Check for "always cause death" phenotypes with low severity scores

[bschilder]

@NathanSkene mentioned that @KittyMurphy showed examples where some phenotypes were lowly ranked in terms of composite severity scores but nevertheless always caused death. Could you share these examples @KittyMurphy and let us know how many of them there are ?

[bschilder]

res_coded <- HPOExplorer::gpt_annot_codify(annot = gpt_annot)
# always=3, death=5: 3x5=15
res_coded$annot_weighted[death==15]

                                                                   hpo_name severity_score_gpt     hpo_id
                                                                      <ord>              <num>     <char>
 1:               Atrophy/Degeneration affecting the central nervous system           54.00000 HP:0007367
 2:                                                             Anencephaly           52.00000 HP:0002323
 3:                                                         Hydranencephaly           52.00000 HP:0002324
 4:                                                 Fetal akinesia sequence           50.66667 HP:0001989
 5:                                                         Arrhinencephaly           47.33333 HP:0002139
 6:                                                            Iniencephaly           47.33333 HP:0034205
 7:                                                Congenital neuroblastoma           46.00000 HP:0006742
 8:                                                   obsolete Glioblastoma           44.66667 HP:0100843
 9:                                       Lethal short-limbed short stature           42.66667 HP:0008909
10:                            Grade IV preterm intraventricular hemorrhage           41.33333 HP:0030751
11:                                        Acute necrotizing encephalopathy           39.33333 HP:0006965
12:                                                             Exencephaly           37.33333 HP:0030769
13:                                 Lethal infantile mitochondrial myopathy           37.33333 HP:0009069
14:                                                 Glioblastoma multiforme           34.66667 HP:0012174
15:                                               Lethal skeletal dysplasia           34.66667 HP:0005716
16:                                               1-minute APGAR score of 0           33.33333 HP:0030927
17:                                            Anaplastic thyroid carcinoma           32.66667 HP:0011779
18:                                        Lethal short-trunk short stature           32.66667 HP:0011404
19:                                           Amyotrophic lateral sclerosis           32.00000 HP:0007354
20:                                          Fatal liver failure in infancy           32.00000 HP:0006583
21:                                                                 Acrania           29.33333 HP:0030716
22:                            Ventilator dependence with inability to wean           29.33333 HP:0005946
23:                                                     Esophageal neoplasm           28.00000 HP:0100751
24:                                                    Esophageal carcinoma           26.66667 HP:0011459
25:                                                         Mortality/Aging           26.66667       <NA>
26:                                                T-cell lymphoma/leukemia           26.66667 HP:0005517
27:                                               Absent aortic valve cusps           26.00000 HP:0031569
28:                                                      Pulmonary necrosis           26.00000 HP:0033243
29:                                                          Cardiac arrest           25.33333 HP:0001695
30:                           Absent left sided atrioventricular connection           24.00000 HP:0011547
31:                              Congenital malformation of the right heart           24.00000 HP:0011723
32:                                                  Cardiac rhabdoid tumor           23.33333 HP:0034559
33:                                                     Respiratory failure           21.33333 HP:0002878
34:                                               Unguarded tricuspid valve           21.33333 HP:0030719
35: Univentricular heart with absent left sided atrioventricular connection           21.33333 HP:0011549
36:                                       obsolete Severe T lymphocytopenia           21.33333 HP:0005379
37:                                                    Aortic valve atresia           20.00000 HP:0010883
38:                                                 Pulmonary valve atresia           20.00000 HP:0010882
39:                                            Aborted sudden cardiac death           18.00000 HP:0031628
40:                                                 Bilateral lung agenesis           18.00000 HP:0005944
41:                                                Cardiorespiratory arrest           18.00000 HP:0006543
42:                Intrauterine fetal demise of one twin after midgestation           18.00000 HP:0030753
43:                                                       Suicide behaviors           18.00000 HP:5200330
44:                                                       Hypovolemic shock           17.33333 HP:0031274
45:                                                                   Shock           17.33333 HP:0031273
46:                                             Ascending aortic dissection           16.66667 HP:0004933
47:                                                Bilateral renal agenesis           16.00000 HP:0010958
48:                                                Zygotic cleavage failure           14.00000 HP:0033336
49:                          Abnormal preimplantation embryonic development           12.00000 HP:0033335
50:                                                        Death in infancy           12.00000       <NA>
51:                                                          Neonatal death           12.00000       <NA>
52:                                                          Prenatal death           12.00000       <NA>
53:                                                              Stillbirth           12.00000       <NA>
54:                                                      Respiratory arrest           10.66667 HP:0005943
55:                                                    Therapeutic abortion           10.66667 HP:0030449
56:                                                Ventricular fibrillation           10.66667 HP:0001663
57:                                                            Age of death           10.00000       <NA>
58:                                                    Death in adolescence           10.00000       <NA>
59:                                                      Death in adulthood           10.00000       <NA>
60:                                                      Death in childhood           10.00000       <NA>
61:                                                Death in early adulthood           10.00000       <NA>
62:                                                 Death in late adulthood           10.00000       <NA>
63:                                                     Death in middle age           10.00000       <NA>
64:                                                                Severity           10.00000       <NA>
65:                                                    Sudden cardiac death           10.00000 HP:0001645
66:                                                            Sudden death           10.00000 HP:0001699
                                                                   hpo_name severity_score_gpt     hpo_id

Many of the death phenotypes (eg 'Death in middle age') only have a composite severity score of 10 bc they're necessarily associated with any of the other severity annotations, partly bc they're so vague.

Interestingly, it rates 'Suicide behaviours' as higher on severity score because it says that this can sometimes (rarely) cause impaired mobility. I suppose that's true in cases where a suicide attempt was unsuccessful. though this highlights the trickiness of assigning "direct causality" to behavioural traits.

For comparison, I selected from other traits with a severity score of 10. This includes some mild physical malformations like syndactyly, which conceptually is definitely not as severe as death.

 Options

1. Add another tier of weights to which only 'death' metric belongs. Currently, our highest weight is 5, so death would be bumped to a weight of 6.
2. Keep as-is and note the limitation in the paper. This avoids us fiddling with the severity score to account for edge scenarios like this. We could note that phenotypes that directly describe death are obvious enough that people using our ranking system would understand these are severe (despite their low rank).

[bschilder]

Looks like Lazarin 2014 suffered from some of these same issues: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114391

We made two noteworthy observations during this exercise. Alpha-thalassemia, specifically Hb Barts disease, invariably causes fetal or neonatal death. While this would be presumed to be a Profound condition, it does not meet the criteria above due to lack of observable intellectual disability. This may suggest the Profound category criteria to be too strict. Likewise, familial dysautonomia carries a non-negligible risk of intellectual disability. But because a minimal 25% risk is proposed for any characteristic, the disease is also categorized as Severe, rather than Profound.

[bschilder]

 Options

1. Add another tier of weights to which only 'death' metric belongs. Currently, our highest weight is 5, so death would be bumped to a weight of 6.
2. Keep as-is and note the limitation in the paper. This avoids us fiddling with the severity score to account for edge scenarios like this. We could note that phenotypes that directly describe death are obvious enough that people using our ranking system would understand these are severe (despite their low rank).

Decided to go with option 1 (bumping death up to 6). This, in combination with using Profound/Severe/Moderate/Mild categories, should allow us to capture the importance of death in the rankings and categories.