feat(app): add complex any not handled guideline matching

app/integration_test/drugs_test.dart

@@ -9,7 +9,7 @@ import 'package:provider/provider.dart';
 
 import 'fixtures/drugs/with_any_fallback_guideline.dart';
 import 'fixtures/drugs/with_any_not_handled_guideline.dart';
-// import 'fixtures/drugs/with_multiple_any_not_handled_fallback_guidelines.dart';
+import 'fixtures/drugs/with_multiple_any_not_handled_fallback_guidelines.dart';
 import 'fixtures/drugs/with_proper_guideline.dart';
 import 'fixtures/drugs/without_guidelines.dart';
 import 'fixtures/set_user_data.dart';
@@ -42,7 +42,7 @@ void main() {
       },
     );
 
-    testWidgets('test drug content with proper guideline', (tester) async {
+    testWidgets('test drug content with guideline', (tester) async {
       await _expectDrugContent(
         tester,
         mockDrugsCubit,
@@ -68,7 +68,9 @@ void main() {
         expectNoGuidelines: true,
       );
     });
+  });
 
+  group('integration test for special guidelines', () {
     testWidgets('test drug content with any fallback guideline', (tester) async {
       await _expectDrugContent(
         tester,
@@ -77,26 +79,31 @@ void main() {
       );
     });
 
-    testWidgets(
-      'test drug content with any not handled fallback guidelines',
-      (tester) async {
-        Future<void> testPerGuideline(Drug drug) async {
-          for (
-            final guideline in drug.guidelines
-          ) {
+    final anyNotHandledTestCases = <String, Drug>{
+      'any not handled fallback guideline':
+        drugWithAnyNotHandledFallbackGuideline,
+      'multiple any not handled fallback guidelines':
+        drugWithMultipleAnyNotHandledFallbackGuidelines,
+    };
+    for (final (anyNotHandledTestCase) in anyNotHandledTestCases.entries) {
+      final description = 'test drug content with ${anyNotHandledTestCase.key}';
+      final drug = anyNotHandledTestCase.value;
+      for (final (index, guideline) in drug.guidelines.indexed) {
+        // Run per case to ensure clean setup
+        testWidgets(
+          '$description (${index + 1}/${drug.guidelines.length})',
+          (tester) async {        
             setUserDataForGuideline(guideline);
             await _expectDrugContent(
               tester,
               mockDrugsCubit,
               drug: drug,
               guideline: guideline,
             );
-          }
-        }
-        await testPerGuideline(drugWithAnyNotHandledFallbackGuideline);
-        // await testPerGuideline(drugWithMultipleAnyNotHandledFallbackGuidelines);
-      },
-    );
+          },
+        );
+      }
+    }
   });
 }
 
@@ -111,7 +118,6 @@ Future<void> _expectDrugContent(
 }) async {
   when(() => mockDrugsCubit.state)
     .thenReturn(isLoading ? DrugState.loading() : DrugState.loaded());
-  final relevantGuideline = guideline ?? drug.guidelines.first;
   await tester.pumpWidget(
     ChangeNotifierProvider(
       create: (context) => ActiveDrugs(),
@@ -159,15 +165,10 @@ Future<void> _expectDrugContent(
       ValueKey('annotationCard'),
     ),
   ) as RoundedCard;
-  expect(
-    card.color,
-    expectNoGuidelines
-      ? WarningLevel.green.color
-      : relevantGuideline.annotations.warningLevel.color,
-  );
   expect(find.byType(Disclaimer), findsOneWidget);
   final context = tester.element(find.byType(Scaffold).first);
   if (expectNoGuidelines) {
+    expect(card.color, WarningLevel.green.color);
     expect(
       find.byTooltip(context.l10n.drugs_page_tooltip_guideline_missing),
       findsOneWidget,
@@ -181,6 +182,8 @@ Future<void> _expectDrugContent(
       findsOneWidget,
     );
   } else {
+    final relevantGuideline = guideline ?? drug.guidelines.first;
+    expect(card.color, relevantGuideline.annotations.warningLevel.color);
     expect(
       find.byTooltip(context.l10n.drugs_page_tooltip_guideline_present(
         relevantGuideline.externalData.first.source,
@@ -196,10 +199,17 @@ Future<void> _expectDrugContent(
       findsOneWidget,
     );
     for (final genotypeKey in drug.guidelineGenotypes) {
-      expect(
-        find.text(genotypeKey),
-        findsOneWidget,
-      );
+      if (genotypeKey.contains(' ')) {
+        expect(
+          find.textContaining(genotypeKey.split(' ').first),
+          findsOneWidget,
+        );
+      } else {
+        expect(
+          find.text(genotypeKey),
+          findsOneWidget,
+        );
+      }
     }
   }
 }

app/integration_test/fixtures/drugs/with_multiple_any_not_handled_fallback_guidelines.dart

@@ -13,6 +13,32 @@ final drugWithMultipleAnyNotHandledFallbackGuidelines = Drug(
     brandNames: ['Votrient'],
   ),
   guidelines: [
+    Guideline(
+      id: '6686a865826414ec5b05c436',
+      version: 1,
+      lookupkey: {
+        'HLA-B': ['*57:01 positive'],
+        'UGT1A1': ['Poor Metabolizer'],
+      },
+      externalData: [
+        GuidelineExtData(
+          source: 'FDA',
+          guidelineName: 'Table of Pharmacogenetic Associations (Section 2)',
+          guidelineUrl: 'https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations#section2',
+          implications: {
+            'HLA-B': 'May result in higher adverse reaction risk (liver enzyme elevations). Monitor liver function tests regardless of genotype.',
+            'UGT1A1': 'Results in higher adverse reaction risk (hyperbilirubinemia).',
+          },
+          recommendation: 'Might be included in implication text (imported from FDA, source only states one text per guideline)',
+          comments: null,
+        ),
+      ],
+      annotations: GuidelineAnnotations(
+        implication: 'You have an increased risk for side effects. (Test case 1)',
+        recommendation: 'You can still use pazopanib at standard dose. Consult your pharmacist or doctor for more information. (Test case 1)',
+        warningLevel: WarningLevel.yellow,
+      ),  
+    ),
     Guideline(
       id: '66b50b2433cbe5c07ee31651',
       version: 1,
@@ -34,10 +60,62 @@ final drugWithMultipleAnyNotHandledFallbackGuidelines = Drug(
         ),
       ],
       annotations: GuidelineAnnotations(
-        implication: 'You have an increased risk for side effects.',
-        recommendation: 'You can still use pazopanib at standard dose. Consult your pharmacist or doctor for more information.',
+        implication: 'You have an increased risk for side effects. (Test case 2)',
+        recommendation: 'You can still use pazopanib at standard dose. Consult your pharmacist or doctor for more information. (Test case 2)',
         warningLevel: WarningLevel.yellow,
       ),  
     ),
+    Guideline(
+      id: '66b50b2433cbe5c07ee31657',
+      version: 1,
+      lookupkey: {
+        'HLA-B': ['*57:01 positive'],
+        'UGT1A1': ['~'],
+      },
+      externalData: [
+        GuidelineExtData(
+          source: 'FDA',
+          guidelineName: 'Table of Pharmacogenetic Associations (Section 2)',
+          guidelineUrl: 'https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations#section2',
+          implications: {
+            'HLA-B': 'May result in higher adverse reaction risk (liver enzyme elevations). Monitor liver function tests regardless of genotype.',
+            'UGT1A1': 'Standard procedure',
+          },
+          recommendation: 'Might be included in implication text (imported from FDA, source only states one text per guideline)',
+          comments: null,
+        ),
+      ],
+      annotations: GuidelineAnnotations(
+        implication: 'You may have an increased risk for side effects. (Test case 3)',
+        recommendation: 'You can still use pazopanib at standard dose. Consult your pharmacist or doctor for more information. (Test case 3)',
+        warningLevel: WarningLevel.yellow,
+      ),  
+    ),
+    Guideline(
+      id: '66b50b2433cbe5c07ee3165d',
+      version: 1,
+      lookupkey: {
+        'HLA-B': ['~'],
+        'UGT1A1': ['~'],
+      },
+      externalData: [
+        GuidelineExtData(
+          source: 'FDA',
+          guidelineName: 'Table of Pharmacogenetic Associations (Section 2)',
+          guidelineUrl: 'https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations#section2',
+          implications: {
+            'HLA-B': 'Standard procedure',
+            'UGT1A1': 'Standard procedure',
+          },
+          recommendation: 'Might be included in implication text (imported from FDA, source only states one text per guideline)',
+          comments: null,
+        ),
+      ],
+      annotations: GuidelineAnnotations(
+        implication: 'Your phenotype does not have a clinically significant influence on pazopanib. (Test case 4)',
+        recommendation: 'You can use pazopanib at standard dose. Consult your pharmacist or doctor for more information. (Test case 4)',
+        warningLevel: WarningLevel.green,
+      ),  
+    ),
   ],
 );

app/integration_test/fixtures/set_user_data.dart

@@ -7,8 +7,8 @@ class _UserDataConfig {
   });
   final String gene;
   final String lookupkey;
-  final String phenotype = 'phenotype does not matter for test';
-  final String variant = 'variant does not matter for test';
+  String get phenotype => lookupkey;
+  String get variant => lookupkey;
   final String allelesTested = 'allelesTested does not matter for test';
 }
 
@@ -32,11 +32,11 @@ void setUserDataForGuideline(Guideline guideline) {
       lookupkey: lookupkey,
     );
     // Need to be careful with non-unique genes here; e.g., is we want to use
-    // multiple HLA-B variants in the tests, we will need to check for the
-    // genotype key (which is in the current setup not possible without the
-    // variant)
+    // multiple HLA-B variants in the tests or overwrite a specific HLA-B
+    // variant, we will need to check for the genotype key (which is in the
+    // current setup not possible without the proper variant)
     UserData.instance.labData = UserData.instance.labData!.filter(
-      (labResult) => labResult.gene != gene  
+      (labResult) => labResult.gene != gene
     ).toList();
     UserData.instance.labData!.add(
       LabResult(
@@ -46,7 +46,9 @@ void setUserDataForGuideline(Guideline guideline) {
         allelesTested: userDataConfig.allelesTested,
       ),
     );
-    UserData.instance.genotypeResults![userDataConfig.gene] = GenotypeResult(
+    UserData.instance.genotypeResults![
+      GenotypeKey(userDataConfig.gene, userDataConfig.variant).value
+    ] = GenotypeResult(
       gene: userDataConfig.gene,
       phenotype: userDataConfig.phenotype,
       variant: userDataConfig.variant,

app/lib/common/models/drug/drug.dart

@@ -1,5 +1,6 @@
 import 'package:freezed_annotation/freezed_annotation.dart';
 import 'package:hive/hive.dart';
+import 'package:trotter/trotter.dart';
 
 import '../../module.dart';
 
@@ -78,24 +79,65 @@ extension DrugExtension on Drug {
       : namesMatch;
   }
 
+  bool _lookupsMatchUserData(String gene, List<String> variants) =>
+    variants.any((variant) => variants.contains(
+      UserData.lookupFor(
+        GenotypeKey(gene, variant).value,
+        drug: name,
+      ),
+    ));
+
+  Guideline? _getExactGuideline() {
+    final exactGuidelines = guidelines.filter(
+      (guideline) => guideline.lookupkey.none(
+        (gene, variants) => variants.contains('~')
+      )
+    );
+    return exactGuidelines.firstOrNullWhere(
+      (guideline) => guideline.lookupkey.all(_lookupsMatchUserData)
+    );
+  }
+
+  Guideline? _getPartiallyHandledGuideline() {
+    if (guidelines.isEmpty) return null;
+    final partialGuidelines = guidelines.filter(
+      (guideline) => guideline.lookupkey.values.any(
+        (values) => values.contains('~'),
+      ),
+    );
+    if (partialGuidelines.isEmpty) return null;
+    final guidelineGenes = guidelines.first.lookupkey.keys.toList();
+    Guideline? partiallyHandledGuideline;
+    var currentMatchingNumber = guidelineGenes.length - 1;
+    while (currentMatchingNumber > 0 && partiallyHandledGuideline == null) {
+      final currentGeneCombinations =
+        Combinations(currentMatchingNumber, guidelineGenes)().toList();
+      for (final geneCombination in currentGeneCombinations) {
+        if (partiallyHandledGuideline != null) break;
+        partiallyHandledGuideline = partialGuidelines.firstOrNullWhere(
+          (guideline) => guideline.lookupkey.all(
+            (gene, variants) => geneCombination.contains(gene)
+              ? _lookupsMatchUserData(gene, variants)
+              : variants.any((variant) => variant == '~'),
+          ),
+        );
+      }
+      currentMatchingNumber--;
+    }
+    return partiallyHandledGuideline;
+  }
+
   Guideline? get userGuideline {
     final anyFallbackGuideline = guidelines.firstOrNullWhere(
       (guideline) => guideline.lookupkey.all(
         (gene, variants) => variants.any((variant) => variant == '*')
       ),
     );
     if (anyFallbackGuideline != null) return anyFallbackGuideline;
-    final exactGuideline = guidelines.firstOrNullWhere(
-      (guideline) => guideline.lookupkey.all(
-        (gene, variants) => variants.any((variant) =>
-          variants.contains(UserData.lookupFor(
-            GenotypeKey(gene, variant).value,
-            drug: name,
-          )
-        )),
-      ),
-    );
+    final exactGuideline = _getExactGuideline();
     if (exactGuideline != null) return exactGuideline;
+    final partiallyHandledGuideline = _getPartiallyHandledGuideline();
+    if (partiallyHandledGuideline != null) return partiallyHandledGuideline;
     return guidelines.firstOrNullWhere(
       (guideline) => guideline.lookupkey.all(
         (gene, variants) => variants.any((variant) => variant == '~')

app/pubspec.lock

@@ -1246,6 +1246,14 @@ packages:
       url: "https://pub.dev"
     source: hosted
     version: "1.0.1"
+  trotter:
+    dependency: "direct main"
+    description:
+      name: trotter
+      sha256: "59c8d5e98904355e887d80aae52b02828a811fe96474645aaf8fa7761ea64851"
+      url: "https://pub.dev"
+    source: hosted
+    version: "2.2.0"
   typed_data:
     dependency: transitive
     description:

app/pubspec.yaml

@@ -44,6 +44,7 @@ dependencies:
   printing: ^5.9.3
   provider: ^6.1.1
   shared_preferences: ^2.0.15
+  trotter: ^2.2.0
   url_launcher: ^6.1.4
 
 dev_dependencies: