Division of Infectious Diseases, Imperial College London, London, United Kingdom.
Department of Infection & Population Health, University College London, London, United Kingdom.
PLoS One. 2018 Apr 11;13(4):e0194760. doi: 10.1371/journal.pone.0194760. eCollection 2018.
The reported prevalence of cognitive impairment remains similar to that reported in the pre-antiretroviral therapy era. This may be partially artefactual due to the methods used to diagnose impairment. In this study, we evaluated the diagnostic performance of the HIV-associated neurocognitive disorder (Frascati criteria) and global deficit score (GDS) methods in comparison to a new, multivariate method of diagnosis.
Using a simulated 'normative' dataset informed by real-world cognitive data from the observational Pharmacokinetic and Clinical Observations in PeoPle Over fiftY (POPPY) cohort study, we evaluated the apparent prevalence of cognitive impairment using the Frascati and GDS definitions, as well as a novel multivariate method based on the Mahalanobis distance. We then quantified the diagnostic properties (including positive and negative predictive values and accuracy) of each method, using bootstrapping with 10,000 replicates, with a separate 'test' dataset to which a pre-defined proportion of 'impaired' individuals had been added.
The simulated normative dataset demonstrated that up to ~26% of a normative control population would be diagnosed with cognitive impairment with the Frascati criteria and ~20% with the GDS. In contrast, the multivariate Mahalanobis distance method identified impairment in ~5%. Using the test dataset, diagnostic accuracy [95% confidence intervals] and positive predictive value (PPV) was best for the multivariate method vs. Frascati and GDS (accuracy: 92.8% [90.3-95.2%] vs. 76.1% [72.1-80.0%] and 80.6% [76.6-84.5%] respectively; PPV: 61.2% [48.3-72.2%] vs. 29.4% [22.2-36.8%] and 33.9% [25.6-42.3%] respectively). Increasing the a priori false positive rate for the multivariate Mahalanobis distance method from 5% to 15% resulted in an increase in sensitivity from 77.4% (64.5-89.4%) to 92.2% (83.3-100%) at a cost of specificity from 94.5% (92.8-95.2%) to 85.0% (81.2-88.5%).
Our simulations suggest that the commonly used diagnostic criteria of HIV-associated cognitive impairment label a significant proportion of a normative reference population as cognitively impaired, which will likely lead to a substantial over-estimate of the true proportion in a study population, due to their lower than expected specificity. These findings have important implications for clinical research regarding cognitive health in people living with HIV. More accurate methods of diagnosis should be implemented, with multivariate techniques offering a promising solution.
报道的认知障碍患病率与抗逆转录病毒治疗前时代报道的患病率相似。这可能部分是由于用于诊断障碍的方法造成的人为因素。在这项研究中，我们评估了与新的多变量诊断方法相比，HIV 相关神经认知障碍（弗朗西斯科标准）和全球缺陷评分（GDS）方法的诊断性能。
使用基于真实世界认知数据的模拟“规范”数据集，该数据集来自观察性 Pharmacokinetic 和临床观察在五十岁以上人群（POPPY）队列研究，我们使用弗朗西斯科和 GDS 定义以及基于马哈拉诺比斯距离的新的多变量方法来评估认知障碍的明显患病率。然后，我们使用 bootstrap 对每个方法进行了 10,000 次重复的诊断特性（包括阳性和阴性预测值和准确性）的量化，其中使用了一个单独的“测试”数据集，其中添加了预先定义比例的“受损”个体。
模拟规范数据集表明，高达约 26%的规范对照人群将根据弗朗西斯科标准被诊断为认知障碍，而根据 GDS 标准则为 20%。相比之下，多变量马哈拉诺比斯距离方法识别出的障碍约为 5%。使用测试数据集，与弗朗西斯科和 GDS 相比，多变量方法的诊断准确性[95%置信区间]和阳性预测值（PPV）最好（准确性：92.8%[90.3-95.2%]与 76.1%[72.1-80.0%]和 80.6%[76.6-84.5%]；PPV：61.2%[48.3-72.2%]与 29.4%[22.2-36.8%]和 33.9%[25.6-42.3%]）。将多变量马哈拉诺比斯距离方法的先验假阳性率从 5%增加到 15%，会导致敏感性从 77.4%（64.5-89.4%）增加到 92.2%（83.3-100%），代价是特异性从 94.5%（92.8-95.2%）降低到 85.0%（81.2-88.5%）。
我们的模拟表明，常用的 HIV 相关认知障碍诊断标准将很大一部分规范参考人群标记为认知障碍，由于其特异性低于预期，这可能会导致研究人群中真实比例的显著高估。这些发现对 HIV 感染者认知健康的临床研究具有重要意义。应该实施更准确的诊断方法，多变量技术提供了有希望的解决方案。
