Natural Product: NPC321400

Natural Product IDNPC321400
Common Name
?
The InCHIKey will be temporarily assigned as the "Common Name" if no IUPAC name or alternative short name is available.
 Dioxane
IUPAC Name 1,4-dioxane
Synonyms 1,4-Dioxane
Synthetic Gene Cluster n.a.
ChEMBL Identifier CHEMBL453716
PubChem CID 31275
Chemical Classification
  • CHEMONTID:0000000 [Organic compounds]
    • [CHEMONTID:0000002] Organoheterocyclic compounds
      • [CHEMONTID:0000368] Dioxanes
        • [CHEMONTID:0001313] 1,4-dioxanes

The Chemical Classification was calculated by Classyfire, a software for chemical taxonomy calculation. Reference: DOI:10.1186/s13321-016-0174-y.

  Chemical Representations

Standard InCHIKey RYHBNJHYFVUHQT-UHFFFAOYSA-N
Standard InCHI InChI=1S/C4H8O2/c1-2-6-4-3-5-1/h1-4H2
SMILES O1CCOCC1

  Calculated Properties

Physi-Chem Properties

Molecular Weight:   88.05 Volume:   86.764
?
Van der Waals volume.
Dense:   1.015 LogP:   -0.081
?
The logarithm of the n-octanol/water distribution coefficients.
logD7.4:   -0.294
?
The logarithm of the n-octanol/water distribution coefficient at pH=7.4.
 LogS:   0.949
?
The logarithm of aqueous solubility value.
Rotatable Bonds:   0.0 Rigid Bonds:   6.0
TPSA:   18.46
?
Topological Polar Surface Area.
 H-Bond Acceptor:   2.0
H-Bond Donor:   0.0 Rings:   1.0
Heavy Atoms:   2.0

MedChem Properties

QED Drug-Likeness Score:   0.416 GASA:   0.0
?
GASA represents the probability of being difficult to synthesize, ranging from 0 to 1.
Synthetic Accessibility Score:   2.231 Fsp3:   1.0
MCE-18:   6.0
?
MCE-18 stands for medicinal chemistry evolution.MCE-18≥45 is considered a suitable value.
 Lipinski Rule-of-5:   Rejected
Pfizer Rule:   Rejected GSK Rule:   Rejected
Golden Triangle Rule:   Accepted BMS Rule:   0
Chelating Alert:   0 PAINS Alert:   0
Colloidal aggregators:   0.001 Fluc inhibitor:   0.0
?
The fluc inhibitor value is the probability of being fLuc inhibitors, within the range of 0 to 1.
Blue fluorescence:   0.01
?
The blue fluorescence value is the probability of being blue fluorescence, within the range of 0 to 1
 Green fluorescence:   0.0
?
The green fluorescence value is the probability of being green fluorescence, within the range of 0 to 1
Reactive compounds:   0.999 Promiscuous compounds:   0.667

ADMET Properties (ADMETlab3.0)

ADMET: Absorption

Caco-2 Permeability:   -4.314 MDCK Permeability:   -4.602
Pgp-inhibitor:   0.239 Pgp-substrate:   0.152
PAMPA:   0.535
?
The experimental data for Peff was logarithmically transformed (logPeff). Molecules with log Peff values below 2.0 were classified as low-permeability (Category 0), while those with log Peff values exceeding 2.5 were classified as high-permeability (Category 1).
 Human Intestinal Absorption (HIA):   0.051
20% Bioavailability (F20%):   0.132 30% Bioavailability (F30%):   0.025
50% Bioavailability (F50%):   0.092

ADMET: Distribution

Blood-Brain-Barrier Penetration (BBB):   0.613 MRP1:   0.767
Plasma Protein Binding (PPB):   1.689% Volume Distribution (VD):   -0.077
Fu: 100.293%
?
The fraction unbound in plasms.
 OATP1B1 inhibitor:   0.36
OATP1B3 inhibitor:   0.634 BCRP inhibitor:   0.024
BSEP inhibitor:   0.601

ADMET: Metabolism

CYP1A2-inhibitor:   0.05 CYP1A2-substrate:   0.016
CYP2C19-inhibitor:   0.101 CYP2C19-substrate:   0.015
CYP2C9-inhibitor:   0.234 CYP2C9-substrate:   0.039
CYP2D6-inhibitor:   0.224 CYP2D6-substrate:   0.027
CYP3A4-inhibitor:   0.133 CYP3A4-substrate:   0.045
CYP2B6-substrate:   0.107 CYP2C8-inhibitor:   0.043
HLM stability:   0.055
?
Human liver microsomal (HLM) stability. Category 0: stable+ (HLM > 30 min); Category 1: unstable- (HLM ≤ 30 min). The output value is the probability of human liver microsomal instability, where a value closer to 1 indicates a higher likelihood of instability.

ADMET: Excretion

Clearance (CL):  7.143 Half-life (T1/2):  1.151

ADMET: Toxicity

hERG Blockers:  0.524 hERG Blockers (10um):  0.425
Human Hepatotoxicity (H-HT):  0.062 Drug-induced Liver Injury (DILI):  0.021
AMES Toxicity:  0.142 Rat Oral Acute Toxicity:  0.297
Maximum Recommended Daily Dose:  0.019 Skin Sensitization:  0.531
Carcinogencity:  0.391 Eye Corrosion:  0.999
Eye Irritation:  0.999 Respiratory Toxicity:  0.339
Drug-induced Neurotoxicity:  0.117 Ototoxicity:  0.078
Hematotoxicity:  0.009 Drug-induced Nephrotoxicity:  0.542
Genotoxicity:  0.0 RPMI-8226 Immunitoxicity:  0.018
A549 Cytotoxicity:  0.006 Hek293 Cytotoxicity:  0.016
BCF:   -0.375
?
Bioconcentration factors are used for considering secondary poisoning potential and assessing risks to human health via the food chain. The unit is -log10[(mg/L)/(1000*MW)].
 IGC50:   1.216
?
48 hour Tetrahymena pyriformis IGC50. The unit of IGC50 is -log10[(mg/L)/(1000*MW)].
LC50DM:   2.015
?
48 hour Daphnia magna LC50. The unit of LC50DM is -log10[(mg/L)/(1000*MW)].
 LC50FM:   1.232
?
96 hour fathead minnow LC50. The unit of LC50FM is -log10[(mg/L)/(1000*MW)].

  Species Source

Organism ID Organism Name Taxonomy Level Family SuperKingdom Isolation Part Collection Location Collection Time Reference
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. Nigeria(latitude 80°N and longitude 4°E) 2005; 2006 DOI[10.1002/ejlt.201000080]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1007/s11240-015-0761-z]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1007/s11306-010-0259-y]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1007/s11306-014-0638-x]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1007/s11746-997-0093-1]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1007/s12010-013-0354-4]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1016/j.jarmap.2018.11.004]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1016/j.phytol.2008.07.007]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Seeds Plovdiv, Plovdiv region in South Bulgaria DOI[10.1051/CTV/20163101031]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1055/S-2006-958077]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1186/s40064-015-0831-z]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. DOI[10.1501/Tarimbil_0000001065]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[11170689]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. leaf n.a. PMID[11312782]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. fruit n.a. PMID[11312782]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[11408943]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. fruit n.a. PMID[12105962]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. Esuela Tecnica Superior de Ingenieros Agrónomos de Albacete 2007 PMID[19256538]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[20826702]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[22537213]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[23759170]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Stalks n.a. n.a. PMID[24521157]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Seeds Benedictine Pannonhalma Archabbey, Hungary PMID[29803478]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[31433178]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[37446586]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. PMID[37570937]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[COCONUT]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Plant n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Fruits n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Stem n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Seed n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Leaf Essent. Oil n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Leaf n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota Fruit n.a. n.a. Database[FooDB]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[HerDing]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[MetaboLights]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[TCMID]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[TCM_Taiwan]
NPO17024 Vitis vinifera Species Vitaceae Eukaryota n.a. n.a. n.a. Database[UNPD]

Note for Reference:
In addition to directly collecting NP source organism data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated them from below databases:
☉ UNPD: Universal Natural Products Database [PMID: 23638153].
☉ StreptomeDB: a database of streptomycetes natural products [PMID: 33051671].
☉ TM-MC: a database of medicinal materials and chemical compounds in Northeast Asian traditional medicine [PMID: 26156871].
☉ TCM@Taiwan: a Traditional Chinese Medicine database [PMID: 21253603].
☉ TCMID: a Traditional Chinese Medicine database [PMID: 29106634].
☉ TCMSP: The traditional Chinese medicine systems pharmacology database and analysis platform [PMID: 24735618].
☉ HerDing: a herb recommendation system to treat diseases using genes and chemicals [PMID: 26980517].
☉ MetaboLights: a metabolomics database [PMID: 27010336].
☉ FooDB: a database of constituents, chemistry and biology of food species [www.foodb.ca].



  NP Quantity Composition/Concentration

Organism ID Organism Name Organism Material Preparation Organism Part NP Quantity (Standard) NP Quantity (Minimum) NP Quantity (Maximum) Quantity Unit Reference

Note for Reference:
In addition to directly collecting NP quantitative data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated NP quantitative records for specific NP domains (e.g., NPS from foods or herbs) from domain-specific databases. These databases include:
☉ DUKE: Dr. Duke's Phytochemical and Ethnobotanical Databases.
☉ PHENOL EXPLORER: is the first comprehensive database on polyphenol content in foods [PMID: 24103452], its homepage can be accessed at here.
☉ FooDB: a database of constituents, chemistry and biology of food species [www.foodb.ca].



 Biological Activity

Molecular-level activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference

In vitro activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT2 Others Unspecified n.a. Potency n.a. 8846.1 nM PubChem BioAssay data set

In vivo activity

Target ID Target Type Target Name Target Organism Activity Type Activity Relation Value Unit Reference
NPT32 Organism Mus musculus Mus musculus pTD50 = 1.883 n.a. PMID[19272677]





 Experimental ADME

Experiment Model Experiment Tissue ADME Type ADME Relation ADME Value ADME Unit Reference





 Experimental Toxicity

Quantitative toxicity

Experiment Model Experiment Organism Toxicity Type Toxicity Relation Toxicity Value Toxicity Unit Reference
- Rattus norvegicus LOEL = 223.0 mg/kg-day ToxVal
- Rattus norvegicus LOAEL = 1115.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 223.0 mg/kg-day ToxVal
- Rattus norvegicus LOEL = 148.0 mg/kg-day ToxVal
- Rattus norvegicus LOEL = 9.6 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 19.0 mg/kg-day ToxVal
- Rattus norvegicus LOEL = 243.2 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 97.28 mg/kg-day ToxVal
- Rattus norvegicus LOEL = 350.0 mg/kg-day ToxVal
- Rattus norvegicus LOAEL <= 350.0 mg/kg-day ToxVal
- Rattus norvegicus LOAEL <= 240.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEC > 400.0 mg/m3 ToxVal
- Rattus norvegicus LOEC = 4504.42 mg/m3 ToxVal
- Rattus norvegicus LOAEC = 180.177 mg/m3 ToxVal
- Rattus norvegicus LOEC ~ 360.0 mg/m3 ToxVal
- Rattus norvegicus LOAEC = 360.354 mg/m3 ToxVal
- Rattus norvegicus NOAEL = 517.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 16.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 9.6 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 148.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 94.0 mg/kg-day ToxVal
- Rattus norvegicus LD50 ~ 5150.0 mg/kg ToxVal
- Rattus norvegicus LC0 ~ 155000.0 mg/m3 ToxVal
- Rattus norvegicus LOAEL = 240.0 mg/kg-day ToxVal
- Rattus norvegicus LEL = 240.0 mg/kg-day ToxVal
- Rattus norvegicus LEL = 350.0 mg/kg-day ToxVal
- Rattus norvegicus LD50 = 4200.0 mg/kg ToxVal
- Rattus norvegicus LOAEL (ADJ) = 32.0715 mg/m3 ToxVal
- Rattus norvegicus LOAEL = 180.177 mg/m3 ToxVal
- Rattus norvegicus LOAEL (HEC) = 32.2 mg/m3 ToxVal
- Rattus norvegicus LOEL = 1000.0 mg/kg-day ToxVal
- Rattus norvegicus NOEL = 2000.0 mg/kg-day ToxVal
- Rattus norvegicus LOAEL = 1.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 0.5 mg/kg-day ToxVal
- Rattus norvegicus LC50 = 23.0 mg/L ToxVal
- Rattus norvegicus NOAEL = 52.0 mg/kg-day ToxVal
- Rattus norvegicus NOAEL = 516.0 mg/kg-day ToxVal
- Rattus norvegicus LOAEL (HEC) = 32.1745 mg/m3 ToxVal
- Rattus norvegicus BMCL (10) = 100.863 mg/m3 ToxVal
- Rattus norvegicus BMCL (10 HEC) = 18.0105 mg/m3 ToxVal
- Mus musculus LD50 = 2.047378393 mg/kg TOXRIC
- Mus musculus NOAEL = 424.0 mg/kg-day ToxVal
- Mus musculus NOAEL = 169.6 mg/kg-day ToxVal
- Mus musculus LOAEL <= 380.0 mg/kg-day ToxVal
- Mus musculus NOAEL = 126.0 mg/kg-day ToxVal
- Mus musculus LOAEL = 504.0 mg/kg-day ToxVal
- Mus musculus LOAEL = 126.0 mg/kg-day ToxVal
- Mus musculus LEL = 720.0 mg/kg-day ToxVal
- Mus musculus LEL = 380.0 mg/kg-day ToxVal
- Mus musculus LD50 = 5300.0 mg/kg ToxVal
- Mus musculus LC50 = 18.5 mg/L ToxVal
- Oryctolagus cuniculus LD50 = 7562.0 mg/kg ToxVal
- Oryctolagus cuniculus LD50 = 2000.0 mg/kg ToxVal
- Homo sapiens RfC = 0.72 mg/m3 ToxVal
- Homo sapiens RfD = 0.5 mg/kg-day ToxVal
- Homo sapiens RfC = 0.03 mg/m3 ToxVal
- Homo sapiens RfD = 0.03 mg/kg-day ToxVal
- Homo sapiens cancer unit risk = 0.005 (mg/m3)-1 ToxVal
- Homo sapiens cancer slope factor = 0.1 (mg/kg-day)-1 ToxVal
- Homo sapiens Medium-Specific Concentration = 0.27 mg/L ToxVal
- Homo sapiens Medium-Specific Concentration = 0.065 mg/L ToxVal
- Homo sapiens Medium-Specific Concentration = 2.7 mg/L ToxVal
- Homo sapiens Medium-Specific Concentration = 0.65 mg/L ToxVal
- Homo sapiens Medium-Specific Concentration = 0.027 mg/L ToxVal
- Homo sapiens Medium-Specific Concentration = 0.0065 mg/L ToxVal
- Homo sapiens LEL = 72070.7 mg/m3 ToxVal
- Homo sapiens PAC-3 = 2738.69 mg/m3 ToxVal
- Homo sapiens PAC-2 = 1153.13 mg/m3 ToxVal
- Homo sapiens PAC-1 = 61.2601 mg/m3 ToxVal
- Homo sapiens MEG = 8.4 mg/L ToxVal
- Homo sapiens MEG = 106000.0 mg/kg ToxVal
- Homo sapiens MEG = 2.47 mg/m3 ToxVal
- Homo sapiens MEG = 4.94 mg/m3 ToxVal
- Homo sapiens MEG = 61.3 mg/m3 ToxVal
- Homo sapiens MEG = 1150.0 mg/m3 ToxVal
- Homo sapiens MEG = 2740.0 mg/m3 ToxVal
- Homo sapiens drinking water quality guideline = 0.001 mg/L ToxVal
- Homo sapiens Reference Exposure Level = 3.0 mg/m3 ToxVal
- Homo sapiens cancer slope factor = 0.027 (mg/kg-day)-1 ToxVal
- Homo sapiens cancer unit risk = 0.0077 (mg/m3)-1 ToxVal
- Homo sapiens NOAEL = 72.0707 mg/m3 ToxVal
- Homo sapiens MRL = 0.1 mg/kg-day ToxVal
- Homo sapiens MRL = 0.5 mg/kg-day ToxVal
- Homo sapiens MRL = 5.0 mg/kg-day ToxVal
- Homo sapiens MRL = 0.108106 mg/m3 ToxVal
- Homo sapiens MRL = 0.720707 mg/m3 ToxVal
- Homo sapiens MRL = 7.20707 mg/m3 ToxVal
- Homo sapiens cancer slope factor = 0.011 (mg/kg-day)-1 ToxVal
- Homo sapiens cancer slope factor = 0.0138 (mg/kg-day)-1 ToxVal
- Homo sapiens cancer unit risk = 0.00031 (mg/L)-1 ToxVal
- Cavia porcellus LD50 = 3150.0 mg/kg ToxVal

Common Abbreviations:
LC: Lethal Concentration; LD: Lethal Dose; LT:Lethal Time; NOAEL: No-observed-adverse-effect Level; BMDL: Benchmark Dose Lower Confidence Limit; BMD: Benchmark Dose; BMC:Benchmark Concentration; LOAEL: Lowest Observed Adverse Effect Level; RfD:Reference Dose; RfC:Reference Concentration; MRL: Minimal Risk Level; MEG: Maximum Exposure Guideline; PAC: Protective Action Criteria

Categorical toxicity labels

Hepatotoxicity Carcinogenicity Mutagenicity Cardiotoxicity Respiratory Toxicity Eye Irritation Endocrine Disruption
Hepatotoxicity Carcinogenicity Mutagenicity Cardiotoxicity Respiratory Toxicity Eye Irritation Endocrine Disruption

Note for Reference:
In addition to directly collecting NP quantitative data from primary literature (where reference will provided as NCBI PMID or DOI links), NPASS also integrated NP toxicity records from domain-specific databases. These databases include:
☉ ToxValDB: a curated database that compiles quantitative toxicity values for chemicals from diverse public sources to support toxicological research and risk assessment.
☉ TOXRIC: a comprehensive, free-to-access, online database providing toxicological/feature data. The toxicity labels are retrieved from this database. [PMID: 36400569]


  Chemically structural similarity

Similar Active Natural Products in NPASS

Top-200 similar NPs were calculated against the active-NP-set (includes approximately 50,000 NPs with experimentally-derived bioactivity available in NPASS)

Similarity is measured using the Tanimoto coefficient (Tc) , which compares the binary fingerprints of two molecules. Tc is calculated as the intersection divided by the union of '1' bits in the fingerprints, ranging from 0 to 1, with 1 indicating highest similarity.

●  The left chart: Distribution of similarity level between NPC321400 and all remaining natural products in the NPASS database.
●  The right table: Most similar natural products (Tc>=0.5 or Top200).

Similarity Score Similarity Level Natural Product ID
0.5556 Remote Similarity NPC196982

Similar Clinical/Approved Drugs

Similarity level is defined by Tanimoto coefficient (Tc) between two molecules.

●  The left chart: Distribution of similarity level between NPC321400 and all drugs/candidates.
●  The right table: Most similar clinical/approved drugs (Tc>=0.5 or Top200).

Similarity Score Similarity Level Drug ID Developmental Stage
0.5556 Remote Similarity NPD8547 Phase 2

Bioactivity similarity

  Bioactivity similarity

Similar Natural Products in NPASS

Similarity level is defined by Bioactivity similarity was calculated based on bioactivity descriptors of compounds. The bioactivity descriptors were calculated by a recently developed AI algorithm Chemical Checker (CC) [Nature Biotechnology, 38:1087–1096, 2020; Nature Communications, 12:3932, 2021], which evaluated bioactivity similarities at five levels:
☉ A: chemistry similarity;
☉ B: biological targets similarity;
☉ C: networks similarity;
☉ D: cell-based bioactivity similarity;
☉ E: similarity based on clinical data.
Those 5 categories of CC bioactivity descriptors were calculated and then subjected to manifold projection using UMAP algorithm, to project all NPs on a 2-Dimensional space. The current NP was highlighted with a small circle in the 2-D map. Below figures: left-to-right, A-to-E.

A: chemistry similarity
B: biological targets similarity
C: networks similarity
D: cell-based bioactivity similarity
E: similarity based on clinical data