Multi-assignment clustering: Machine learning from a biological perspective
Affiliations.
- 1 School of Bioscience, University of Skövde, Skövde, Sweden. Electronic address: [email protected].
- 2 School of Informatics, University of Skövde, Skövde, Sweden.
- 3 School of Informatics, University of Skövde, Skövde, Sweden; Department of Computer Science and Informatics, School of Engineering, Jönköping University, Jönköping, Sweden.
- 4 Takara Bio Europe AB, Gothenburg, Sweden.
- 5 School of Bioscience, University of Skövde, Skövde, Sweden.
- PMID: 33285150
- DOI: 10.1016/j.jbiotec.2020.12.002
A common approach for analyzing large-scale molecular data is to cluster objects sharing similar characteristics. This assumes that genes with highly similar expression profiles are likely participating in a common molecular process. Biological systems are extremely complex and challenging to understand, with proteins having multiple functions that sometimes need to be activated or expressed in a time-dependent manner. Thus, the strategies applied for clustering of these molecules into groups are of key importance for translation of data to biologically interpretable findings. Here we implemented a multi-assignment clustering (MAsC) approach that allows molecules to be assigned to multiple clusters, rather than single ones as in commonly used clustering techniques. When applied to high-throughput transcriptomics data, MAsC increased power of the downstream pathway analysis and allowed identification of pathways with high biological relevance to the experimental setting and the biological systems studied. Multi-assignment clustering also reduced noise in the clustering partition by excluding genes with a low correlation to all of the resulting clusters. Together, these findings suggest that our methodology facilitates translation of large-scale molecular data into biological knowledge. The method is made available as an R package on GitLab (https://gitlab.com/wolftower/masc).
Keywords: Annotation enrichment; Clustering; K-means; Multiple cluster assignment; Pathways; Transcriptomics.
Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.
- Algorithms*
- Cluster Analysis
- Gene Expression Profiling
- Machine Learning*
Sequential, Multiple Assignment, Randomized Trials (SMART)
- Living reference work entry
- First Online: 12 August 2021
- Cite this living reference work entry
- Nicholas J. Seewald 3 ,
- Olivia Hackworth 3 &
- Daniel Almirall 3
324 Accesses
1 Citations
4 Altmetric
A dynamic treatment regimen (DTR) is a prespecified set of decision rules that can be used to guide important clinical decisions about treatment planning. This includes decisions concerning how to begin treatment based on a patient’s characteristics at entry, as well as how to tailor treatment over time based on the patient’s changing needs. Sequential, multiple assignment, randomized trials (SMARTs) are a type of experimental design that can be used to build effective dynamic treatment regimens (DTRs). This chapter provides an introduction to DTRs, common types of scientific questions researchers may have concerning the development of a highly effective DTR, and how SMARTs can be used to address such questions. To illustrate ideas, we discuss the design of a SMART used to answer critical questions in the development of a DTR for individuals diagnosed with alcohol use disorder.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Institutional subscriptions
Similar content being viewed by others
Adaptive Intervention Designs in Substance Use Prevention
Randomized Controlled Trials in Substance Abuse Treatment Research: Fundamental Aspects and New Developments in Random Assignment Strategies, Comparison/Control Conditions, and Design Characteristics
Almirall D, DiStefano C, Chang Y-C, Shire S, Kaiser A, Lu X, Nahum-Shani I, Landa R, Mathy P, Kasari C (2016) “Longitudinal Effects of Adaptive Interventions With a Speech-Generating Device in Minimally Verbal Children With ASD.” J Clin Child Adolesc 45 (4): 442–56. https://doi.org/10.1080/15374416.2016.1138407
Almirall D, Nahum-Shani I, Lu W, Kasari C (2018) Experimental designs for research on adaptive interventions: singly and sequentially randomized trials. In: Collins LM, Kugler KC (eds) Optimization of behavioral, biobehavioral, and biomedical interventions: advanced topics, Statistics for social and behavioral sciences. Springer International Publishing, Cham, pp 89–120. https://doi.org/10.1007/978-3-319-91776-4_4
Chapter Google Scholar
August GJ, Piehler TF, Bloomquist ML (2016) Being ‘SMART’ about adolescent conduct problems prevention: executing a SMART pilot study in a juvenile diversion agency. J Clin Child Adolesc Psychol 45(4):495–509. https://doi.org/10/ghpbrn
Article Google Scholar
Cable N, Sacker A (2007) Typologies of alcohol consumption in adolescence: predictors and adult outcomes. Alcohol Alcoholism 43(1):81–90. https://doi.org/10/fpmm33
Chakraborty B, Moodie EEM (2013) Statistical Methods for Dynamic Treatment Regimes . Statistics for biology and health. Springer New York, New York, NY. https://doi.org/10.1007/978-1-4614-7428-9
Book Google Scholar
Cheung YK, Chakraborty B, Davidson KW (2015) Sequential multiple assignment randomized trial (SMART) with adaptive randomization for quality improvement in depression treatment program: SMART with adaptive randomization. Biometrics 71(2):450–459. https://doi.org/10.1111/biom.12258
Article MathSciNet MATH Google Scholar
Chronis-Tuscano A, Wang CH, Strickland J, Almirall D, Stein MA (2016) Personalized treatment of mothers with ADHD and their young at-risk children: a SMART pilot. J Clin Child Adolesc Psychol 45(4):510–521. https://doi.org/10/gg2h36
Collins LM, Nahum-Shani I, Almirall D (2014) Optimization of behavioral dynamic treatment regimens based on the sequential, multiple assignment, randomized trial (SMART). Clin Trials 11(4):426–434. https://doi.org/10/f6cjxm
Dragalin V (2006) Adaptive designs: terminology and classification. Drug Inf J 40(4):425–435. https://doi.org/10/ghpbrt
Article MathSciNet Google Scholar
Dziak JJ, Yap JRT, Almirall D, McKay JR, Lynch KG, Nahum-Shani I (2019) A data analysis method for using longitudinal binary outcome data from a SMART to compare adaptive interventions. Multivar Behav Res 0(0):1–24. https://doi.org/10/gftzjg
Google Scholar
Feng W, Wahed AS (2009) Sample size for two-stage studies with maintenance therapy. Stat Med 28(15):2028–2041. https://doi.org/10.1002/sim.3593
Gunlicks-Stoessel M, Mufson L, Westervelt A, Almirall D, Murphy SA (2016) A pilot SMART for developing an adaptive treatment strategy for adolescent depression. J Clin Child Adolesc Psychol 45(4):480–494. https://doi.org/10/ghpbrv
Hall KL, Nahum-Shani I, August GJ, Patrick ME, Murphy SA, Almirall D (2019) Adaptive intervention designs in substance use prevention. In: Sloboda Z, Petras H, Robertson E, Hingson R (eds) Prevention of substance use, Advances in prevention science. Springer International Publishing, Cham, pp 263–280. https://doi.org/10.1007/978-3-030-00627-3_17
Heilig M, Egli M (2006) Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther 111(3):855–876. https://doi.org/10/cfs7df
Kasari C, Kaiser A, Goods K, Nietfeld J, Mathy P, Landa R, Murphy SA, Almirall D (2014) Communication interventions for minimally verbal children with autism: a sequential multiple assignment randomized trial. J Am Acad Child Adolesc Psychiatry 53(6):635–646. https://doi.org/10.1016/j.jaac.2014.01.019
Kidwell KM, Seewald NJ, Tran Q, Kasari C, Almirall D (2018) Design and analysis considerations for comparing dynamic treatment regimens with binary outcomes from sequential multiple assignment randomized trials. J Appl Stat 45(9):1628–1651. https://doi.org/10.1080/02664763.2017.1386773
Kilbourne AM, Almirall D, Eisenberg D, Waxmonsky J, Goodrich DE, Fortney JC, JoAnn E. Kirchner, et al. (2014) Protocol: adaptive implementation of effective programs trial (ADEPT): cluster randomized SMART trial comparing a standard versus enhanced implementation strategy to improve outcomes of a mood disorders program. Implement Sci 9(1):132. https://doi.org/10/f6q9fc
Kilbourne AM, Smith SN, Choi SY, Koschmann E, Liebrecht C, Rusch A, Abelson JL et al (2018) Adaptive school-based implementation of CBT (ASIC): clustered-SMART for building an optimized adaptive implementation intervention to improve uptake of mental health interventions in schools. Implement Sci 13(1):119. https://doi.org/10/gd7jt2
Kosorok MR, Moodie EEM (eds) (2015) Adaptive treatment strategies in practice: planning trials and analyzing data for personalized medicine. Society for Industrial and Applied Mathematics, Philadelphia, PA. https://doi.org/10.1137/1.9781611974188
Book MATH Google Scholar
Laber EB, Lizotte DJ, Qian M, Pelham WE, Murphy SA (2014) Dynamic treatment regimes: technical challenges and applications. Electron J Stat 8(1):1225–1272. https://doi.org/10/gg29c8
Lavori PW, Dawson R (2004) Dynamic treatment regimes: practical design considerations. Clin Trials 1(1):9–20. https://doi.org/10/cqtvnn
Lavori PW, Dawson R (2014) Introduction to dynamic treatment strategies and sequential multiple assignment randomization. Clin Trials 11(4):393–399. https://doi.org/10.1177/1740774514527651
Lei H, Nahum-Shani I, Lynch K, Oslin D, Murphy SA (2012) A ‘SMART’ design for building individualized treatment sequences. Annu Rev Clin Psychol 8(1):21–48. https://doi.org/10.1146/annurev-clinpsy-032511-143152
Li Z (2017) Comparison of adaptive treatment strategies based on longitudinal outcomes in sequential multiple assignment randomized trials. Stat Med 36(3):403–415. https://doi.org/10.1002/sim.7136
Li Z, Murphy SA (2011) Sample size formulae for two-stage randomized trials with survival outcomes. Biometrika 98(3):503–518. https://doi.org/10.1093/biomet/asr019
Longabaugh R, Zweben A, Locastro JS, Miller WR (2005) Origins, issues and options in the development of the combined behavioral intervention. J Stud Alcohol Suppl (15):179–187. https://doi.org/10/ghpb9f
Lu X, Nahum-Shani I, Kasari C, Lynch KG, Oslin DW, Pelham WE, Fabiano G, Almirall D (2016) Comparing dynamic treatment regimes using repeated-measures outcomes: modeling considerations in SMART studies. Stat Med 35(10):1595–1615. https://doi.org/10/gg2gxc
Lunceford JK, Davidian M, Tsiatis AA (2002) Estimation of survival distributions of treatment policies in two-stage randomization designs in clinical trials. Biometrics 58(1):48–57. https://doi.org/10/bk2dj9
McKay JR (2005) Is there a case for extended interventions for alcohol and drug use disorders? Addiction 100(11):1594–1610. https://doi.org/10/btpvtr
Meurer WJ, Lewis RJ, Berry DA (2012) Adaptive clinical trials: a partial remedy for the therapeutic misconception? JAMA-J Am Med Assoc 307(22):2377–2378. https://doi.org/10/gf3pmm
Moodie EEM, Richardson TS, Stephens DA (2007) Demystifying optimal dynamic treatment regimes. Biometrics 63(2):447–455. https://doi.org/10/ffcq8r
Murphy SA (2003) Optimal dynamic treatment regimes. J R Stat Soc B 65(2):331–355. https://doi.org/10/dmmr89
Murphy SA (2005) An experimental Design for the Development of adaptive treatment strategies. Stat Med 24(10):1455–1481. https://doi.org/10.1002/sim.2022
Murphy SA, Almirall D (2009) Dynamic treatment regimens. In: Encyclopedia of Medical Decision Making , 1:419–22. SAGE Publications, Thousand Oaks
Murphy SA, Bingham D (2009) Screening experiments for developing dynamic treatment regimes. J Am Stat Assoc 104(485):391–408. https://doi.org/10/dk2gpv
Naar-King S, Ellis DA, Carcone AI, Templin T, Jacques-Tiura AJ, Hartlieb KB, Cunningham P, Jen K-LC (2016) Sequential multiple assignment randomized trial (SMART) to construct weight loss interventions for African American adolescents. J Clin Child Adolesc Psychol 45(4):428–441. https://doi.org/10/gf4ks4
Nahum-Shani I, Qian M, Almirall D, Pelham WE, Gnagy B, Fabiano GA, Waxmonsky JG, Yu J, Murphy SA (2012a) Q-learning: a data analysis method for constructing adaptive interventions. Psychol Methods 17(4):478–494. https://doi.org/10.1037/a0029373
Nahum-Shani I, Qian M, Almirall D, Pelham WE, Gnagy B, Fabiano GA, Waxmonsky JG, Yu J, Murphy SA (2012b) Experimental design and primary data analysis methods for comparing adaptive interventions. Psychol Methods 17(4):457–477. https://doi.org/10.1037/a0029372
Nahum-Shani I, Ertefaie A, Xi (Lucy) Lu, Lynch KG, McKay JR, Oslin DW, Almirall D (2017) A SMART data analysis method for constructing adaptive treatment strategies for substance use disorders. Addiction 112(5):901–909. https://doi.org/10/ghpb9n
Nahum-Shani I, Almirall D, Yap JRT, McKay JR, Lynch KG, Freiheit EA, Dziak JJ (2020) SMART longitudinal analysis: a tutorial for using repeated outcome Measures from SMART studies to compare adaptive interventions. Psychol Methods 25(1):1–29. https://doi.org/10/ggttht
NeCamp T, Kilbourne A, Almirall D (2017) Comparing cluster-level dynamic treatment regimens using sequential, multiple assignment, randomized trials: regression estimation and sample size considerations. Stat Methods Med Res 26(4):1572–1589. https://doi.org/10.1177/0962280217708654
Oetting AI, Levy JA, Weiss RD, Murphy SA (2011) Statistical methodology for a SMART Design in the Development of adaptive treatment strategies. In: Shrout PE, Keyes KM, Ornstein K (eds) Causality and psychopathology: finding the determinants of disorders and their cures. Oxford University Press, New York, pp 179–205
Ogbagaber SB, Karp J, Wahed AS (2016) Design of Sequentially Randomized Trials for testing adaptive treatment strategies. Stat Med 35(6):840–858. https://doi.org/10.1002/sim.6747
Oslin DW, Berrettini WH, O’Brien CP (2006) Targeting treatments for alcohol dependence: the pharmacogenetics of naltrexone. Addict Biol 11(3–4):397–403. https://doi.org/10/fgcfbk
Pelham WE Jr, Fabiano GA, Waxmonsky JG, Greiner AR, Gnagy EM, Pelham WE III, Coxe S et al (2016) Treatment sequencing for childhood ADHD: a multiple-randomization study of adaptive medication and behavioral interventions. J Clin Child Adolesc Psychol 45(4):396–415. https://doi.org/10/gfn9xr
Quanbeck A, Almirall D, Jacobson N, Brown RT, Landeck JK, Madden L, Cohen A et al (2020) The balanced opioid initiative: protocol for a clustered, sequential, multiple-assignment randomized trial to construct an adaptive implementation strategy to improve guideline-concordant opioid prescribing in primary care. Implement Sci 15(1):26. https://doi.org/10/gjh5tx
Rubin DB (1974) Estimating causal effects of treatments in randomized and nonrandomized studies. J Educ Psychol 66(5):688–701. https://doi.org/10.1037/H0037350
Schmitz JM, Stotts AL, Vujanovic AA, Weaver MF, Yoon JH, Vincent J, Green CE (2018) A sequential multiple assignment randomized trial for cocaine cessation and relapse prevention: tailoring treatment to the individual. Contemp Clin Trials 65(February):109–115. https://doi.org/10/gc3tqr
Seewald NJ, Kidwell KM, Nahum-Shani I, Wu T, McKay JR, Almirall D (2020) Sample size considerations for comparing dynamic treatment regimens in a sequential multiple-assignment randomized trial with a continuous longitudinal outcome. Stat Methods Med Res 29(7):1891–1912. https://doi.org/10/gf85ss
Sherwood NE, Butryn ML, Forman EM, Almirall D, Seburg EM, Lauren Crain A, Kunin-Batson AS, Hayes MG, Levy RL, Jeffery RW (2016) The BestFIT trial: a SMART approach to developing individualized weight loss treatments. Contemp Clin Trials 47(March):209–216. https://doi.org/10.1016/j.cct.2016.01.011
Thall PF, Kyle Wathen J (2005) Covariate-adjusted adaptive randomization in a sarcoma trial with multi-stage treatments. Stat Med 24(13):1947–1964. https://doi.org/10/d5ztnt
Thall PF, Millikan RE, Sung H-G (2000) Evaluating multiple treatment courses in clinical trials. Stat Med 19(8):1011–1028. https://doi.org/10/bmv5jc
Thall PF, Sung H-G, Estey EH (2002) Selecting therapeutic strategies based on efficacy and death in multicourse clinical trials. J Am Stat Assoc 97(457):29–39. https://doi.org/10/dx3fkb
Tsiatis AA, Davidian M, Holloway ST, Laber EB (2019) Dynamic Treatment Regimes: Statistical Methods for Precision Medicine . Monographs on statistics and applied probability 164. CRC Press LLC, Milton
Vock DM, Almirall D (2018) Sequential multiple assignment randomized trial (SMART). In: Balakrishnan N, Colton T, Everitt W, Piegorsch F, Teugels JL (eds) Wiley StatsRef: statistics reference online. https://doi.org/10.1002/9781118445112.stat08073
Wahed AS, Tsiatis AA (2004) Optimal estimator for the survival distribution and related quantities for treatment policies in two-stage randomization designs in clinical trials. Biometrics 60(1):124–133. https://doi.org/10/dc4kfb
Wahed AS, Tsiatis AA (2006) Semiparametric efficient estimation of survival distributions in two-stage randomisation designs in clinical trials with censored data. Biometrika 93(1):163–177. https://doi.org/10/cgchp6
Zhao Y-Q, Laber EB (2014) Estimation of optimal dynamic treatment regimes. Clin Trials 11(4):400–407. https://doi.org/10/f6cjrn
Download references
Acknowledgments
Funding was provided by the National Institutes of Health (P50DA039838, R01DA039901) and the Institute for Education Sciences (R324B180003). Funding for the ExTENd study, which was used to illustrate ideas, was provided by the National Institutes of Health (R01AA014851; PI: David Oslin).
Author information
Authors and affiliations.
University of Michigan, Ann Arbor, MI, USA
Nicholas J. Seewald, Olivia Hackworth & Daniel Almirall
You can also search for this author in PubMed Google Scholar
Corresponding author
Correspondence to Nicholas J. Seewald .
Editor information
Editors and affiliations.
Samuel Oschin Comprehensive Cancer Insti, WEST HOLLYWOOD, CA, USA
Steven Piantadosi
Bloomberg School of Public Health, Johns Hopkins Center for Clinical Trials Bloomberg School of Public Health, Baltimore, MD, USA
Curtis L. Meinert
Section Editor information
Statistician, MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
Babak Choodari-Oskooei
MRC Clinical Trials Unit and Institute of Clinical Trials and Methodology, University College of London, London, England
Mahesh Parmar
The Johns Hopkins Center for Clinical Trials and Evidence Synthesis, Johns Hopkins School of Public Health, Baltimore, MA, USA
Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Rights and permissions
Reprints and permissions
Copyright information
© 2021 Springer Nature Switzerland AG
About this entry
Cite this entry.
Seewald, N.J., Hackworth, O., Almirall, D. (2021). Sequential, Multiple Assignment, Randomized Trials (SMART). In: Piantadosi, S., Meinert, C.L. (eds) Principles and Practice of Clinical Trials. Springer, Cham. https://doi.org/10.1007/978-3-319-52677-5_280-1
Download citation
DOI : https://doi.org/10.1007/978-3-319-52677-5_280-1
Received : 09 April 2021
Accepted : 28 April 2021
Published : 12 August 2021
Publisher Name : Springer, Cham
Print ISBN : 978-3-319-52677-5
Online ISBN : 978-3-319-52677-5
eBook Packages : Springer Reference Mathematics Reference Module Computer Science and Engineering
- Publish with us
Policies and ethics
- Find a journal
- Track your research
IMAGES
VIDEO