A systems perspective on rare diseases: integrating human phenotype ontology with the Anukta framework of Ayurveda

Abstract

Rare diseases, though individually uncommon, collectively affect millions and remain among the most underdiagnosed and poorly managed conditions in conventional healthcare. Ayurveda, with its systems approach and emphasis on Dosha imbalance, offers a complementary lens to interpret such unlisted conditions, known as Anukta Vyadhi. Human Phenotype Ontology (HPO) that catalogs 10,610 phenotypes across 12,678 rare diseases can be used to bridge modern phenotype vocabularies and Ayurvedic classifications. This study explores whether integrating the Anukta framework can enable meaningful assessment of rare diseases in Ayurveda clinical settings. A curated list of 140 Nanatmaja Vikara (NV)-Vata (80), Pitta (40), and Kapha (20) was mapped to HPO terms, preserving the semantic context of Ayurvedic descriptions. Noteworthy, 128 of NV phenotypes mapped to 199 HPO terms. Over 7200 rare diseases had representation of Nanatmaja Vikara. Vata-linked features were the most enriched (4786), followed by Pitta (465) and Kapha (240). 1349 of diseases showed dual Dosha involvement and 360 of all three. Seizures, short stature, and ptosis were most prevalent features of nV; gastroesophageal reflux, fever, and abnormal skin blistering of nP; and obesity, lethargy, and pallor of nK. Detailed case interpretation of Steinert Myotonic Dystrophy, Syndromic Diarrhea and Alstrom Syndrome revealed association with Vata-Kapha, Vata-Pitta, and Tridosha features respectively. This integration of Anukta framework with structured ontologies provides a practical pathway for understanding rare diseases for management in Ayurveda clinics and integrative decision-making when biomedical options are limited.

1. Introduction

Rare diseases, collectively affecting 3.5–5.9 % of the global population, present a major challenge to modern healthcare due to their low prevalence, complex etiology, and limited treatment options [1]. Despite advances in genomics and precision medicine, the average time to diagnosis remains 7–10 years, often leading to delayed or missed interventions [2,3]. These conditions are frequently degenerative, severely affecting quality of life and imposing significant financial burdens on patients and healthcare systems [4]. Consequently, many patients turn to alternative and complementary approaches such as Ayurveda, which offers a holistic and personalized view of health and disease progression [5,6].

In contemporary medicine, rare diseases are typically classified according to the primary organ or tissue affected. Ayurveda, in contrast, conceptualizes diseases as disturbances in dynamic physiological systems involving multiple organs. Organs are not seen as the source of disease but as sites where systemic disequilibrium manifests [[7], [8], [9]]. This foundational difference poses a challenge when patients with syndromic diagnoses present to an ayurvedic clinic, as modern disease classifications often do not directly map onto ayurvedic nosology. For an Ayurveda practitioner, the ability to interpret and manage rare diseases requires deconvolving clinical phenotypes within an ayurvedic framework. One key barrier is the absence of a shared interoperable language that can unify the conceptual foundations of both medical systems.

Genomic studies increasingly reveal that seemingly unrelated diseases often share mutations in the same genes. These conditions are categorized into distinct syndromes based on a subset of their phenotypic manifestations rather than their shared molecular or systemic roots. To address this complexity, the Human Phenotype Ontology (HPO) has been developed to deconvolute rare diseases based on phenotypic features, enabling one-to-many and many-to-one mappings among genes, features, and diseases [10]. HPO thus provides an interface to move beyond organ-based classification and to explore diseases through converging or overlapping phenotypic signatures. What may appear as two distinct diseases from an organ-centric viewpoint can, through shared phenotypes, reveal a deeper systemic basis. Its interoperable framework has been integrated into electronic health records (EHRs) across major biobanks and translated into ten languages [11] and is being widely applied in phenotype-driven differential diagnostics, genomic analysis, and translational research [12,13]. This capacity to reorganize disease understanding from a feature and network-based perspective offers a promising starting point for dialogue with Ayurveda, which also views diseases as perturbations within interconnected physiological systems rather than isolated organ pathologies.

In Ayurveda, disease perturbation is viewed as an imbalance among the Tridosha—Vata (governing communication and movement), Pitta (regulating metabolism and transformation), and Kapha (maintaining structure and stability) [[14], [15], [16]] (Supplementary note verse:1,7–9). Diseases (Vikriti) are described based on the predominance of these Dosha. They are broadly categorized as endogenous (Nija Vyadhi) or exogenous (Agantuja Vyadhi), with the former further divided into Nanatmaja Vikara (NV) and Samanyaja Vikara (SV), depending on whether single or multiple Dosha are involved. NV represents the foundational framework for understanding disease, comprising 80 Vata, 40 Pitta, and 20 Kapha types [14,[17], [18], [19]] (Supplementary note verse:2). For instance, pain, inflammation, and obesogenic phenotypes—irrespective of their anatomical sites are categorized under broad phenotypic groups nV, nP, and nK, respectively.

Unlike conventional medicine, Ayurveda describes disease states in a dynamic, system-based manner. Many conditions recognized today are not explicitly named in classical texts. Such unlisted or newly emerging conditions are addressed under the Anukta Vyadhi (unsaid or unexplained diseases) framework, where classical scholars emphasized understanding disease based on phenotypic attributes rather than nomenclature [20] (Supplementary note verse: 3). It is explicitly stated that the number of rare diseases is innumerable [14,19,20] (Supplementary note verse:4), encompassing hundreds of phenotypes and considerable clinical heterogeneity making one-to-one mapping with classical categories impractical. The Anukta Vyadhi principle allows application of foundational diagnostic logic to novel conditions through abductive reasoning (Atidesha Tantrayukti), where analogy and similarity facilitate systemic understanding beyond direct textual descriptions [21,22]. This reasoning aims to elucidate the root cause of disease by linking its manifestation to Dosha imbalance using the Trividha Bodhya Sangraha—the triad of (i) involved Dosha (Vikara Prakriti), (ii) site of manifestation (Adhisthana), and (iii) primary cause (Samutthana) [20].

This manuscript examines rare diseases from the Ayurvedic foundational principles of Anukta Vyadhi, framed through Dosha-based logic underlying NV and SV. We reasoned that the HPO, by providing a standardized vocabulary of unified human phenotype codes (HP IDs), could serve as a useful bridge for cross-system dialogue. Such integration can align the feature-based granularity of modern genomics with Ayurveda's systems-level understanding of health and disease [9]. By anchoring NV and SV with HPO phenotypic descriptors, we first explored whether these could enable a cross-talk between diseases described in modern medicine and Ayurveda. Subsequently we synthesized this information in three illustrative scenarios to demonstrate the utility of the Anukta framework. This first-of-its-kind study proposes an algorithm for the reclassification of rare diseases to enhance their comprehension and management in Ayurveda clinics. This integrative approach (a) deepens the understanding of rare diseases through Ayurveda's systemic perspective; (b) reveals Dosha-specific signatures underlying clinical heterogeneity; and (c) lays the groundwork for developing an interoperable ontological framework for seamless dialogue in integrative medicine.

2. Methods

2.1. Feasibility study for exploration of Dosha in diseases using human phenotype ontology

Ayurveda literature is primarily descriptive and qualitative, whereas Human Phenotype Ontology (HPO) relies on quantitative, measurable phenotypes. Diseases in Ayurveda are broadly classified into NV if caused by a single Dosha imbalance and SV when two or more Dosha are involved. Also the cryptic nature of sanskrit terms depending on context and lack of direct equivalents terminology for Ayurveda concepts like cold body temperature (Sheeta Agnita), burning sensation (Osha) and many more (Supplementary Table 1) make it further challenging. To overcome this, we first explored the feasibility of utilizing HPO as an inter-operable interface for mapping Ayurveda and modern medicine clinical descriptions. We carried out this exercise in two pilot cases

• (i)Bleeding abnormality described in Ayurveda as Rakta Pitta with primary involvement of Pittaj Nanatmaj Vikara. Also, association of bleeding has been linked to variation in a VWF gene in an earlier ayurgenomics study [23]. A search term for “Abnormality of von Willebrand factor” links to 19 distinct diseases in HPO (Supplementary Pilot Study 1:Table- S1). The OMIM and ORPHA ID along with their associated features were retrieved and annotated as described below (Supplementary Pilot Study 1:Table- S2 and S3).
• (ii)A set of heterogeneous groups of neurodegenerative disorders under the broad umbrella of ataxia that would be more commonly considered as predominantly Vata disturbances with other complications (Samanyaja Vikara) in Ayurveda. Ataxia listed as a feature (HP:0001251) also yields 1255 diseases along with a set of 4029 non-redundant phenotypes. Despite its heterogeneity, an Ayurveda clinician in practice would ascribe ataxia as a disease of Vata manifestation [1]. A similar exercise as above was conducted on a subset of 25 diseases associated with ataxia (Supplementary Pilot Study 2).

A team of Ayurveda doctors manually correlated each of the HPO terms with one of the three Dosha (Vata, Pitta, or Kapha) based on the foundational principles of Ayurveda described in ancient texts [9]. This annotation encompasses the entire disease spectrum, from onset to progression and prognosis. Each Dosha carries distinct attributes, and its imbalance manifests through characteristic symptoms across multiple organ systems. For instance, Vata imbalance is marked by dryness, which presents in various forms such as dry skin (HP: 0000958), dry mouth (HP: 0000217), vaginal dryness (HP: 0031088), dry cough (HP: 0031246) and many others. In contrast, Pitta imbalance is often associated with increased heat and inflammation, manifesting as bleeding tendencies (HP: 0000421), hemorrhage (HP: 0040242) and burning sensations (HP: 6000420). Meanwhile, Kapha imbalance tends to result in stagnation and heaviness, leading to symptoms such as anorexia (HP: 0002039), excessive salivation (HP: 0003781), and lethargy (HP: 0001254). Also, phenotypic attributes related to sweat, stool, urine etc. and Dosha involvement in symptoms from different tissues like lymph, blood, muscle, adipose, bones, marrow, reproductive tissue, skin, nervous were also considered. By mapping these phenotypic expressions to Dosha imbalances, we create a structured framework that integrates Ayurveda and modern clinical description, through unifying phenotype ontologies (Supplementary Table 2).

Diseases associated with abnormal bleeding and ataxia were curated from HPO along with their associated features and descriptions and were annotated as NV or SV. The relative proportions of V/P/K were assessed in each of these diseases (Supplementary Pilot Study 1: Table -S4).

2.2. Mapping of Nanatamja and Samanyaj Vikara: from textual descriptions to HPO IDs

A comprehensive mining of Ayurveda literature with respect to basic principles of Ayurveda was carried out. This included 80 nV, 40 nP and 20 nK Nanatmaja Vikara used for understanding and diagnosis of diseases. For understanding clinical phenotypes of HPO that would map to Samanyaja Vikara, the information was curated from Ayurveda with respect to Dosha (basic humor), Dhatu (Body tissues), Mala (waste product), Srotas (microchannels), Trisutra (Cause, symptoms, treatment), Aavarana (obstruction of/by Vata), Anukta (Unsaid/undescribed), Trividh Bodhya Sangraha (triads of disease) etc. Charaka Samhita along with authoritative commentaries such as Ayurvedadipika by Chakrapani were referenced to ensure authenticity and appropriateness (https://niimh.nic.in/ebooks/ecaraka). Contemporary medical interpretations and terminologies were also used for better comprehension and interpretation and mapping to modern terminologies.

2.3. Assessment of Nanatamaja Vikara in rare diseases

An extensive exercise was carried out to identify HPIDs that resonate with descriptions of Nanatmaja Vikara. The HPO IDs were manually curated by matching the closest descriptive equivalents. For instance-brittle nails (Nakhbheda), in Ayurveda is considered a disorder associated with the Vata Dosha (nV), while HPO classifies it as a phenotypic abnormality of nails (HPO ID: HP:0001808) related to 28 different diseases. Excessive thirst (Polydipsia, Trishna-adhikya) is a Pitta related disorder (nP), whereas HPO lists it as a symptom (HPO ID: HP: 0001959) found in over 62 diseases. Excessive

Sleepiness (Nidra adhikya) is categorized as a Kapha related disorder (nK) in Ayurveda HPO (HPO ID: HP: 0100786) associated with 28 diseases. There were few NV feature annotations not found in HPO (Supplementary Table 1).

To minimize bias, the initial NV annotations were independently performed by two Ayurveda clinicians (DJ and AK) and subsequently validated by SRT. To further ensure objectivity, all annotations were then reviewed and ratified by an external four-member panel of Ayurveda experts who were not associated with the study. The consensus matrix recorded whether each reviewer agreed with the curated HPO assignment or proposed an alternative term. All disagreements were evaluated relative to the original annotations, and alternative HPO IDs identified as better matches were incorporated. The resulting consensus matrix was used to assess inter-rater agreement, quantify concordance, and highlight points of divergence (Supplementary Table 3).

Because of the overlapping nature of Dosha involvement, multiple Doshas (Sannipataja conditions) often mapped to a single phenotype, reflecting the complex and multifactorial pathophysiology of rare diseases. Moreover, certain HPO entries, such as Insulin resistance (HP:0000855), appear both as phenotypes associated with multiple rare disorders and as distinct disease entities, leading to context-dependent variability in Dosha assignment. Such overlaps lowered inter-observer agreement, reflecting genuine clinical and epistemic ambiguity rather than annotation error.

In order to assess reproducibility, and interpretability of the ontology curation framework Fleiss' Kappa [24] and GWET's AC1 [25] statistics were used to quantify agreement. Fleiss' Kappa and GWET's AC1 for Samanyaja conditions and GWET's AC1 for Nanatmaja Vikara, which had a smaller dataset (Supplementary Note :Python code).

2.4. Prevalence and Co-occurrence network of Nanatamja Vikara in rare diseases

The distribution of NVs in rare diseases was assessed after the annotation exercise in all the rare diseases. To map the co-occurrence of Nanatmaja Vikara in diseases, (Supplementay Note: R code) using phenotype–disease association data. The input included all mapped NV (Vata, Pitta, and Kapha) along with their corresponding diseases sourced from the Human Phenotype Ontology (HPO). Co-occurrence was calculated based on the number of diseases shared between two or more phenotypes.

2.5. Interpretation of rare diseases in Ayurveda setting with HPO integrated Anukta framework

Phenotypes were mapped onto Ayurveda categories using the Anukta Vyadhi framework, which considers Trividha Bodhya Sangraha including Dosha involvement (Vikara Prakriti), site of disease (Adhisthana), and primary causes of disease (Samutthana). Specifically, phenotypes were assigned to one of the NV categories—Vata (nV), Pitta (nP), or Kapha (nK) as described above.

A two-tiered annotation strategy was employed:

• 1.NV Mapping: Selected HPO terms that showed a direct conceptual alignment with Nanatmaja categories were annotated accordingly.
• 2.SV Mapping: Remaining HPO terms were classified under the broader Dosha categories (Vata, Pitta, Kapha or combination of these) based on previously conducted mapping exercises and Ayurveda reasoning.

The distribution of Dosha annotations including counts of nV, nP, nK, and V, P, K categories are visualized using bar plots to identify dominant patterns. These Dosha patterns were then correlated with classical Ayurveda descriptions of disease progression, pathophysiology, and system-level dysfunctions.

Three rare diseases—Steinert Myotonic Dystrophy (SMD, ORPHA:273), Syndromic Diarrhea (SD, ORPHA:84064), and Alstrom Syndrome (ALMS, ORPHA:64)—were selected for analysis from an Ayurveda perspective based on their multisystem involvement and availability of well-annotated phenotypic data in the Human Phenotype Ontology (HPO) and published literature. These disorders exhibit contrasting phenotypic profiles, are clinically heterogeneous, and contain many HPO terms, making them suitable for demonstrating the application of the Anukta Vyadhi framework.

For each of three diseases, phenotypic features were extracted from the HPO database and further supplemented with clinical information from comprehensive peer-reviewed sources [[26], [27], [28]].

In addition, Ayurveda textual descriptors were mapped onto the clinical descriptions from modern medicine using interpretative methods grounded in Ayurveda epistemology. This ensured the semantic integrity of Sanskrit terms and avoided superficial or literal translation mismatches.

Each disease was then re-contextualized within an Ayurveda clinical framework by identifying:

• 1.Dosha progression over time,
• 2.Disease classification (e.g., Sahaja Vyadhi, Adibala Pravritta Vyadhi) (Supplementary note verse:5)
• 3.Possible categorization under Yapya Roga (manageable but not curable) (Supplementary note verse:6)

The resulting synthesis was used to generate disease-specific Ayurveda profiles and to propose potential therapeutic and palliative strategies based on Ayurveda principles.

3. Results

3.1. Feasibility of HPO as an inter-operable interface for enabling crosstalk between Ayurveda and modern medicine

The feasibility study carried out diseases reported on bleeding disorder and ataxia in HPO revealed distinct patterns of dosha distribution. A graphical presentation of Vata, Pitta and Kapha for these diseases showed differences with respect to the three doshas.

The prevalence of Pitta among the three Dosha was comparatively higher. All these diseases were relatable to Raktapitta (Nanatamja Pitta Vikara) when analysed from Ayurveda perspective (Fig. 1, Supplementary Pilot Study1:Table S4). In contrast to the bleeding associated diseases, ataxia shows the prevalence of Vata as comparatively higher compared to Pitta and Kapha (Fig. 2).

Fig. 1.

The barplot depicts the total count of V, P and K phenotypes across all the 19 diseases associated with “Abnormality of von Willebrand factor”.

Fig. 2.

The barplot depicts the total count of V, P and K phenotypes across 25 diseases (subset) associated with “Ataxia”. The cumulative count of V is observed high for this subset.

3.2. Mapping of Nanatmaj Vikara to HPO

128 terms out of 140 Nanatmaja Vikara with exception of a few (2 nV, 6 nP and 4 nK) could be successfully mapped to at least one HP term. A few of them were map-able also to multiple terms. (Table 1). There was an almost consensus inter-rater agreement (0,92) among raters as quantified using Gwet's AC1(Supplementary Table 4)

Table 1.

Count of Nanatamja Vikara mapping to HPO phenotypes and rare diseases.

	nV	nP	nK	Total
No. of NV Features	80	40	20	140
No. of NV Mapped to HPO Phenotypes	78	34	16	128
No. of HPO Phenotypes Mapped to NV	134	42	23	199

Over 7200 of all rare diseases were found to have at least one phenotypic feature corresponding to NV. The NV features showed distinct differences in prevalence with nV the most prevalent (4786) among rare diseases, followed by those nP (465) and nK dominance (240). However, the disease associated with combination of Vata with Pitta (858) or Kapha (419) were more likely. This resonates with Ayurveda descriptions, wherein Vata, regarded as the most dominant Dosha, affects multiple systems and is prone to early imbalances. Pitta and Kapha are significantly lower in the number of diseases they uniquely impact. In 360 of the diseases all the three NVs are present (Fig. 3).

Fig. 3.

Distribution of diseases associated with NV - Vata (nV), Pitta (nP), and Kapha (nK). This Venn diagram illustrates the overlap and prevalence of disease associations across the three Doshas. A total of 7200 unique diseases were identified, with Vata associated phenotypes showing the largest exclusive share (4786). Shared intersections highlight overlapping disease associations across Dosha profiles, with 360 diseases common to all three.

3.3. Co-occurrence network of Nanatamja Vikara

In all the groups of NVs there were several features that emerged as the most reported in the context of rare disease associations while others were relatively less frequent as described below:

3.3.1. Vata Nanatamja Vikara

Within the subset of 80 nV features, seizure or involuntary movement (Aakshepaka), short as well as severely short stature (Vamantva), and abdominal distension (Udavarta) were the most frequently co-occurring phenotypes. The co-occurrence was associated with 2426, 1921 and 837 rare diseases respectively. Conversely, features like stiff ankle (Gulphagraha), proximal limb muscle stiffness (Urusaada), and parageusia (Kashayasyata) were reported only in single diseases. Also, multiple NVs were reported in many rare diseases (Fig. 4). The chord diagram also reflects the above and reveals extensive connectivity of the central players across a broad range of neurological, musculoskeletal, and systemic conditions.

Fig. 4.

Disease Co-occurrence Network of Vata NVs: The figure illustrates the chord network for 78 out of 80 classical Vata NV that mapped to HPO terms. The figure explains the widespread inter-phenotype associations, underscoring the systemic nature of Vata linked disorders. Phenotypes with a greater number of diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary Table 1.

3.3.2. Pitta Nanatamja Vikara

Among the 40 nP features, hot flashes (Daha), skin blistering, pustules, vesicles (Raktavisphota), eczema (Twakawadarana) emerged as the most mapped phenotypes, associated with 431, 216, 191 rare diseases respectively. On the other hand, phenotypes like parageusia (Tiktasyata) and balanitis, penile freckling (Medhrapaka), and abnormal liver physiology (Kamala) are associated with single rare diseases (Fig. 5). The chords also reflect the extent of shared disease associations between phenotype pairs. Prominent phenotypes such as hot flashes (Daha), skin blistering, pustules, vesicles (Raktavisphota), and eczema (Twakawadarana) indicating their frequent appearance across diverse Pitta linked clinical profiles—particularly in conditions associated with inflammation, dermatological manifestations.

Fig. 5.

Disease Co-occurrence Network of Pitta Nanatamja Vikara: Depicted here is the co-occurrence pattern of 34 Pitta NV, mapped from a total of 40 classical phenotypes to HPO terms. Phenotypes with a greater number of diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary Table 1.

3.3.3. Kapha Nanatamja Vikara

Out of 20 classical Kapha phenotypes, 16 were successfully mapped to HPO terms. Within the 20 nK features, early satiety (Tripti), lethargy (Alasyam), obesity (Atisthulata) were the most frequently reported, associated with 163, 189, 340, rare diseases respectively. In contrast, features like abnormal sputum (Shleshmodirnam), laryngeal edema (Kanthuplaepha), and dyspepsia (Apakti) were the least frequently reported (Fig. 6). The width and density of the chords represent the frequency of overlapping diseases between phenotypes. Notably, early satiety (Tripti), lethargy (Alasyam), obesity (Atisthulata) and pallor (Shwetaavabhasata) emerged as central phenotypic hub, exhibiting strong connectivity and frequent co-occurrence with other traits reflecting their shared involvement across a spectrum of metabolic and respiratory conditions.

Fig. 6.

Disease Co-occurrence Network of Kapha NV: Chord diagram visualizes Kapha NV mapped to the Human Phenotype Ontology (HPO). One mapped phenotype, Dyspepsia (Apakti) was excluded from the diagram due to its lack of shared disease co-occurrence. Phenotypes with more diseases have been labelled with English terms. All the Ayurveda phenotypes mapped to HPO have been mentioned in Supplementary Table 1.

3.4. Dosha based interpretation of three rare diseases based on Anukta framework

Across all three diseases, distinct Dosha signatures were observed in the three cases as given in the (Table 2).

Table 2.

Dosha count in SMD, SD and ALMS.

Disease	Dominant Dosha	NV Count (nV/nP/nK)	Total Dosha-Linked Phenotypes (V/P/K)
SMD	Vata-Kapha	6/0/2	94/24/25
SD	Vata-Pitta	2/2/1	43/16/7
ALMS	Tridoshaja	1/3/1	83/43/21

A detailed assessment of the three diseases based on the Anukta framework is provided below.

3.4.1. Steinert Myotonic Dystrophy (SMD) (ORPHA: 273)

Overview of the disease based on synthesis from HPO reveals Steinert Myotonic Dystrophy (SMD) as a multisystem muscle disorder characterized by myotonia, progressive muscle weakness, cardiac conduction abnormalities, cataracts, endocrine dysfunction, sleep disorders, and baldness. SMD is caused by mutations in the DMPK gene. It acts as a non-receptor serine/threonine protein kinase which is necessary for the maintenance of skeletal muscle structure and function [26]. Among the 108 documented HPO phenotypes (Supplementary Table 5), the most frequently observed includes:

• 1.Neuromuscular abnormalities: Facial muscle weakness, masticatory muscle abnormality, distal muscle weakness, myotonia with warm-up phenomenon, foot dorsiflexor weakness.
• 2.Cardiac and endocrine manifestations: Prolonged QRS complex, conduction abnormalities, atrial fibrillation.
• 3.Neurological and behavioral symptoms: Personality impairment, cognitive decline, hypersomnia, abnormal REM sleep, atypical behavior, sleep apnea, excessive daytime somnolence.
• 4.Motor and sensory dysfunction: Poor fine motor coordination, gait disturbance.
• 5.Pain and Fatigue: Myalgia, fatigue.

Annotations of SMD-associated phenotypes through the Anukta Vyadhi framework reveal predominant involvement of nV (six) followed by nK (one) and no nP. The features of Nanatmaja along with the HPO terms are given in Table 3.

Table 3.

Associated Nanatamja (nV,nP,nK) features with SMD, SD and ALMS in HPO.

Disease Name	NV	HPO ID	HPO Term
SMD	Atipralapa (nV)	HP:0000712	Emotional lability
	Vishada (nV)	HP:0000716	Depression
	Vidbheda (nV)	HP:0002014	Diarrhea
	Padbhransa (nV)	HP:0009027	Foot dorsiflexor weakness
	Anavasthita Chitta (nV)	HP:0031466	Impairment in personality
	Vata Khuddata (nV)	HP:0001762	Talipes equinovarus
	Nidradhikyam (nK)	HP:0001262	Excessive daytime somnolence
SD	Rukshata (nV)	HP:0000958	Dry skin
	Vamantva (nV)	HP:0004322	Short stature
	Jiva Dan (nP)	HP:0025085	Bloody diarrhea
	Antrdaha (nP)	HP:0005263	Gastritis
	Shweta Avabhasata (nK)	HP:0007513	Generalized hypopigmentation
ALMS	Vamantva (nV)	HP:0004322	Short stature
	Amlak (nP)	HP:0002020	Gastroesophageal reflux
	Atitriptisch (nP)	HP:0002591	Polyphagia
	Kamla (nP)	HP:0031865	Abnormal liver physiology
	Atisthulata (nK)	HP:0001513	Obesity

Remaining of phenotypes mapped to V (94), P [24] and K [25] (Fig. 7a).

Fig. 7.

Distribution of phenotypes across three rare diseases:Vata (V), Pitta (P), Kapha (K) and their NV subtypes (nV, nP, nK), with the x-axis representing Dosha and the y-axis indicating the number of associated disease count. (a) For Steinert myotonic dystrophy (SMD), Vata-associated phenotypes predominate, followed by comparable counts of Kapha and Pitta, with no nP phenotypes observed. (b) In Syndromic diarrhea (SD), Vata again shows the highest association, followed by Pitta and Kapha, with nV and nP subtypes equally represented, and one phenotype categorized under nK. (c) For Alstrom syndrome (ALMS), Vata related phenotypes are dominant, followed by Pitta and Kapha, with a higher count of nP phenotypes and equal representation of nV and nK.

This clearly demonstrates Vata predominance in SMD, both at the phenotype and NV levels, with lesser involvement of Kapha and minimal association with Pitta. The Dosha distribution pattern, visualized in the accompanying histogram (Fig. 7a), underscores the central role of Vata vitiation in SMD's clinical manifestation. According to Ayurveda, this would also belong to the class of congenital (Sahaja Vyadhi) and hereditary disorder (Adibala Pravritta Vyadhi), (Beeja Bhaga Avyava Dusti) which is not curable but manageable (Yapya Roga).

Using the Anukta Vyadhi principle in conjunction with the detailed SMD description, the insights can be threaded from Ayurveda perspective as illustrated in Table 4.

Table 4.

Clinical presentation of SMD with associated key symptoms and Ayurveda overview.

Clinical Presentation	Age at Onset	Key Symptoms	Ayurvedic Overview
Congenital SMD	Intrauterine	Polyhydramnios, fetal weakness, hypotonia, delayed milestones, cerebral atrophy	V/K – Severe Vata derangement (Vyana, Prana); Kapha impairs growth
Childhood Onset SMD	Early Childhood	Facial weakness, myotonia, psychosocial issues	V – Delayed cognition due to Kapha (Gurutva) & Vata (Chala Guna)
Classical Adult Onset	Adult	Muscle weakness, ptosis, facial wasting	V – Vyana Vata degeneration
Myotonia	Adult	Handgrip, percussion, eye closure myotonia	V – Vyana Vata in neuromuscular conduction
Ocular	Adult	Posterior subcapsular cataracts	V – Timira; Vata NV
Cardiac	Adult	Arrhythmias, conduction defects, cardiomyopathy	V – Prana/Vyana Vata affecting Pranavaha Srotas
CNS	Adult	Cognitive issues, apneas, personality disorders	V – Manovaha Srotas affected
Gastrointestinal	Adult	Constipation, diarrhea, IBS, aspiration pneumonia	V + P – Apana Vata with Pitta affecting metabolism
Endocrinopathy	Adult	Thyroid, gonadal disturbances, infertility	V + K – Vata affects signaling; Kapha impacts glands
Skin	Adult	Balding, cysts, tumors	P + V + K – Inflammation (P), cysts (K), hair loss (V, P)
Respiratory	Adult	Diaphragm myotonia, aspiration pneumonia	V – Udana/Prana Vata disturbance
Psychiatry	Adult	Anxiety, depression	V – Rajo Guna and Vata predominance
Pregnancy	Adult	Spontaneous abortion, prolonged labor	V + P – Apana Vata and Rakta/Pitta imbalance
Neuropathology	Adult	Limbic issues, apathy	V – Manovaha Srotas derangement

The above mapping shows concordance betweenAyurveda NV and SMD phenotypes from HPO and clinical summary from Ref. [26]:

• (a)Atipralapa (irrelevant talkativeness) aligns with emotional lability (HP: 0000712), reflecting Vata in psychiatric/CNS manifestations.
• (b)Vidbheda corresponds to diarrhea (HP: 0002014), linked to Vata disturbance.
• (c)Padbhransa maps to foot dorsiflexor weakness (HP: 0009027), showing Vata dysfunction.
• (d)Vishada (depression) and Anavasthita Chitta (unstable mind) match depression and personality impairment, pointing to Vata imbalance in Manovaha Srotas.
• (e)Vata Khuddata (deformity) aligns with talipes equinovarus (HP: 0001762), another Vata related anomaly.
• (f)Nidradhikyam corresponds to Excessive Somnolence (HP: 0001262), indicative of Kapha vitiation.

This analysis demonstrates the explanatory power of Ayurveda Dosha theory, especially Vata derangement, in SMD's multisystem involvement.

3.4.2. Case study 2: syndromic diarrhea (ORPHA:84064)

Overview of the disease based on synthesis from HPO reveals Syndromic Diarrhea (SD) as a severe congenital enteropathy characterized by intractable diarrhea in the first month of life, leading to failure to thrive. It is commonly associated with facial dysmorphism, hair abnormalities, immune disorders, and intrauterine growth restriction. Syndromic Diarrhea (SD), is caused by mutations in the SKIC2 and SKIC3 genes, a multi-protein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways [27].

Among the 52 documented phenotypic features of SD (Supplementary Table 6), the most frequently observed include:

• 1.Gastrointestinal manifestations: Intractable diarrhea, failure to thrive
• 2.Immune and metabolic dysfunction: Immunodeficiency, hepatomegaly, cirrhosis
• 3.Dermatological and structural Features: Abnormal skin, café-au-lait spots, woolly hair, abnormal facial shape
• 4.Developmental abnormalities: Intrauterine growth restriction

Annotation of SD-associated phenotypes through the Anukta Vyadhi framework revealed involvement of nV (two) followed by nP (two) and nK (one) features. Table 3 lists the Nanatamja features along with the HPO terms. The remaining phenotypes mapped to V (43), P (16) and K (7) (Fig. 7b). The dual-layered annotation clearly demonstrates the dominance of Vata and Pitta Dosha in SD's clinical expression, with minimal Kapha involvement. The Dosha distribution, illustrated in (Fig. 7b), underscores the central role of Vata-Pitta vitiation in SD pathophysiology.

Using the Anukta Vyadhi principle in conjunction with the detailed description from Ref. [27], the following insights from Ayurveda perspective can be threaded as mentioned in Table 5. Ayurveda would also classify this as a congenital hereditary disorder which is not curable but can be managed.

Table 5.

Clinical presentation of SD with associated key symptoms and Ayurveda overview.

Clinical Presentation	Age at Onset	Key Symptoms & Dosha Association	Ayurveda Overview
Chronic diarrhea	Infancy	Feeding issues, colitis, gastritis	V + P – Udana, Samana Vata and Pachaka Pitta derangement
Hair abnormalities	Childhood	Brittle, woolly, unmanageable hair	V + P – Vyana Vata, Bhrajaka Pitta derangement; Ruksha Guna of Vata
Facial dysmorphism	Childhood	Wide forehead, coarse features	V – Vata derangement
Immune defect	Childhood	Low immunoglobulins, low lymphocytes	V + P – Ranjaka Pitta and Vyana Vata derangement
IUGR	Intrauterine	Low birth weight, preterm birth	V – Vata vitiation
Liver disease	Childhood	Cirrhosis, hepatomegaly, hepatoblastoma	P – Pachaka Pitta and Samana Vata imbalance
Skin abnormalities	Childhood	Café-au-lait spots, xerosis	P – Bhrajaka Pitta; with Vata's Ruksha Guna
Cardiac abnormalities	Childhood	Tetralogy of Fallot, septal defects	V – Vyana Vata derangement
Platelet abnormality	Childhood	Increased platelet size	P + V – Ranjaka Pitta and Vyana Vata involvement

Nanatamja Vikara based in HPO vis-a-vis with Dosha based data interpretation shows concordance between Ayurveda NV and SD phenotypes from HPO and clinical summary from Ref. [27] shows clear Ayurveda parallels-

• 1.Rukshata (dryness), a Vata NV, maps to dry skin (HP: 0000958), correlating with xerosis and rubbery skin in SD.
• 2.Vamantva (short stature), also a Vata NV, aligns with short stature (HP: 0004322), linked to IUGR and growth retardation.
• 3.Jiva Dan (bloody diarrhea), a Pitta NV, maps to bloody diarrhea (HP: 0025085), reflecting colitis and chronic digestive issues.
• 4.Antrdaha (internal burning), a Pitta Vikara, corresponds to gastritis (HP: 0005263), commonly reported in SD.
• 5.Shweta Avabhasata (hypopigmentation), a Kapha NV, maps to generalized hypopigmentation (HP: 0007513), associated with skin anomalies.

3.4.3. Case study 3: Alstrom Syndrome (ORPHA: 64)

Overview of the disease based on synthesis from HPO reveals Alstrom Syndrome (ALMS) as a rare multi-systemic disorder characterized by cone-rod dystrophy, progressive hearing loss, obesity, insulin resistance, type 2 diabetes mellitus, dilated cardiomyopathy (DCM), and progressive hepatic and renal dysfunction. Alstrom Syndrome is caused by mutations in the ALMS1 gene. The encoded protein functions in microtubule organization, particularly in the formation and maintenance of cilia. According to Ayurveda this could also be classified as a congenital hereditary disorder that is manageable but not curable.

Among the 117 documented phenotypic features of ALMS (Supplementary Table 7), the most frequently observed includes:

• 1.Developmental and growth abnormalities: Short stature, obesity
• 2.Sensory and neurological manifestations: Otitis media, progressive sensorineural hearing loss, visual loss, retinal dystrophy, blindness
• 3.Metabolic and endocrine dysfunction: Insulin resistance, hypertriglyceridemia, type 2 diabetes mellitus
• 4.Cardiac and systemic complications: Dilated cardiomyopathy, progressive hepatic and renal dysfunction

Annotations of ALMS-associated phenotypes based on dosha reveal involvement of nV (one) followed by nP (three) and nK (one). The Nanatmaja features along with the HPO terms are given in Table 3. The remaining phenotypes mapped to V (83), P (43) and to K [21] (Fig. 7c). This annotation underscores the multi-systemic nature of ALMS, with all three Dosha involved in the disease's expression. Pitta-related NV are most frequent, followed by those associated with Vata and Kapha (Fig. 7c).

Using the information from above and an authoritative review [28] and applying the Anukta Vyadhi principle, the disease expression is interpreted through Dosha specific characteristics as depicted in Table 6.

Table 6.

Clinical presentation of ALMS with associated key symptoms and Ayurveda overview.

Clinical Presentation	Age at Onset	Key Symptoms	Ayurveda overview
Visual impairment	<6 months	Retinal dystrophy, photophobia, strabismus	Aalochaka Pitta with Vata disturbance
Deafness	Early childhood	Sensorineural hearing loss	Chala Guna of Vata disturbance
Cardiovascular disease	Infant to adult	Cardiomyopathy, obesity, pulmonary issues	Margavarodhjanya Vyana Vata with Avabodhaka Kapha vitiation
Endocrine/metabolic issues	After puberty	Hypothyroidism, short stature, scoliosis	Asthivaha Srotas vitiation with Kapha disturbance
Male hypogonadism	After puberty	Testicular atrophy, erectile dysfunction	Shukravaha Srotodusti due to Vata
Female hyperandrogenism	After puberty	Hirsutism, PCOS, obesity, hyperinsulinemia	Kapha vitiation with Apana Vata
Childhood obesity	Early childhood	Hyperphagia, obesity	Atisthulya; Kapha NV
Diabetes and dyslipidemia	Early childhood	T2DM, pancreatitis, hypertriglyceridemia	Tridosha involvement
Fatty liver disease	Early childhood	Cirrhosis, liver fibrosis, insulin resistance	Pachaka Pitta with Samana Vata
Respiratory issues	Early childhood	Otitis, pneumonia, fibrosis	Inflammatory pathology; Pranavaha Srotas vitiation
Renal/urological complications	Mid-childhood–adulthood	Renal failure, hypertension, uricemia	Tridosha vitiation; Mutravaha Srotas
Dysuria	Late teens	Urinary incontinence, pain	Apana Vata disturbance
Gastrointestinal dysfunction	Childhood	GERD, nausea, volvulus	Pachaka Pitta with Vata vitiation
Neurodevelopmental issues	Early childhood	Autism, seizures, sleep issues	Vyana Vata with Pitta; Manovaha Srotas involvement
Psychosocial symptoms	Adolescence	Anxiety, depression, learning difficulties	Manovaha Srotas vitiation; Vishada (nV)

Mapping NV to HPO terms and clinical features reported by Ref. [28] reveals strong correlations:

• 1.Vamantva (short stature), a Vata NV, corresponds to short stature (HP: 0004322), aligning with developmental delay.
• 2.Amlak (acid reflux) and Atitriptisch (polyphagia), both Pitta NV, correspond to gastroesophageal reflux (HP: 0002020) and polyphagia (HP: 0002591), seen in metabolic and GI dysfunctions.
• 3.Kamala (abnormal liver physiology), a Pitta NV, maps to abnormal liver physiology (HP: 0031865), present in hepatic disorders and systemic complications.
• 4.Atisthulata (obesity), a Kapha NV, maps to obesity (HP: 0001513), characteristic of early ALMS presentation.

This mapping demonstrates the translational value of Ayurveda Dosha theory in explaining the phenotypic complexity of ALMS.

4. Discussion

In this study, we propose the Human Phenotype Ontology (HPO) as an inter-operable interface for integrating the clinical descriptions of Ayurveda with modern medicine for delineating rare diseases from an Ayurvedic perspective through the Anukta framework. By deconvoluting the syndromes into granular and interoperable phenotypic features, HPO offers a structured entry point to align biomedical descriptions with Dosha-based attributes. Our pilot analysis demonstrated rare diseases, through the HPO features, can be effectively mapped to dosha related attributes and the presentations understood from an Ayurveda perspective. We could also carry out systematic mapping of Ayurvedic disease constructs like those that might be related to Nanatmaja Vikara into contemporary clinical phenotypes. Synthesizing Dosha attributes with HPO annotations provides a coherent operational framework for interpreting rare diseases through the Anukta lens. This first-of-its-kind approach opens new possibilities for complementary Ayurvedic strategies in the therapeutic management of chronic rare diseases through Atidesha Tantrayukti (reasoning), especially those that are not directly described in Ayurveda and could thus be considered as Anukta Vyadhi.

4.1. Inter-operability of Ayurveda and modern medicine clinical descriptions through HPO

The principles of Ayurveda are inherently qualitative, holistic, and non-linear, whereas modern biomedicine relies on quantitative, reductionist, and pathology-based frameworks. This epistemological gap has historically impeded interoperability between the two systems. By evaluating the feasibility of cross-ontology mapping between HPO terms and Dosha categories, we addressed this foundational challenge using two illustrative case examples that reflect distinct Ayurvedic perspectives.

The first example focused on bleeding disorders, which are predominantly classified under Pitta Nanatamja Vikara in Ayurveda and correspond to Rakta-Pitta manifestations. Earlier work from our group had linked variation in the platelet glycoprotein VWF—mutations in which underlie several bleeding conditions—to Pitta attributes. A search of OMIM and ORPHA revealed 19 related diseases in HPO. When these were examined through their HP ID, we observed a clear predominance of phenotypic features aligning with Pitta Vikriti consistent with ayurvedic descriptions (Supplementary Pilot Study 1 Verse 1).

In contrast, the second example centered on ataxia, a neurodegenerative condition characterized by substantial phenotypic and genetic heterogeneity. Despite this diversity, Ayurveda would primarily interpret ataxia as a Vata-dominant manifestation, with variable co-involvement of other Doshas. Analysis of HPO terms across a subset of ataxia-related diseases revealed an enrichment of features corresponding to Vata attributes, markedly distinct from the Pitta-predominant signature observed in bleeding disorders.The concordance between HPO-derived phenotypic patterns and classical Ayurvedic interpretations in both cases demonstrates the feasibility of this cross-ontology approach.

4.2. Topographical presentation and systemic manifestations of Nanatamja Vikara

We next explored the prevalence of Nanatmaja Vikara in the rare diseases. Nanatmaja Vikara has primary involvement of one Dosha and these contribute to contrasting phenotypic attributes in the system. Vikriti in each of these Dosha would impact specific organs to different extents. Thus these could map to different system manifestations often reported in syndromic conditions. This approach may also help resolve clinical heterogeneity within rare diseases and clarify the phenotypic overlaps observed across distinct conditions. The annotation of NV with modern medical phenotype databases through literature mining posed multiple challenges as described above. Nevertheless all the terms were mappable to HPIDs. The inter-rater variability revealed substantial agreement between independent Ayurveda clinicians, underscoring its reliability and suggesting that it can be applied consistently across diverse clinical settings.

Surprisingly, the HP annotations corresponding to Vata Nanatamja display an ordering of phenotypes that appears to follow the natural anatomical axis of the body—from the toes to head (Supplementary Table 1) (Supplementary note verse 7). These also reflect progressive manifestation of Vata related disorders that primarily impacts the musculo-skeletal, neurological as well as psychological functions encompassing a wide spectrum of phenotypes. For instance:

• a)Musculoskeletal: pain (Padshool, Gud Arti), stiffness (Urustambh, Trikgraha), Muscle spasm (Pindiko udvestan), deformities (Vatakhuddata).
• b)Neurological: weakness (Akshivyudas), sensory loss (Padsuptata), seizures (Aakshepaka), paralysis (Ardita).
• c)Autonomic: bowel irregularities (Vidbheda), abnormal respiration (Vaksh uprodha), tachycardia/bradycardia (Hritdrava, Hritmoha)
• d)Cranial Sensory: hearing loss (Badhirya), anosmia (Ghran nasha), tinnitus (Ashabdashravana).
• e)Cognitive & Psychological: depression (Vishada), insomnia (Aswapana), drowsiness (Jarimbha), syncope (Tama).

Unlike Vata, Pitta NV mainly impacts physiological functions linked to impaired inflammation, metabolism, and blood-related conditions. The phenotypes described have manifestations in skin, mucosa, and sensory tissues. For instance:

• (a)Thermoregulatory: fever (Ushmadhikya), burning sensations (Osha).
• (b)Digestive and hepatic: reflux (Amlak), biliary dysfunction (Kamla), halitosis (Putimukhata).
• (c)Blood and Immune: purpura (Rakta kotha), abnormal bleeding (Rakta pitta), jaundice (Haritata).
• (d)Dermatological: skin lesions (Rakta visphota), ulcers (Angavadarana), flushing (Daha) hyperhidrosis (Atiswedasch).
• (e)Oral and Upper Respiratory: stomatitis (Aasyapaka), pharyngitis (Galapaka).
• (f)Ocular: conjunctival icterus (Nilika).

Kapha disorders predominantly reflect hypo-functionality — a slowing down of physiological activities, accumulation of fluids, decreased metabolism, and cooling of body systems. This is in sharp contrast to the hyperactivity and inflammatory profile of Pitta and the degenerative/mobility spectrum of Vata. The phenotypes of these also manifest in various systems. For instance:

• (a)Neurological: lethargy (Alasyam), excessive sleep (Nidradhikyam)
• (b)Gastrointestinal: poor appetite (Tripti), dyspepsia (Apakti).
• (c)Cardiovascular and Metabolic: obesity (Atisthulata), atherosclerosis (Dhamani pratichaya), pericardial effusion (Hridya upalepa).
• (d)Respiratory and Mucosal: excessive salivation (Mukhshrava), abnormal sputum (Shleshm udeernam), laryngeal edema (Kanth upalepa).
• (e)Cold Disorders: coldness (Balasaka), hypothermia (Staimitya).
• (f)Skin and Immunological: urticarial (Udard), pallor (Sweta avabhasata).

As would be anticipated from the Ayurveda perspective the number of rare diseases with Nanatmaja Vikara is higher for Vata followed by Pitta and Kapha. However, we observed that certain features from each Nanatmaja Vikara (NV) category appeared quite frequently across a wide range of modern clinical conditions—for example, seizures or involuntary movements (Aakshepaka), eczema (Tvak-avadarana) and obesity (Atisthulata) representing presence of Vata, Pitta and Kapha respectively. In contrast, some features such as parageusia (Kasayasyata), balanitis or penile freckling (Medhrapaka), and dyspepsia (Apakti) from Vata, Pitta, and Kapha, respectively, were reported far less often. Since Nanatmaja Vikara represent dimension-reduced attributes for a multitude of Samanyaja Vikara [9], it is possible that inclusion of HP features corresponding to the Nanatmaja Vikara might help resolve endophenotypes in rare disease for therapeutic management. This is exemplified by the three cases that we studied in detail from the Anukta framework perspective. Noteworthy, in a parallel study we observe that doshas associated with SV in a large number of rare diseases was found to be consistent with the fundamental axes defined by NV characteristics. Even for diseases lacking a direct mapping to NV, the predominance of Dosha features within their HPO phenotypic profiles allowed their classification within the Ayurveda Tridosha framework [9].

4.3. HPO based Anukta framework for understanding rare diseases in Ayurveda settings for palliative management

According to Ayurveda, rare diseases belong to the class of congenital (Sahaja Vyadhi) and hereditary disorder (Adibala Pravritta Vyadhi), (Beeja Bhaga Avyava Dusti) (Supplementary note verse:5) which is not curable but manageable (Yapya Roga) (Supplementary note verse:6). However, the first exercise is to understand the rare diseases from a holistic perspective since there is no direct mapping of the diseases to textual descriptions.Understanding the rare diseases from the foundational perspective of doshas through the Anukta framework can open up possibilities for palliative management. For a comprehensive understanding of a rare disease from an Ayurveda perspective, a prerequisite would be to have a holistic understanding of the disease and then test its feasibility in a clinical setting. Since HPO provides an exhaustive list of features that otherwise are not observable in any single patient we decided to use this in three case scenarios. We studied Steinert Myotonic Dystrophy (SMD) (ORPHA: 273), Syndromic Diarrhea (SD) (ORPHA:84064) and Alstrom Syndrome (ALMS) (ORPHA: 64) to test the hypothesis whether threading the Dosha anchored HP features through the Anukta framework could help enhance the understanding of rare diseases from Ayurveda perspective. In addition we also extensively used information about diseases from reviews on the diseases to consolidate the information [[26], [27], [28]]. Using this framework we demonstrate that each disorder exhibits a distinct yet logically consistent Dosha pattern aligned with classical Ayurvedic principles.

Across the three conditions—SMD, SD, and ALMS—Ayurveda interpretation integrated with phenotype mapping and gene function highlights distinct Dosha patterns grounded in classical principles. SMD exhibits a predominantly Vata-driven degenerative profile, with neuromuscular decline corresponding to the functions of the DMPK gene, which regulates muscle contraction, ion balance, and conduction—core attributes of Vata's kinetic role. SD shows Vata–Pitta predominance, and the genes commonly implicated in syndromic diarrheal disorders (involved in epithelial polarity, mucosal integrity, and metabolic homeostasis) align with disrupted Agni, impaired absorption, and heightened Vata–Pitta activity. ALMS, linked to dysfunction of the ALMS1 gene responsible for ciliary structure and multisystem regulation, presents a stage-wise Tridosha pattern—early Kapha derangement (growth, metabolism), followed by Pitta-mediated inflammatory and metabolic dysfunction, and later Vata aggravation affecting neurodevelopment and degeneration. Collectively, these insights demonstrate how gene functions and phenotypic trajectories can be meaningfully mapped onto Ayurvedic Dosha dynamics to guide holistic, stage-specific palliative strategies. For example in SMD, given the Ayurveda understanding that Vata aggravation increases with age and disease progression, early regulation of Vata — beginning in childhood — could offer therapeutic advantage. Addressing associated Pitta and Kapha imbalances may help delay progression and mitigate complications.This could offer valuable palliative strategies for improving function, delaying degeneration, and enhancing the quality of life in SMD. This integrative annotation revealed disease-specific Ayurveda pathophysiological patterns. The mapping not only demonstrated semantic compatibility betweenAyurveda and contemporary phenotyping but also provided insights into Dosha progression and systemic involvement.

The Anukta Vyadhi framework thus offers a valuable lens for interpreting complex, heterogeneous phenotypes in rare diseases and guiding personalized, Dosha oriented clinical strategies. Such an approach could open new possibilities for holistic management and palliative care of rare disease patients. Furthermore, the integration of curated rare disease datasets with Ayurveda-based phenotyping, supported by Natural Language Processing (NLP) and Artificial Intelligence can enable building of knowledge graphs and new Large Language Models (LLMs) based on Anukta framework. Coupled with Ayurgenomics, this could significantly augment the future developments in integrative medicine and also enable novel drug repurposing strategies guided by Dosha based endophenotypes. This offers a complementary approach for rare disease management and therapeutics.

This work however is exploratory, and several limitations must be acknowledged. First, the annotation of phenotypes into Dosha categories relies on clinical interpretation rooted in Ayurvedic textual descriptions, while the underlying HPO descriptors arise from modern biomedical observation. Because the epistemological foundations of the two systems differ, perfect semantic equivalence is neither expected nor always achievable. Some Sanskrit terms are context-dependent, or lack direct biomedical analogs, which may introduce ambiguity despite expert consensus procedures. Second, the mapping was performed at the phenotype level rather than through direct clinical examination of patients by Ayurveda practitioners; thus, some subtleties of disease expression relevant to Dosha assessment may not be captured. Third, the applicability of these findings across diverse clinical contexts requires validation. Rare diseases seen in contemporary clinics may not fully align with classical patterns and may require re-interpretation through the lens of Ayurveda using fresh clinical observations. To refine and validate this framework, future work must include prospective case documentation, systematic case series from Ayurveda-based rare disease clinics, and triangulation with longitudinal phenotyping that captures progression, prognosis, and therapeutic response.

5. Conclusion

In summary, this study provides the first structured attempt to map Nanatmaja and Samanyaja Vikara to the Human Phenotype Ontology, offering a scalable method to interpret rare diseases within the Anukta paradigm of Ayurveda. The strong correspondence between Dosha-linked phenotypes and multisystem rare disease profiles, supported by co-occurrence patterns and detailed case analyses, demonstrates the feasibility of a unified vocabulary for cross-system dialogue. While further clinical validation is required, especially through systematic case series in Ayurveda settings, this integrative framework lays the groundwork for enhancing diagnostic reasoning, improving interoperability, and supporting individualized care of rare diseases when conventional therapeutic options are limited.

Authors' contributions

MM designed the study. DJ, SRT, and AK contributed to the Ayurveda interpretation. DJ curated HPO terms and conducted Ayurveda mining. DJ, AJ, and MM performed the data analysis and prepared the figures. DJ, AJ, and MM wrote the manuscript.

Funding sources

Authors receive financial support from MOA (Ministry of Ayush) forCenter of Excellence “AyurTech” (S/MOA/MTM/AA/20210105), IIT Jodhpur, Rajasthan, India, 342037.

Conflict of interest

None

Appendix A. Supplementary data

The following are the Supplementary data to this article:

Data availability

The supplementary data includes: supplementary tables, supplementary note, python and R codes available at (https://github.com/DrDeepikaJ/Supplementary_Material_AnkutaFramework).