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Editorial: Transdiagnostic research: transitory or transformative?
Journal of Child Psychology and Psychiatry ( IF 6.5 ) Pub Date : 2022-06-05 , DOI: 10.1111/jcpp.13644
Angelica Ronald 1
Affiliation  

Transdiagnostic is arguably one of the most ‘in vogue’ terms at the moment in child and adolescent psychiatry. A search for the word ‘transdiagnostic’ in PubMed shows an exponential increase over the last decade in medical research, with 2021 showing the highest ever use of this word. Within child and adolescent psychiatry, there are many reasons this word might be used. Conditions within child and adolescent psychiatry exist within a multi-dimensional space: they show high co-occurrence with each other; they share underlying brain and neurocognitive constructs, they share epidemiological risk factors, they share outcome pathways and they share treatments. In this editorial, I discuss transdiagnostic research, drawing on four impactful articles from the present issue of the Journal of Child Psychology and Psychiatry, and consider whether transdiagnostic research is likely, longer term, to be transitory or transformative.

What does transdiagnostic mean? A loosely constructed brief definition at this point in time might be: something that applies across specific diagnoses and unifies them. For longer discussions of transdiagnostic approaches to neurodevelopment and mental health, I refer the reader elsewhere (Astle, Holmes, Kievit, & Gathercole, 2022; Dalgleish, Black, Johnston, & Bevan, 2020; Sonuga-Barke, 2020). A search for the word ‘transdiagnostic’ in PubMed shows an exponential increase over the last decade, with 868 uses in titles or abstracts in 2021, the highest rate to date. In this brief editorial, I will discuss transdiagnostic research through drawing on four impactful articles from the present issue of the Journal of Child Psychology and Psychiatry.

I start with two papers investigating polygenic scores in community samples. Askeland et al. (2022) investigated which neurodevelopmental traits were associated with polygenic scores for autism, ADHD and schizophrenia. They worked with the Norwegian Mother, Father and Child Cohort Study (MoBa) on mother-rated scales of children's development from age 6 months to age 8 years. The rich cross-domain and cross-age trait data allowed multiple hypotheses to be tested within a single study. They found that the ADHD polygenic score was significantly associated with both inattention and hyperactivity traits from age 18 months up to age 8 years as well as with language difficulties at age 5 and 8 years. The autism polygenic score was associated with language difficulties at 18 months (though not at the later ages) and with motor difficulties at 3 years (but not at 6 or 18 months or 5 years). The autism polygenic score was associated with hyperactivity and inattention at age 8 years, in line with a large literature on genetic associations between autism and ADHD traits e.g., (Grove et al., 2019; Ronald, Simonoff, Kuntsi, Asherson, & Plomin, 2008). It did not associate with repetitive behaviours or social communication at any ages. The schizophrenia polygenic score did not associate significantly with any of the traits.

By publishing all these analyses together, Askeland et al.'s paper encourages the reader to think transdiagnostically and to consider neurodevelopment broadly. This is closer to how child development actually operates (i.e. in a multi-domain and longitudinal space). If Askeland had split up their analyses and published their ADHD, ASD and schizophrenia polygenic score analyses separately, or published the results for each type of outcome separately (ADHD traits, autistic traits, motor development and so on), arguably these would have been less rich and less innovative papers.

To tackle multiple testing, Askeland et al. determined the number of effective tests by running a principal component analysis on their 25 neurodevelopmental outcome measures. The number of tests was decided based on the number of principal components that explained 80% of the variance. This number of tests was then applied in Bonferroni correction. In addition, they consider the effect sizes of results, regardless of significance. Overall, this seems a thoughtful and measured approach to correction for multiple testing.

A potential pitfall of some transdiagnostic research that aims to tackle multiple conditions or traits simultaneously might be a potential increase either in false positives or false negatives. Askeland et al.'s approach of including all the analyses together may have led to false negatives if an over-stringent correction had been applied. On the other hand, without sufficient correction, their present study, with so many tests run simultaneously, could have led to false positives even if objective effect sizes were small.

Next, I turn to Gidziela et al.'s (2022) study, which aimed to study how associations between behaviour problems and polygenic scores for neurodevelopmental and psychiatric conditions can be improved (i.e. increased in effect size). In a longitudinal genotyped cohort, the Twins Early Development Study, unrelated children were assessed on behaviour problems from age 2 to age 21. The outcome measures included total behaviour problems as well as internalising and externalising scores, all constructed from confirmatory factor analysis and studied separately for childhood (ages 2–9 years), adolescence (ages 12–16 years) and adulthood (age 21). The authors showed that associations with polygenic scores were stronger when ratings on behaviour problems from different raters were combined as well as when data across ages were combined.

Importantly, and relevant to this editorial's theme on transdiagnostic research, Gidziela et al. found that models that included multiple polygenic scores together explained more variance in behaviour problems than individual polygenic scores for single conditions. By harnessing polygenic effects across conditions, this work gives us an improved sense of the overall scope of these gene–behaviour relationships in childhood.

The breadth of transdiagnostic research, such as the two studies mentioned above, can be awe-inspiring. A second potential pitfall of transdiagnostic research is delineating where exactly does the research start and end. Pre-registration helps with this, because the ambitions and end point of analyses is defined prior to data analysis. The Gidziela et al. paper pre-registered their hypotheses and analyses in Open Science Framework prior to accessing the data. This gives reviewers, editors and readers evidence of a time-stamped plan of analysis prior to data access.

Transdiagnostic research has also reached neuroscience, as demonstrated in the final two papers I focus on from this journal issue. Mewton et al. (2022) reported on the relationship between general and specific psychopathology in preadolescents (9–10-year-olds) and brain structure measured using MRI in a community cohort study, the Adolescent Brain and Cognitive Development study. Their variables for general psychopathology as well as externalising, internalising and thought disorder ‘lower order’ dimensions were derived from a higher-order model of psychopathology using confirmatory factor analysis (for a discussion of the p-factor model of psychopathology, see elsewhere (Caspi & Moffitt, 2018; Ronald, 2019).

Mewton et al. reported that lower global surface area and lower global cortical volume, though not cortical thickness, were both associated with general psychopathology. The externalising, internalising and thought disorder ‘lower order’ dimensions showed similar patterns of results as for general psychopathology. Furthermore, in regional analyses, the authors did not tend to find many specific associations between brain regions and lower order dimensions: most associations with cortical volume or surface area were present across multiple lower order dimensions or with the general psychopathology measure. The authors concluded that these brain structural associations were ‘transdiagnostic markers’ of general psychopathology because of the lack of specific associations with lower order psychopathology dimensions.

Indeed, claims of transdiagnostic relevance only stand up to scrutiny if researchers have ruled out that any findings are driven by associations with a single diagnosis or trait dimension. This was a strength of how the Mewton et al. study was conducted as well as the next paper I turn to, also within neuroscience, by Cañigueral et al. (2022). Cañigueral et al. also had a robust design to tackle specific versus transdiagnostic effects.

In Cañigueral et al.'s EEG study of attention in neurodevelopmental conditions, rather than ignoring the high co-occurrence of autism spectrum disorder (ASD) and ADHD, they make it central to their study design. ASD and ADHD both involve challenges with attention. Cañigueral et al. investigate whether ASD, when co-occurring with ADHD, involves an additive profile of atypical attention differences or if having both conditions leads to a distinct profile of attention, separate from either ADHD or ASD occurring alone.

Their results showed that children with ASD (either alone or with ADHD) showed greater post-stimulus N2 amplitude which was thought to reflect greater effortful attentional control. In contrast, children with ADHD (either alone or with ASD) showed reduced N2 and P3 amplitude; ADHD appeared to involve atypical integration of bottom up and top down attention, atypical attention allocation and attentional control. Cañigueral et al. conclude that children with a dual diagnosis show an additive profile of attentional signatures from both conditions.

In conclusion, given the high co-occurrence of conditions and their many shared facets, transdiagnostic research acts like glue that brings our field together. Does child and adolescent psychiatry need to shift itself towards conducting more transdiagnostic alongside condition-specific research?

Does child and adolescent psychiatry need to shift itself towards conducting more transdiagnostic alongside condition-specific research?

In this editorial, I've aimed to highlight some strengths in the approaches taken by the authors of the papers discussed here. Poorly planned and poorly conducted transdiagnostic research could easily lack direction, impact, hypothetical or theoretical grounding and be riddled with false positive (or false negative) results. Transdiagnostic research may end up transitory if it is poorly conducted, or if it is rebelled against because it is misunderstood as attempting to replace condition-specific research rather than complement it.

Despite the clear novelty and value of the above findings, one could argue that these four sets of authors sacrificed the potential impact of their work by making it transdiagnostic. I say this because transdiagnostic research can fall in the gaps of how child and adolescent psychiatric research is currently organised, funded and communicated. Transdiagnostic research is a harder ‘sell’ at disorder-specific conferences, it may be missed and thus less likely to be cited by disorder-specific researchers or to impact policy documents for example, (Policy paper: The national strategy for autistic children, young people and adults: 2021 to 2026, 2021), it may not be read by clinicians with disorder expertise and, importantly for the authors' future funding success, it may be disregarded by disorder-specific funders.

Transdiagnostic research is transformative in the sense that it helps to reveal a part of the truth underlying child and adolescent psychiatry that single condition research misses and for that reason it is essential to our field. If the usage of ‘transdiagnostic’ in PubMed continues in its upward trajectory, transdiagnostic research is here to stay. It is time for our field to allow this type of work to share the stage with disorder-specific endeavours.



中文翻译:

社论:跨诊断研究:暂时的还是变革的?

跨诊断可以说是目前儿童和青少年精神病学中最“流行”的术语之一。在PubMed中搜索“transdiagnostic”这个词显示,在过去十年中,医学研究呈指数级增长,2021 年出现了该词的最高使用率。在儿童和青少年精神病学中,使用这个词的原因有很多。儿童和青少年精神病学中的病症存在于多维空间中:它们彼此高度共现;他们共享潜在的大脑和神经认知结构,共享流行病学风险因素,共享结果途径,共享治疗方法。在这篇社论中,我讨论了跨诊断研究,并借鉴了本期杂志中的四篇有影响力的文章。Journal of Child Psychology and Psychiatry,并考虑跨诊断研究是否可能,从长远来看,是暂时的或变革性的。

跨诊断是什么意思?在这个时间点,一个结构松散的简短定义可能是:适用于特定诊断并将它们统一起来的东西。对于神经发育和心理健康的跨诊断方法的更长时间讨论,我会在其他地方推荐读者(Astle、Holmes、Kievit 和 Gathercole,  2022 年;Dalgleish、Black、Johnston 和 Bevan,  2020 年;Sonuga-Barke,  2020 年)。在PubMed中搜索“transdiagnostic”一词显示在过去十年中呈指数增长,到 2021 年标题或摘要中有 868 次使用,这是迄今为止的最高比率。在这篇简短的社论中,我将通过借鉴本期杂志中的四篇有影响力的文章来讨论跨诊断研究。儿童心理学和精神病学杂志

我从两篇研究社区样本中多基因分数的论文开始。阿斯克兰等人。( 2022) 研究了哪些神经发育特征与自闭症、多动症和精神分裂症的多基因评分相关。他们与挪威母亲、父亲和儿童队列研究 (MoBa) 合作,研究母亲评定的 6 个月至 8 岁儿童发育量表。丰富的跨领域和跨年龄特征数据允许在单个研究中测试多个假设。他们发现,ADHD 多基因评分与 18 个月至 8 岁的注意力不集中和多动特征以及 5 岁和 8 岁的语言困难显着相关。自闭症多基因评分与 18 个月时的语言困难(尽管不是在较晚的年龄)和 3 岁时的运动困难相关(但不是在 6 个月或 18 个月或 5 岁)。 2019 年;Ronald、Simonoff、Kuntsi、Asherson 和 Plomin,  2008 年)。它与任何年龄段的重复行为或社交交流无关。精神分裂症多基因评分与任何特征均无显着关联。

通过将所有这些分析一起发表,Askeland 等人的论文鼓励读者进行跨诊断思考并广泛考虑神经发育。这更接近于儿童发展的实际运作方式(即在多领域和纵向空间中)。如果 Askeland 将他们的分析分开并分别发布他们的 ADHD、ASD 和精神分裂症多基因评分分析,或者分别发布每种结果的结果(ADHD 特征、自闭症特征、运动发育等),可以说这些结果会更少丰富而缺乏创新的论文。

为了解决多重测试,Askeland 等人。通过对他们的 25 个神经发育结果测量进行主成分分析来确定有效测试的数量。测试的数量是根据解释 80% 方差的主成分的数量来决定的。然后将这个数量的测试应用于 Bonferroni 校正。此外,他们考虑结果的影响大小,而不考虑显着性。总体而言,这似乎是一种经过深思熟虑和衡量的方法来校正多重测试。

一些旨在同时解决多种疾病或特征的跨诊断研究的潜在缺陷可能是假阳性或假阴性的潜在增加。如果应用了过度严格的校正,Askeland 等人将所有分析包含在一起的方法可能会导致假阴性。另一方面,如果没有足够的校正,他们目前的研究,同时进行了如此多的测试,即使客观效应量很小,也可能导致误报。

接下来,我转向 Gidziela 等人的 ( 2022) 研究,旨在研究如何改善行为问题与神经发育和精神疾病的多基因评分之间的关​​联(即增加效应量)。在纵向基因分型队列双胞胎早期发展研究中,对无关儿童从 2 岁到 21 岁的行为问题进行了评估。结果测量包括总体行为问题以及内化和外化分数,所有这些均由验证性因素分析构建并单独研究适用于儿童期(2-9 岁)、青春期(12-16 岁)和成年期(21 岁)。作者表明,当不同评分者对行为问题的评分相结合以及跨年龄的数据相结合时,与多基因评分的关联更强。

重要的是,与这篇社论关于跨诊断研究的主题相关,Gidziela 等人。发现包含多个多基因评分的模型比单个条件下的单个多基因评分解释了更多的行为问题差异。通过利用跨条件的多基因效应,这项工作让我们更好地了解儿童时期这些基因-行为关系的整体范围。

跨诊断研究的广度,例如上面提到的两项研究,可能令人敬畏。跨诊断研究的第二个潜在陷阱是描绘研究的确切起点和终点。预注册对此有帮助,因为分析的目标和终点是在数据分析之前定义的。Gidziela 等人。论文在访问数据之前在开放科学框架中预先注册了他们的假设和分析。这为审稿人、编辑和读者提供了在数据访问之前有时间戳的分析计划的证据。

跨诊断研究也涉及神经科学,正如我在本期期刊中关注的最后两篇论文中所展示的那样。梅顿等人。(2022 年)在一项社区队列研究、青少年大脑和认知发展研究中报告了青春期前(9-10 岁)的一般和特定精神病理学与使用 MRI 测量的大脑结构之间的关系。他们的一般精神病理学以及外化、内化和思维障碍“低阶”维度的变量来自使用验证性因子分析的高阶精神病理学模型(关于精神病理学的 p 因子模型的讨论,请参见其他地方(Caspi & 莫菲特,  2018 年;罗纳德,  2019 年)。

梅顿等人。据报道,较低的整体表面积和较低的整体皮质体积,虽然不是皮质厚度,但都与一般精神病理学有关。外化、内化和思维障碍“低阶”维度显示出与一般精神病理学相似的结果模式。此外,在区域分析中,作者并没有发现大脑区域和低阶维度之间的许多特定关联:大多数与皮质体积或表面积的关联存在于多个低阶维度或一般精神病理学测量中。作者得出结论,这些大脑结构关联是一般精神病理学的“跨诊断标记”,因为缺乏与低阶精神病理学维度的特定关联。

事实上,只有在研究人员排除任何发现是由与单一诊断或特征维度的关联驱动的情况下,跨诊断相关性的说法才经得起审查。这是 Mewton 等人的优势。Cañigueral 等人的研究和我转向的下一篇论文一样,也在神经科学领域进行。(2022 年)。Cañigueral 等人。还具有强大的设计来解决特定与跨诊断效应。

在 Cañigueral 等人对神经发育条件下注意力的脑电图研究中,他们并没有忽视自闭症谱系障碍 (ASD) 和 ADHD 的高度共存,而是将其作为研究设计的核心。ASD 和 ADHD 都涉及注意力的挑战。Cañigueral 等人。调查 ASD 是否与 ADHD 共同发生时,是否涉及非典型注意力差异的附加特征,或者是否同时具有这两种情况会导致不同的注意力特征,与单独发生的 ADHD 或 ASD 分开。

他们的结果表明,患有 ASD 的儿童(单独或患有 ADHD)表现出更大的刺激后 N2 振幅,这被认为反映了更努力的注意力控制。相比之下,患有 ADHD(单独或患有 ASD)的儿童的 N2 和 P3 振幅降低;ADHD 似乎涉及自下而上和自上而下注意力、非典型注意力分配和注意力控制的非典型整合。Cañigueral 等人。得出的结论是,具有双重诊断的儿童显示出两种情况下的注意力特征的附加特征。

总之,鉴于条件的高度共现及其许多共同方面,跨诊断研究就像胶水将我们的领域结合在一起。儿童和青少年精神病学是否需要将自身转向进行更多的跨诊断以及针对具体情况的研究?

儿童和青少年精神病学是否需要将自身转向进行更多的跨诊断以及针对具体情况的研究?

在这篇社论中,我旨在强调本文讨论的论文作者所采取的方法的一些优势。计划不周和执行不力的跨诊断研究很容易缺乏方向、影响、假设或理论基础,并充斥着假阳性(或假阴性)结果。如果跨诊断研究执行不当,或者因为被误解为试图取代特定条件的研究而不是对其进行补充而遭到反对,则它可能最终会变得短暂。

尽管上述发现具有明显的新颖性和价值,但人们可能会争辩说,这四组作者通过使其具有跨诊断性而牺牲了他们工作的潜在影响。我这样说是因为跨诊断研究可能会陷入儿童和青少年精神病学研究目前如何组织、资助和交流的空白。跨诊断研究在特定疾病会议上更难“推销”,它可能会被遗漏,因此不太可能被特定疾病研究人员引用或影响政策文件,例如,(政策文件:自闭症儿童的国家战略,年轻人和成人:2021 年至 2026年,  2021 年),具有疾病专业知识的临床医生可能不会阅读它,而且对于作者未来的资助成功而言,重要的是,它可能会被特定疾病的资助者忽视。

跨诊断研究具有变革性,因为它有助于揭示儿童和青少年精神病学中单一条件研究遗漏的部分真相,因此它对我们的领域至关重要。如果PubMed中“跨诊断”的使用继续呈上升趋势,那么跨诊断研究将继续存在。是时候让我们的领域允许这类工作与针对特定疾病的努力共享舞台了。

更新日期:2022-06-07
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