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The predictive power of polygenic scores (PGSs) for lithium treatment response in bipolar disorder remains limited.
Aims
To enhance the prediction of lithium responsiveness by developing a multi-trait PGS (mt-PGS) combining genetic information from multiple phenotypes implicated in lithium response and/or bipolar disorder aetiology.
Method
We analysed data collected from bipolar disorder patients who had received lithium treatment for at least 6 months and participated in the International Consortium on Lithium Genetics study (N = 2367). The Alda scale was used to assess lithium responsiveness, and treatment outcome was defined as continuous total Alda score (0–10) and categorical outcome (favourable ≥7 versus unfavourable response). PGSs were calculated for 60 phenotypes grouped into 5 clinical–biological clusters: psychiatric and behavioural (#23 phenotypes), cardiometabolic (#17), autoimmune/inflammatory (#5), neurocognitive (#8) and renal function (#7). We applied cross-validated machine learning regression approaches in both outcomes within each cluster, with the selected features from each cluster subsequently combined to construct the final mt-PGS models. Model performance was assessed using explained variance (R2) for the continuous outcome, and both McFadden’s pseudo-R2 and standard classification model parameters for the categorical outcome.
Results
mt-PGS explained between 5.70% (continuous outcome) and 9.11% (categorical outcome) of the interindividual variability in lithium responsiveness. Classification accuracy (area under the curve) for the categorical outcome was 68.24% (95% CI: 64.98–71.66), with a Brier score of 0.257. Of the 5 clusters, the PGSs for psychiatric and behavioural phenotypes were most strongly associated with lithium responsiveness, accounting for 3.67–6.52% of its variability.
Conclusions
By integrating PGSs for multiple relevant phenotypes, predictive accuracy for lithium response improved substantially compared with single-trait methods. Future research incorporating larger, more diverse populations and combining genetic scores with clinical data holds promise for further enhancing prediction and advancing clinical implementation.
For those who ended up incarcerated, prison life was defined by inequality and social stratification. Imprisonment was an uncomfortable and costly ordeal for most, but one in which wealth could mitigate the harshest conditions. Chapter 3 turns to these day-to-day experiences of imprisonment, exploring living conditions and social structures in prison (including the physical division of master’s and common sides along lines of wealth and status), as well as the place of commerce and trade in prison life. It reveals the crowded and unsanitary conditions in which prisoners lived, not to mention the high costs of doing so. This chapter also considers how prisoners prosecuted their grievances, including strategies of petitioning and their relationship to rioting. Significantly, prisoners regularly appealed to local custom, arguments that could win concessions, but that also risked shoring up dominant carceral ideologies by conflating their interests with those of state authority, defending institutional integrity against supposedly corrupt gaolers.
By the early seventeenth century, England’s prisons were reaching breaking point. Prison unrest and rioting became increasingly common as prisoners agitated against reportedly parlous conditions, extortionate fees and abusive treatment. In the process, they formulated more general critiques of the prison system. Chapter 5 explores in detail an interrelated set of disturbances within London’s Fleet and King’s Bench prisons between 1618 and 1621. This period of collective violence and the petitioning that followed precipitated political and rhetorical shifts in prisoners’ arguments, from opposing corruption within prisons (based on local custom) to new calls for the abolition of imprisonment for debt (based on the ancient constitution). By this means, prisoners developed a diagnosis of their condition alongside a set of remedies that challenged prevailing carceral ideologies rather than reinforcing them. Thus, this chapter suggests that while political languages based on the past could help negotiate the terms of subordination, they could also directly challenge assumptions about social order.
By 1647, the abolition of imprisonment for debt had become a staple of radical demands. Yet like so many radical projects, it ultimately suffered defeat and moderation. Chapter 8 traces the rise and fall of the abolitionist campaign, and the legacy of prison reform in the later seventeenth century. First, it follows arguments for abolition and the activists who made them into the new political and intellectual context of the English republic, revealing the significance of prison activism and arguments for abolition in debates over the future of the English polity. Yet these activists struggled to secure the change they envisioned. Worse still, their ideas dwindled in significance after the restoration of Charles II, giving way to prison campaigning that prioritised moderate calls for episodic relief and the reform of conditions. Yet, this also involved ambitious nationwide campaigning, connecting central prisons with county gaols for the first time. This led to increased concern with local inspection, due process and penal proportionality that anticipated the eighteenth-century prison reform movement. By the end of the seventeenth century, many aspects of imprisonment for debt and prison campaigning settled into patterns that would define the institution for another two centuries.
Debtors’ prisons played a vital – albeit seemingly paradoxical – role in early modern society. In many cases, those incarcerated could not or would not pay their debts. Instead, they languished in prison and racked up new debts to their gaolers. Chapter 2 addresses this seemingly self-contradictory system by showing that, even when it prevented the repayment of debts, imprisonment helped to protect wider social and economic interests, balancing those of landed wealth and emergent capital. It analyses the social, economic, legal and ideological shifts that underwrote this convoluted system, excavating emergent carceral ideologies. In turn, it considers the array of measures taken to alleviate the pressure that growing numbers of insolvent debtors placed on England’s prisons, mitigating the worst effects of the structural weakness of debt incarceration. These attempts to relieve an overburdened system – which ultimately stabilised the debtors’ prison into the eighteenth century – were essential because prisons had developed disciplinary purposes that proved vital to early modern social relations, even when its coercive functions failed.
Prisons were emblematic of early modern state formation, expanding in tandem with the growing impingement of state officers and the legal system on everyday life. Chapter 1 focuses on the institutional development of prisons, the officers who ran them and their place within the officeholding state. It surveys the variety of prisons in England, the product of gradual and uneven development that gave rise to institutions that operated within a series of overlapping jurisdictions and that struggled with a rapidly expanding carceral population. This decentralised carceral infrastructure – so typical of the early modern state – also posed challenges for prison governance and regulation, opening the system to claims of corruption and profiteering. Thus, this chapter explores the place of the gaoler within the wider dynamics of early modern officeholding authority and the disciplinary maintenance of economic and social stability. It argues that as unpopular state agents, gaolers posed challenges to political legitimacy, in extreme cases generating hostility towards state and legal authority.
Agitation in England’s prisons came to a head in unison with midcentury political tensions. By 1641, prisoners for debt had begun to connect their suffering at the hands of a supposedly corrupt and unjust legal system with developing national concerns about tyranny and arbitrary rule under Charles I. Indeed, the anti-carceral sentiments explored in Chapter 5 had not died out in the 1620s, but formed a tradition of prison politics that simmered under the surface of Caroline rule and increasingly intersected with concerns about political uses of incarceration. Chapter 7 thus explores the civil war legacy of prison activism and abolitionist arguments first developed in the 1620s, following them into a wider political realm. It reconstructs a new period of turmoil within the King’s Bench between 1640 and 1649. On the eve of civil war, prisoners republished abolitionist arguments developed in the 1620s, now placing particular emphasis on legal and political oppression. This agitation also provided the basis for new collaboration between prisoners and London’s radicals, facilitating exchanges of ideas that impacted upon prison activists, radical movements and contemporary political debates alike. Thus, prisons had become crucibles of radical thought and organisation as disaffection with state and legal authority fed into political conspiracy.
Between 1560 and 1700, England became an increasingly carceral society; that is, a society in which the prison became a dominant tool of order, permeated by a disciplinary logic that began to shape social relations well beyond the prison walls. Imprisonment posed an ever greater threat to men and women across the social spectrum thanks to the quickening activity of the criminal justice system, growing political and religious conflict and a precipitous rise in civil litigation. This Introduction outlines the significance of these developments, before explaining their significance to wider historiographies of credit and debt, legal practice, state formation and political conflict in early modern England. It suggests that a focus on growing levels of debt imprisonment (which served particular class interests) helps explain how rapid socioeconomic change and social stratification forced many people into often involuntary and negative participation in state institutions and the law. In turn, this conditioned an emergent politics of prison abolition that became increasingly important to the radical politics of the English Revolution, helping to explain interactions of social change and political conflict. Finally, this Introduction outlines the source base for this study and summarises the chapters that follow.
As imprisonment proliferated in cases of debt, its prominence also grew as an instrument of political and religious discipline. Incarceration sent a clear message about the consequences of religious and political dissent. Yet conversely, it also offered new modes of publicity and organisation to opponents of ecclesiastical and civil government. Chapter 6 explores how prisons became both venues for illicit political and religious activity and emblems of absolute power. Between the early stages of the Reformation and Charles I’s Personal Rule, incarceration became a mark of honour, a source of fame and a tool of publicity, all of which took on new significance during the civil war. Notably, with the rise of imprisonment for debt in the latter half of the sixteenth century, the prison’s increased social significance leant it new rhetorical power in political contexts. As everyday anxieties about the threat of incarceration grew, the prison became an ever more poignant as a symbol of tyranny, oppression and lost liberty. Martyrologies that emphasised spiritual solitude and monasticism in prison gave way to greater emphasis on common experiences of incarceration. This chapter thus explores new rhetorical and interpersonal connections between political activism and increasingly widespread incarceration from the reformation to the civil war
By 1649, the authors of the second Digger manifesto identified the prison – alongside the scaffold and the sword – as a key facet of the state’s violent and coercive power. Although prisons were not yet the primary means of punishing crime, early modern England was witnessing new experimentations in incarceration as a form of social, economic, political and religious discipline. While the quickening activity of the criminal justice system left growing numbers of suspected felons in custody awaiting trial and houses of correction innovated new carceral responses to poverty and vagrancy, the sixteenth- and seventeenth-century debt crisis drove a precipitous growth in prison populations and widespread social concern with incarceration. Rapidly expanding credit networks, the commercialisation of the economy and growing levels of civil litigation created new extremes of downward mobility and social dislocation that led growing numbers of debtors to the prison. Unprecedented levels of incarceration underpinned fragile credit relations built upon trust and interpersonal judgement. Imprisonment for debt played a vital role in maintaining financial and social stability in a time of economic change. It regulated and publicised financial failure by generating and disseminating social knowledge about morality, trustworthiness and (dis)honesty.