Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

Losses and External Outcomes Interact to Produce the Gambler’s Fallacy

<div><p>When making serial predictions in a binary decision task, there is a clear tendency to assume that after a series of the same external outcome (e.g., heads in a coin flip), the next outcome will be the opposing one (e.g., tails), even when the outcomes are independent of one another. This so-called “gambler’s fallacy” has been replicated robustly. However, what drives gambler’s fallacy behavior is unclear. Here we demonstrate that a run of the same external outcome by itself does not lead to gambler’s fallacy behavior. However, when a run of external outcomes is accompanied by a concurrent run of failed guesses, gambler’s fallacy behavior is predominant. These results do not depend on how participants’ attention is directed. Thus, it appears that gambler’s fallacy behavior is driven by a combination of an external series of events and a concurrent series of failure experiences.</p></div

Experiment 3: Controlled external-outcome conditions.

<p>Proportion of participants predicting a changed-dice outcome (gambler’s fallacy) on the critical trial in the controlled external-outcome conditions following a run of (A) even or (B) odd dice outcomes. Participants were tested in either the even-run or odd-run condition whereas those in experiment 1 were tested in both conditions. Participants are grouped according to whether they concurrently had a run of incorrect predictions (Dice+Incorrect), a run of correct predictions (Dice+Correct), or no runs of prediction outcomes (Dice only). Horizontal bars indicate the average baseline probability of predicting a changed-dice outcome for each group. Error bars represent ±1 standard error of the mean. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 reflect Wilcoxon signed-rank test against baseline within each group or pairwise Chi-squared comparisons across groups.</p

Experiment 1: Controlled prediction-outcome conditions.

<p>Proportion of participants predicting a changed-dice outcome (gambler’s fallacy) on the critical trial in the controlled prediction-outcome conditions following a run of (A) incorrect or (B) correct outcomes. Participants are grouped according to whether they concurrently had a run of a dice outcome (Dice+Incorrect for A or Dice+Correct for B) or not (Incorrect only for A or Correct only for B). Horizontal bars indicate the average baseline probability of predicting a changed-dice outcome for each group. Error bars represent ±1 standard error of the mean. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 reflect Wilcoxon signed-rank test against baseline within each group or pairwise Chi-squared comparisons across groups.</p

Experiment 2: Controlled prediction-outcome conditions.

<p>Proportion of participants predicting a changed-dice outcome (gambler’s fallacy) on the critical trial in the controlled prediction-outcome conditions following a run of (A) incorrect or (B) correct outcomes. Participants are grouped according to whether they concurrently had a run of a dice outcome (Dice+Incorrect for A or Dice+Correct for B) or not (Incorrect only for A or Correct only for B). Horizontal bars indicate the average baseline probability of predicting a changed-dice outcome for each group. Error bars represent ±1 standard error of the mean. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 reflect Wilcoxon signed-rank test against baseline within each group or pairwise Chi-squared comparisons across groups.</p

Example trials for each condition type.

<p>Example trials from one of the controlled external-outcome conditions (A) and one of the controlled prediction-outcome conditions (B). The top panels show the prediction screens, and the bottom panels show the outcome screens.</p

Experiment 1: Controlled external-outcome conditions.

<p>Proportion of participants predicting a changed-dice outcome (gambler’s fallacy) on the critical trial in the controlled external-outcome conditions following a run of (A) even or (B) odd dice outcomes. Participants are grouped according to whether they concurrently had a run of incorrect predictions (Dice+Incorrect), a run of correct predictions (Dice+Correct), or no runs of prediction outcomes (Dice only). Horizontal bars indicate the average baseline probability of predicting a changed-dice outcome for each group. Error bars represent ±1 standard error of the mean. * <i>p</i> < 0.05, ** <i>p</i> < 0.01, and *** <i>p</i> < 0.001 reflect Wilcoxon signed-rank test against baseline within each group or pairwise Chi-squared comparisons across groups.</p

Experiments 1–3: Summary statistics.

<p><i>z</i>-scores for binomial tests versus chance (50%) the number of participants predicting a changed dice outcome (i.e., gambler’s fallacy) versus continuation of the dice outcome on the post-run critical trial. Positive values indicate that more participants predicted a change in the dice outcome (e.g., predicting an even sum after an odd sum), while negative values indicate that more participants predicted that the previous dice outcome would continue (e.g., predicting an even sum after an even sum). Asterisks indicate significance at <i>p</i><0.001. Where asterisks do not appear, the binomial test was not significant at <i>p</i><0.05.</p