–1191
Lindhout P, Meijer D, Schotte T, Hutten RCB, Visser RGF, van Eck HJ (2011) Towards F1 hybrid seed potato breeding. Potato Res 54:301–312
Love SL, Werner BK, Pavek JJ (1997) Selection for individual traits in the early generations of a potato breeding program dedicated to producing cultivars with tubers having long shape and russet skin. Am Potato J 74:199–213
Malmberg MM, Pembleton LW, Baillie RC, Drayton MC, Sudheesh S, Kaur S, Shinozuka H, Verma P, Spangenberg GC, Daetwyler HD, Forster JW, Cogan NOI (2017) Genotyping-by-sequencing through transcriptomics: implementation in a range of crop species with varying reproductive habits and ploidy levels. Plant Biotechnol J 16:877–889. https://doi.org/10.1111/pbi.12835
Maris B (1986) The effect of seed tuber weight on characters in the first and the second clonal generation of potato populations. Euphytica 35:465–482
Meuwissen THE, Hayes BJ, Goddard ME (2001) Prediction of total genetic value using genome-wide dense marker maps. Genetics 157:1819–1829
Milbourne D, Byrne S, Meade F, Mesiti F, Griffin D (2017) Using genomic variants to predict fry colour in potato. 20th Triennial Conference of the European Association for Potato Research, 9–14 July 2017, Versailles, France
Milczarek D, Flis B, Przetakiewicz A (2011) Suitability of molecular markers for selection of potatoes resistant to Globodera spp. Am J Potato Res 88:245–255
Milczarek DPA, Kamiński P, Flis B (2014) Early selection of potato clones with the H1 resistance gene—the relation of nematode resistance to quality characteristics. Czech J Genet Plant Breed 50:278–284
Mochida K, Shinozaki K (2011) Advances in omics and bioinformatics tools for systems analyses of plant functions. Plant Cell Physiol 52:2017–2038
Moloney C, Griffin D, Jones P, Bryan G, McLean K, Bradshaw J, Milbourne D (2010) Development of diagnostic markers for use in breeding potatoes resistant to Globodera pallida pathotype Pa2/3 using germplasm derived from Solanum tuberosum ssp. andigena CPC 2802. Theor Appl Genet 120:679–689
Moose SP, Mumm RH (2008) Molecular plant breeding as the foundation for 21st century crop improvement. Plant Physiol 147:969–977
Neele AEF, Louwes KM (1989) Early selection for chip quality and dry matter content in potato seedling populations in greenhouse or screenhouse. Potato Res 32:293–300
Ottoman R, Hane D, Brown C, Yilma S, James S, Mosley A, Crosslin J, Vales M (2009) Validation and implementation of marker-assisted selection (MAS) for PVY resistance (Ry adg gene) in a tetraploid potato breeding program. Am J Potato Res 86:304–314
Park J, Yang H, De Jong WS, Wang X (2017) An evaluation of two H1-linked markers and their suitability for selecting Globodera rostochiensis resistant potatoes in the New York breeding program. Am J Potato Res on-line 22 December 2017
Phillips MS (1981) A method of assessing potato seedling progenies for resistance to the white potato cyst nematode. Potato Res 24:101–103
Resende MFR, Muñoz P, Resende MDV, Garrick DJ, Fernando RL, Davis JM, Jokela EJ, Martin TA, Peter GF, Kirst M (2012) Accuracy of genomic selection methods in a standard data set of loblolly pine (Pinus taeda L.). Genetics 190:1503–1510
Riedelsheimer C, Czedik-Eysenberg A, Grieder C, Lisec J, Technow F, Sulpice R, Altmann T, Stitt M, Willmitzer L, Melchinger AE (2012) Genomic and metabolic prediction of complex heterotic traits in hybrid maize. Nat Genet 44:217–220
Ritter E, Debener T, Barone A, Salamini F, Gebhardt C (1991) RFLP mapping on potato chromosomes of two genes controlling extreme resistance to potato virus X (PVX). Mol Gen Genet 227:81–85
Ruiz De Galarreta JI, Ezpeleta B, Pascualena J, Ritter E (2006) Combining ability and correlations for yield components in early generations of potato breeding. Plant Breed 125:183–186
Schultz L, Cogan NOI, Forster JW, Slater AT (2010) Evaluation and optimisation of the TG689 marker linked to PCN resistance. Potato Res 53:247–248
Schultz L, Cogan NOI, McLean K, Dale MFB, Bryan GJ, Forster JW, Slater AT (2012) Evaluation and implementation of a potential diagnostic molecular marker for H1-conferred potato cyst nematode resistance in potato (Solanum tuberosum L.). Plant Breed 131:315–321
Selga C, Reslow F, Andersson M, Ortiz R (2017) Genomic estimated breeding value approach for selection in potato. 20th Triennial Conference of the European Association for Potato Research, 9–14 July 2017, Versailles, France
Simko I, Jansky S, Stephenson S, Spooner DM (2007) Genetics of resistance to pests and diseases. In: Vreugdenhil D, Bradshaw J, Gebhardt C, Govers F, MacKerron DKL, Taylor MA, Ross HA (eds) Potato biology and biotechnology: advances and perspectives. Elsevier, Amsterdam, pp 117–155
Slater AT (2013) Molecular and quantitative genetic studies for potato germplasm enhancement (PhD Thesis). La Trobe University, Bundoora, Australia
Slater T, Wilson G, Schultz L, Cogan N, Forster J, Verstraten M (2011) National potato breeding program trials 2009/2010. Department of Primary Industries, Knoxfield
Slater T, Forster J, Cogan N, Schultz L, Lombardi M, Hayes B, Rodoni B, Milinkovic M, Zheng L, Wilson G, Verstraten M (2012a) National potato breeding program: strategic trait development. Project No. PT08033. Final Report for Horticulture Australia., p 80
Slater T, Wilson G, Verstraten M (2012b) National potato breeding program: Cultivar improvement. Project No. PT07017. Final Report for Horticulture Australia
Slater AT, Cogan NOI, Forster JW (2013) Cost analysis of the application of marker-assisted selection in potato breeding. Mol Breed 32:299–310
Slater AT, Cogan NOI, Hayes BJ, Schultz L, Dale MFB, Bryan GJ, Forster JW (2014a) Improving breeding efficiency in potato using molecular and quantitative genetics. Theor Appl Genet 127:2279–2292
Slater AT, Wilson GM, Cogan NOI, Forster JW, Hayes BJ (2014b) Improving the analysis of low heritability complex traits for enhanced genetic gain in potato. Theor Appl Genet 127:809–820
Slater AT, Cogan NOI, Forster JW, Hayes BJ, Daetwyler HD (2016) Improving genetic gain with genomic selection in autotetraploid potato. Plant Genome 9
Song Y-S, Hepting L, Schweizer G, Hartl L, Wenzel G, Schwarzfischer A (2005) Mapping of extreme resistance to PVY (Ry sto) on chromosome XII using anther-culture-derived primary dihaploid potato lines. Theor Appl Genet 111:879–887
Stich B, Van Inghelandt D (2018) Prospects and potential uses of genomic prediction of key performance traits in tetraploid potato. Front Plant Sci 9
Sverrisdóttir E, Byrne S, Sundmark EHR, Johnsen HØ, Kirk HG, Asp T, Janss L, Nielsen KL (2017) Genomic prediction of starch content and chipping quality in tetraploid potato using genotyping-by-sequencing. Theor Appl Genet 130:2091–2108
Tai G, Young D (1984) Early generation selection for important agronomic characteristics in a potato breeding population. Am J Potato Res 61:419–434
Tanksley SD, Ganal MW, Prince JP, de Vicente MC, Bonierbale MW, Broun P, Fulton TM, Giovannoni JJ, Grandillo S, Martin GB et al (1992) High density molecular linkage maps of the tomato and potato genomes. Genetics 132:1141–1160
Valkonen JPT, Wiegmann K, Hämäläinen JH, Marczewski W, Watanabe KN (2008) Evidence for utility of the same PCR-based markers for selection of extreme resistance to potato virus Y controlled by Ry sto of Solanum stoloniferum derived from different sources. Ann Appl Biol 152:121–130
van Eck HJ (2007) Genetics of morphological and tuber traits. In: Vreugdenhil D, Bradshaw J, Gebhardt C, Govers F, MacKerron DKL, Taylor MA, Ross HA (eds) Potato biology and biotechnology: advances and perspectives. Elsevier, Amsterdam, pp 91–115
Van Os H, Andrzejewski S, Bakker E, Barrena I, Bryan GJ, Caromel B, Ghareeb B, Isidore E, De Jong W, Van Koert P, Lefebvre V, Milbourne D, Ritter E, Rouppe Van Der Voort JNAM, Rousselle-Bourgeois F, Van Vliet J, Waugh R, Visser RGF, Bakker J, Van Eck HJ (2006) Construction of a 10,000-marker ultradense genetic recombination map of potato: providing a framework for accelerated gene isolation and a genomewide physical map. Genetics 173:1075–1087
VanRaden PM, Van Tassell CP, Wiggans GR, Sonstegard TS, Schnabel RD, Taylor JF, Schenkel FS (2009) Invited review: reliability of genomic predictions for North American Holstein bulls. J Dairy Sci 92:16–24
Vos PG, Paulo MJ, Voorrips RE, Visser RGF, van Eck HJ, van Eeuwijk FA (2017) Evaluation of LD decay and various LD-decay estimators in simulated and SNP-array data of tetraploid potato. Theor Appl Genet 130:123–135
Wastie RL (1991) Resistance to powdery scab of seedling progenies of Solanum tuberosum. Potato Res 34:249–252
Wastie RL, Bradshaw JE (1996) Comparison of resistance to Fusarium spp. of glasshouse- and field-grown tuber progenies of potato. Potato Res 38:345–351
Wastie RL, Caligari PDS, Stewart HE, Mackay GR (1988) Assessing the resistance to gangrene of progenies of potato (Solanum tuberosum L.) from parents differing in susceptibility. Potato Res 31:355–365
Wiggans GR, Vanraden PM, Cooper TA (2011) The genomic evaluation system in the United States: past, present, future. J Dairy Sci 94:3202–3211
Witek K, Strzelczyk-Żyta D, Hennig J, Marczewski W (2006) A multiplex PCR approach to simultaneously genotype potato towards the resistance alleles Ry-f sto and Ns. Mol Breed 18:273–275
Wolc A, Stricker C, Arango J, Settar P, Fulton J, O’Sullivan N, Preisinger R, Habier D, Fernando R, Garrick D, Lamont S, Dekkers J (2011) Breeding value prediction for production traits in layer chickens using pedigree or genomic relationships in a reduced animal model. Genet Sel Evol 43:5
Wolc A, Zhao H, Arango J, Settar P, Fulton J, O’Sullivan N, Preisinger R, Stricker C, Habier D, Fernando R, Garrick D, Lamont S, Dekkers J (2015) Response and inbreeding from a genomic selection experiment in layer chickens. Genet Sel Evol 47:59
Xiong X, Tai GCC, Seabrook JEA (2002) Effectiveness of selection for quality traits during the early stage in the potato breeding population. Plant Breed 121:441–444
Xu Y, Lu Y, Xie C, Gao S, Wan J, Prasanna B (2012) Whole-genome strategies for marker-assisted plant breeding. Mol Breed 29:833–854
Acknowledgements
The authors thank Graeme Wilson, Mark Verstraten, Lee Schultz, Maria Lombardi, Mirko Milinkovic, Chris Bottcher, Linda Zheng and Rob Faggian for their input into the trials. We also thank Andrew Powell and Phil Keane from La Trobe University and Finlay Dale, Glenn Bryan and Karen McLean from the James Hutton Institute.
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This work was supported by funding from Hort Innovation Australia and the Victorian Department of Economic Development, Jobs, Transport and Resources.
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Slater, A.T., Cogan, N.O.I., Rodoni, B.C. et al. Breeding Differently—the Digital Revolution: High-Throughput Phenotyping and Genotyping. Potato Res. 60, 337–352 (2017). https://doi.org/10.1007/s11540-018-9388-x
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DOI: https://doi.org/10.1007/s11540-018-9388-x