require_relative 'test_helper' module MESH class MeshCoreTest < Minitest::Test def test_yield_to_a_block_for_each block_called = false @mesh_tree.each do |h| block_called = true break end assert block_called end def test_not_have_nil_headings @mesh_tree.each do |h| refute_nil h end end def test_find_by_unique_id mh = @mesh_tree.find('D000001') refute_nil mh end def test_find_by_tree_number mh = @mesh_tree.find_by_tree_number('G14.640.079') refute_nil mh assert_equal 'D000065', mh.unique_id end def test_find_by_original_heading mh = @mesh_tree.find_by_original_heading('Allergens') refute_nil mh assert_equal 'D000485', mh.unique_id end def test_not_find_original_heading_that_doesnt_exist mh = @mesh_tree.find_by_original_heading('Lorem') assert_nil mh end def test_find_by_entry expected_entries = [ 'Adult Reye Syndrome', 'Adult Reye\'s Syndrome', 'Fatty Liver with Encephalopathy', 'Reye Johnson Syndrome', 'Reye Like Syndrome', 'Reye Syndrome', 'Reye Syndrome, Adult', 'Reye\'s Like Syndrome', 'Reye\'s Syndrome', 'Reye\'s Syndrome, Adult', 'Reye\'s-Like Syndrome', 'Reye-Johnson Syndrome', 'Reye-Like Syndrome' ] entries_to_test = expected_entries.flat_map do |e| [e, e.upcase, e.downcase, " #{e.downcase} ", "\n\n\t #{e.downcase}\t "] end entries_to_test.each do |entry| refute_nil mh = @mesh_tree.find_by_entry(entry), "Failed to find heading by entry '#{entry}'" assert_equal 'D012202', mh.unique_id, "Found wrong heading by entry '#{entry}'" end end def test_find_by_entry_doesnt_match assert_nil @mesh_tree.find_by_entry('foo') end def test_have_the_correct_unique_id mh = @mesh_tree.find('D000001') assert_equal 'D000001', mh.unique_id end def test_have_the_correct_tree_number mh = @mesh_tree.find('D000001') assert_equal 1, mh.tree_numbers.length assert_includes mh.tree_numbers, 'D03.438.221.173' end def test_have_the_correct_tree_numbers mh = @mesh_tree.find('D000224') assert_equal 2, mh.tree_numbers.length assert_includes mh.tree_numbers, 'C19.053.500.263' assert_includes mh.tree_numbers, 'C20.111.163' end def test_have_the_correct_root_letters mh = @mesh_tree.find('D000224') assert_equal ['C'], mh.roots mh = @mesh_tree.find('D064946') assert_equal ['H', 'N'], mh.roots end def test_have_the_correct_descriptor_class mh = @mesh_tree.find('D000224') assert_equal :topical_descriptor, mh.descriptor_class mh = @mesh_tree.find('D005260') assert_equal :check_tag, mh.descriptor_class end def test_have_the_correct_original_heading mh = @mesh_tree.find('D000224') assert_equal 'Addison Disease', mh.original_heading mh = @mesh_tree.find('D000014') assert_equal 'Abnormalities, Drug-Induced', mh.original_heading end def test_have_anglicised_original_heading mh = @mesh_tree.find('D001471') assert_equal 'Barrett Esophagus', mh.original_heading assert_equal 'Barrett Oesophagus', mh.original_heading(:en_gb) end def test_have_natural_language_name mh = @mesh_tree.find('D000224') assert_equal 'Addison Disease', mh.natural_language_name mh = @mesh_tree.find('D000014') assert_equal 'Drug-Induced Abnormalities', mh.natural_language_name end def test_have_anglicised_natural_language_name mh = @mesh_tree.find('D001471') assert_equal 'Barrett Esophagus', mh.natural_language_name assert_equal 'Barrett Oesophagus', mh.natural_language_name(:en_gb) end def test_have_the_correct_summary mh = @mesh_tree.find('D000238') assert_equal 'A benign tumor of the anterior pituitary in which the cells do not stain with acidic or basic dyes.', mh.summary end def test_have_anglicised_summary mh = @mesh_tree.find('D001471') assert_equal 'A condition with damage to the lining of the lower ESOPHAGUS resulting from chronic acid reflux (ESOPHAGITIS, REFLUX). Through the process of metaplasia, the squamous cells are replaced by a columnar epithelium with cells resembling those of the INTESTINE or the salmon-pink mucosa of the STOMACH. Barrett\'s columnar epithelium is a marker for severe reflux and precursor to ADENOCARCINOMA of the esophagus.', mh.summary assert_equal 'A condition with damage to the lining of the lower OESOPHAGUS resulting from chronic acid reflux (OESOPHAGITIS, REFLUX). Through the process of metaplasia, the squamous cells are replaced by a columnar epithelium with cells resembling those of the INTESTINE or the salmon-pink mucosa of the STOMACH. Barrett\'s columnar epithelium is a marker for severe reflux and precursor to ADENOCARCINOMA of the oesophagus.', mh.summary(:en_gb) end def test_linkify_summary mh = @mesh_tree.find('D001471') original_summary = 'A condition with damage to the lining of the lower ESOPHAGUS resulting from chronic acid reflux (ESOPHAGITIS, REFLUX). Through the process of metaplasia, the squamous cells are replaced by a columnar epithelium with cells resembling those of the INTESTINE or the salmon-pink mucosa of the STOMACH. Barrett\'s columnar epithelium is a marker for severe reflux and precursor to ADENOCARCINOMA of the esophagus.' assert_equal original_summary, mh.summary found = { 'ESOPHAGUS' => false, 'ESOPHAGITIS, REFLUX' => false, 'INTESTINE' => false, 'STOMACH' => false, 'ADENOCARCINOMA' => false } #start = Time.now linkified_summary = mh.linkify_summary do |text, heading| found[text] = true unless heading.nil? "#{text.downcase}" end #finish = Time.now #puts start #puts finish #puts finish - start assert_equal 5, found.length assert found['ESOPHAGUS'] assert found['ESOPHAGITIS, REFLUX'] assert found['INTESTINE'] assert found['STOMACH'] assert found['ADENOCARCINOMA'] assert_equal original_summary, mh.summary assert_equal 'A condition with damage to the lining of the lower esophagus resulting from chronic acid reflux (esophagitis, reflux). Through the process of metaplasia, the squamous cells are replaced by a columnar epithelium with cells resembling those of the intestine or the salmon-pink mucosa of the stomach. Barrett\'s columnar epithelium is a marker for severe reflux and precursor to adenocarcinoma of the esophagus.', linkified_summary end def test_linkifies_all_summaries mesh = MESH::Tree.new mesh.linkify_summaries do |text, heading| "#{text.downcase}" end mh = mesh.find('D001471') assert_equal 'A condition with damage to the lining of the lower esophagus resulting from chronic acid reflux (esophagitis, reflux). Through the process of metaplasia, the squamous cells are replaced by a columnar epithelium with cells resembling those of the intestine or the salmon-pink mucosa of the stomach. Barrett\'s columnar epithelium is a marker for severe reflux and precursor to adenocarcinoma of the esophagus.', mh.linkified_summary end def test_to_s mh = @mesh_tree.find('D001471') assert_equal 'D001471, Barrett Esophagus, [C06.198.102,C06.405.117.102]', mh.to_s end def test_have_the_correct_entries expected_entries = ['Activity Cycles', 'Ultradian Cycles', 'Activity Cycle', 'Cycle, Activity', 'Cycle, Ultradian', 'Cycles, Activity', 'Cycles, Ultradian', 'Ultradian Cycle'] expected_entries.sort! mh = @mesh_tree.find('D000204') assert_equal expected_entries, mh.entries end def test_have_anglicised_entries expected_entries = ['Barrett Esophagus', 'Barrett Syndrome', 'Esophagus, Barrett', 'Barrett Epithelium', 'Barrett Metaplasia', 'Barrett\'s Esophagus', 'Barrett\'s Syndrome', 'Barretts Esophagus', 'Barretts Syndrome', 'Epithelium, Barrett', 'Esophagus, Barrett\'s', 'Syndrome, Barrett', 'Syndrome, Barrett\'s'] expected_entries_en = ['Barrett Oesophagus', 'Barrett Syndrome', 'Oesophagus, Barrett', 'Barrett Epithelium', 'Barrett Metaplasia', 'Barrett\'s Oesophagus', 'Barrett\'s Syndrome', 'Barretts Oesophagus', 'Barretts Syndrome', 'Epithelium, Barrett', 'Oesophagus, Barrett\'s', 'Syndrome, Barrett', 'Syndrome, Barrett\'s'] expected_entries.sort! expected_entries_en.sort! mh = @mesh_tree.find('D001471') assert_equal expected_entries.sort, mh.entries assert_equal expected_entries_en.sort, mh.entries(:en_gb) end def test_have_the_correct_parent mh = @mesh_tree.find('D000001') assert_equal 1, mh.parents.length assert_equal 'D001583', mh.parents[0].unique_id end def test_have_the_correct_parents mh = @mesh_tree.find('D000224') p1 = @mesh_tree.find('D000309') p2 = @mesh_tree.find('D001327') assert_equal 2, mh.parents.length assert_includes mh.parents, p1 assert_includes mh.parents, p2 end def test_have_the_correct_parents_again child = @mesh_tree.find_by_original_heading('Questionnaires') assert_equal 1, child.parents.length expected_parent = @mesh_tree.find_by_original_heading('Data Collection') assert_includes child.parents, expected_parent end def test_have_the_correct_children parent = @mesh_tree.find_by_tree_number('C19.053.500') child1 = @mesh_tree.find_by_tree_number('C19.053.500.263') child2 = @mesh_tree.find_by_tree_number('C19.053.500.270') child3 = @mesh_tree.find_by_tree_number('C19.053.500.480') child4 = @mesh_tree.find_by_tree_number('C19.053.500.740') assert_equal 4, parent.children.length assert_includes parent.children, child1 assert_includes parent.children, child2 assert_includes parent.children, child3 assert_includes parent.children, child4 end def test_have_the_correct_children_again parent = @mesh_tree.find_by_original_heading('Data Collection') expected_children = [ 'Health Surveys', 'Interviews as Topic', 'Questionnaires', 'Records as Topic', 'Registries', 'Vital Statistics', 'Geriatric Assessment', 'Nutrition Assessment', 'Health Care Surveys', 'Narration', 'Lot Quality Assurance Sampling', 'Checklist', 'Health Impact Assessment', 'Crowdsourcing' ].map { |oh| @mesh_tree.find_by_original_heading(oh) } assert_equal expected_children.length, parent.children.length expected_children.each do |ec| assert_includes parent.children, ec end end def test_have_the_correct_siblings skip end def test_match_on_conditions_for_original_heading mh = @mesh_tree.find('D001471') assert mh.matches(original_heading: /^Barrett Esophagus$/) end def test_not_match_on_incorrect_condition_for_original_heading mh = @mesh_tree.find('D001471') refute mh.matches(original_heading: /^Foo$/) end def test_match_on_conditions_for_entries mh = @mesh_tree.find('D001471') assert mh.matches(entries: /Metaplasia/) end def test_not_match_on_incorrect_conditions_for_entries mh = @mesh_tree.find('D001471') refute mh.matches(entries: /Foo/) end def test_match_on_descriptor_class mh = @mesh_tree.find('D000224') assert mh.matches(descriptor_class: :topical_descriptor) refute mh.matches(descriptor_class: :check_tag) mh = @mesh_tree.find('D005260') assert mh.matches(descriptor_class: :check_tag) refute mh.matches(descriptor_class: :topical_descriptor) end def test_match_on_conditions_for_tree_numbers mh = @mesh_tree.find('D001471') assert mh.matches(tree_numbers: /C06\.198\.102/) assert mh.matches(tree_numbers: /^C06\.198\.102$/) assert mh.matches(tree_numbers: /^C06/) assert mh.matches(tree_numbers: /\.198\./) assert mh.matches(tree_numbers: /^C06\.405\.117\.102$/) end def test_not_match_on_incorrect_conditions_for_tree_numbers mh = @mesh_tree.find('D001471') refute mh.matches(tree_numbers: /Foo/) end def test_match_on_conditions_for_summary mh = @mesh_tree.find('D001471') assert mh.matches(summary: /the lower ESOPHAGUS resulting from chronic acid reflux \(ESOPHAGITIS, REFLUX\)\./) end def test_not_match_on_incorrect_conditions_for_summary mh = @mesh_tree.find('D001471') refute mh.matches(summary: /Foo/) end def test_match_on_conditions_for_useful mh = @mesh_tree.find('D001471') begin mh.useful = true assert mh.matches(useful: true) refute mh.matches(useful: false) mh.useful = false assert mh.matches(useful: false) refute mh.matches(useful: true) ensure mh.useful = true end end def test_match_on_multiple_conditions mh = @mesh_tree.find('D001471') assert mh.matches(original_heading: /^Barrett Esophagus$/, summary: /the lower ESOPHAGUS/) end def test_not_match_on_incorrect_multiple_conditions mh = @mesh_tree.find('D001471') refute mh.matches(original_heading: /^Barrett Esophagus$/, summary: /Foo/) refute mh.matches(original_heading: /^Foo/, summary: /the lower ESOPHAGUS/) end def test_match_headings_that_occur_in_given_text expected_ids = %w(D001491 D001769 D001792 D001853 D002470 D002477 D002648 D002965 D002999 D003561 D003593 D003643 D004194 D004314 D004813 D004912 D005091 D005123 D005293 D005333 D005385 D005544 D005796 D006128 D006225 D006309 D006321 D006331 D006405 D007107 D007223 D007231 D007239 D007246 D007938 D007947 D008099 D008168 D008214 D008423 D008533 D008607 D008722 D009035 D009055 D009132 D009154 D009190 D009196 D009369 D009666 D010372 D010641 D011153 D012008 D012106 D012146 D012306 D012307 D012380 D012680 D012867 D013534 D013601 D013812 D013921 D013961 D014034 D014157 D014171 D014960 D015032 D015470 D015994 D015995 D016424 D016433 D017584 D017668 D018387 D018388 D019021 D019070 D019368 D019369 D032882 D036801 D038042 D041905 D052016 D054198 D055016) expected = expected_ids.map { |id| @mesh_tree.find(id) } matches = @mesh_tree.match_in_text(@example_text) actual = matches.map { |match| match[:heading] }.uniq assert_equal expected.sort, actual.sort end def test_sort_based_on_unique_id skip end def test_only_match_the_most_specific_matches_in_given_text expected = @mesh_tree.find('D054144') actual = @mesh_tree.match_in_text('Diastolic Heart Failure') assert_equal 1, actual.length assert_equal expected, actual.first[:heading] end def test_only_match_useful_headings_that_occur_in_given_text expected_ids = %w(D001491 D001769 D001792 D001853 D002470 D002648 D002875 D002965 D003561 D003593 D003643 D004194 D004314 D004813 D004912 D005091 D005123 D005293 D005333 D005385 D005544 D005796 D006128 D006225 D006309 D006321 D006331 D006405 D007107 D007231 D007239 D007938 D007947 D008099 D008168 D008214 D008423 D008607 D008722 D009035 D009055 D009132 D009154 D009190 D009196 D009369 D009666 D010372 D010641 D011153 D012008 D012106 D012146 D012306 D012307 D012380 D012680 D012867 D013534 D013601 D013812 D013921 D013961 D014034 D014157 D014171 D015032 D015470 D015994 D015995 D016424 D017584 D017668 D018387 D018388 D019021 D019070 D019368 D019369 D032882 D036801 D038042 D041905 D052016 D054198) not_useful_ids = %w(D007246 D002477 D014960 D008533 D016433 D006664 D055016 D002999 D007223) begin not_useful_ids.each { |id| @mesh_tree.find(id).useful = false } expected = expected_ids.map { |id| @mesh_tree.find(id) } matches = @mesh_tree.match_in_text(@example_text) actual = matches.map { |match| match[:heading] }.uniq assert_equal expected, actual ensure not_useful_ids.each { |id| @mesh_tree.find(id).useful = true } end end def test_match_headings_at_start_of_text text = 'Leukemia, lorem ipsum dolor sit amet, consectetur adipiscing elit. Donec pretium leo diam, quis adipiscing purus bibendum eu.' matches = @mesh_tree.match_in_text(text) assert_equal 1, matches.length assert_equal @mesh_tree.find('D007938'), matches[0][:heading] end def test_match_headings_at_end_of_text text = 'Lorem ipsum dolor sit amet, consectetur adipiscing elit. Donec pretium leo diam, quis adipiscing purus bibendum eu leukemia' matches = @mesh_tree.match_in_text(text) assert_equal 1, matches.length assert_equal @mesh_tree.find('D007938'), matches[0][:heading] end def test_return_no_matches_when_given_nil_text assert_equal [], @mesh_tree.match_in_text(nil) end def test_only_match_uppercase_entries_with_uppercase_text text = 'Lorem amet, consectetur adipiscing elit. Donec pretium ATP leo diam, quis adipiscing purus bibendum.' matches = @mesh_tree.match_in_text(text) assert_equal 1, matches.length assert_equal @mesh_tree.find('D000255'), matches[0][:heading] text = 'Lorem ipsum consectetur adipiscing elit. Donec pretium atp leo diam, quis adipiscing purus bibendum.' assert_equal [], @mesh_tree.match_in_text(text) end def test_match_anglicised_terms_in_text text = 'Lorem ipsum dolor sit amet, consectetur adipiscing elit. Donec pretium leo diam, quis adipiscing purus bibendum eu leukaemia' matches = @mesh_tree.match_in_text(text) assert_equal 1, matches.length assert_equal @mesh_tree.find('D007938'), matches[0][:heading] end def test_allow_headings_to_be_marked_as_not_useful mh = @mesh_tree.find('D055550') mh.useful = true assert mh.useful mh.useful = false refute mh.useful mh.useful = true assert mh.useful end def test_allow_headings_to_be_found_with_a_where_match_on_original_heading expected = [@mesh_tree.find('D003561'), @mesh_tree.find('D016238')] actual = @mesh_tree.where(original_heading: /^Cyta/) assert_equal expected, actual end def test_match_on_entries_in_where expected_ids = %w( D002397 D003064 D003400 D003532 D004284 D004289 D004555 D005412 D006054 D006196 D007059 D007497 D007695 D009990 D010473 D012091 D012487 D012758 D013215 D015027 D020410 D023721 D023761 D023781 D024541 D029961 D037401 D037462 D048251 D049832 D052656 D057096 ) expected = expected_ids.map { |id| @mesh_tree.find(id) } actual = @mesh_tree.where(entries: /fish/) assert_equal expected, actual end def test_match_on_tree_numbers_in_where expected_ids = %w( D000005 D001415 D010388 D013909 ) expected = expected_ids.map { |id| @mesh_tree.find(id) } actual = @mesh_tree.where(tree_numbers: /^A01\.923\.[0-9]{3}$/) assert_equal expected, actual end def test_match_on_useful_in_where expected = [@mesh_tree.find('D012000'), @mesh_tree.find('D064906'), @mesh_tree.find('D064966')] begin expected.each { |mh| mh.useful = false } actual = @mesh_tree.where(useful: false) assert_equal expected, actual ensure expected.each { |mh| mh.useful = true } end end def test_match_on_descriptor_class_in_where expected = [@mesh_tree.find('D012000'), @mesh_tree.find('D064906'), @mesh_tree.find('D064966')] begin expected.each { |mh| mh.descriptor_class = :foo } actual = @mesh_tree.where(descriptor_class: :foo) assert_equal expected, actual ensure expected.each { |mh| mh.descriptor_class = :topical_descriptor } end end def test_only_include_useful_headings_in_each begin @mesh_tree.each do |mh| mh.useful = false end @mesh_tree.where(unique_id: /^D0000/).each do |mh| mh.useful = true end count = 0 @mesh_tree.each do |mh| assert mh.useful count += 1 end assert_equal 95, count ensure @mesh_tree.where(useful: false).each do |mh| mh.useful = true end end end def test_know_its_deepest_position_in_the_tree #single tree numbers assert_equal 1, @mesh_tree.find('D002319').deepest_position assert_equal 2, @mesh_tree.find('D001808').deepest_position assert_equal 3, @mesh_tree.find('D001158').deepest_position assert_equal 4, @mesh_tree.find('D001981').deepest_position end def test_know_its_shallowest_position_in_the_tree #single tree numbers assert_equal 1, @mesh_tree.find('D002319').shallowest_position assert_equal 2, @mesh_tree.find('D001808').shallowest_position assert_equal 3, @mesh_tree.find('D001158').shallowest_position assert_equal 4, @mesh_tree.find('D001981').shallowest_position end def test_know_if_one_heading_is_the_descendant_of_another parent = @mesh_tree.find('D002319') child = @mesh_tree.find('D001808') grandchild = @mesh_tree.find('D001158') great_grandchild = @mesh_tree.find('D001981') unrelated = @mesh_tree.find('D008091') refute parent.has_descendant(parent), 'should not consider itself a desecendant' assert parent.has_descendant(child), "should consider child #{child.inspect} a descendant of #{parent.inspect} in #{parent.children}" assert parent.has_descendant(grandchild), "should consider grandchild #{grandchild.inspect} a descendant #{parent.inspect}" assert parent.has_descendant(great_grandchild), "should consider great grandchild #{great_grandchild.inspect} a descendant #{parent.inspect}" refute parent.has_descendant(unrelated), 'should not consider an unrelated heading a descendant' end def test_know_if_one_heading_is_the_ancestor_of_another child = @mesh_tree.find('D001981') parent = @mesh_tree.find('D001158') grandparent = @mesh_tree.find('D001808') great_grandparent = @mesh_tree.find('D002319') unrelated = @mesh_tree.find('D008091') refute child.has_ancestor(child), 'should not consider itself an ancestor' assert child.has_ancestor(parent), "should consider parent #{parent.inspect} an ancestor of #{child.inspect} in #{child.parents}" assert child.has_ancestor(grandparent), "should consider grandparent #{grandparent.inspect} an ancestor #{child.inspect}" assert child.has_ancestor(great_grandparent), "should consider great grandparent #{great_grandparent.inspect} an ancestor #{child.inspect}" refute child.has_ancestor(unrelated), 'should not consider an unrelated heading an ancestor' end def test_know_if_headings_are_siblings_at_the_same_level_below_a_common_parent parent = @mesh_tree.find_by_tree_number('C19.053.500') child1 = @mesh_tree.find_by_tree_number('C19.053.500.263') child2 = @mesh_tree.find_by_tree_number('C19.053.500.270') child3 = @mesh_tree.find_by_tree_number('C19.053.500.480') child4 = @mesh_tree.find_by_tree_number('C19.053.500.740') unrelated = @mesh_tree.find('D008091') children = [child1, child2, child3, child4] children.each { |c| refute parent.sibling?(c) } children.each { |c| refute c.sibling?(parent) } children.each { |c| assert child1.sibling?(c) unless c == child1 } children.each { |c| assert c.sibling?(child1) unless c == child1 } children.each { |c| refute unrelated.sibling?(c) } children.each { |c| refute c.sibling?(unrelated) } end def test_override_inspect_to_prevent_issues_in_test_diagnostics mh = @mesh_tree.find('D001471') expected = "#{mh.unique_id}, #{mh.original_heading}, [#{mh.tree_numbers.join(',')}]" assert_equal expected, mh.inspect end def setup @@mesh_tree ||= MESH::Tree.new @@mesh_tree.load_translation(:en_gb) @mesh_tree = @@mesh_tree @example_text ||= 'Leukaemia in Downs Syndrome Overview Downs Syndrome Leukaemia The link between Downs Syndrome and Leukaemia Epidemiology Aetiology Future research Implications for other leukaemias Treatment Downs Syndrome Originally described in 1866 Associated with Trisomy 21 in 1959 Prevalence 1/1000 births 95% due to chromosomal non-disjunction; 5% due to translocations Risk factors: increased maternal age 1/1000 maternal age 30 years 9/1000 maternal age 40 years infertility treatment Clinical Features physical appearance intellectual disability developmental delay sensory abnormalities congenital heart disease Alzheimers Disease GI malformations thyroid disorders poor immune system LEUKAEMIA Downs Syndrome Leukaemia cancer WBC proliferation in the bone marrow Classification: acute/chronic type of WBC Current leukaemia model: 2 co-operating mutations 1 leading to impaired differentiation 1 leading to increased proliferation/cell survival Picture: Hitzler & Zipursky, 2005 Leukaemia Acute lymphoblastic leukaemia (ALL) derived from B lymphocyte or T lymphocyte precursors 80% childhood leukaemia Acute myeloid leukaemia (AML) e.g. myeloid, monocytic, megakaryocytic, erythroid 20% childhood leukaemia Acute megakaryoblastic leukaemia (AMKL) AML subtype: leukaemic cells have platelet precursor phenotype 6% childhood AML cases Leukaemia in Downs Syndrome 10-20 fold increased risk of leukaemia ALL 80% childhood leukaemia; 60% Downs Syndrome leukaemia 20 times higher incidence children with Downs Syndrome compared to children without Downs Syndrome AML 20% childhood leukaemia; 40% Downs Syndrome leukaemia AMKL 6% childhood AML; 62% Downs Syndrome AML 500 times higher incidence children with Downs Syndrome compared to children without Downs Syndrome Leukaemia in Downs Syndrome AML in Downs Syndrome AMKL in most cases younger median age of onset 2 in Downs Syndrome 8 in non-Downs Syndrome myelodysplastic syndrome more common prior to leukaemia Transient Leukaemia Transient Leukaemia Also termed: Transient Abnormal Myelopoiesis and Transient Myeloproliferative Disorder 10% newborn infants with Downs Syndrome peripheral blood contains clonal population of megakaryoblasts cannot be distinguished from AMKL blasts by routine methods usually clinically silent usually disappear within 3 months majority of cases totally resolve However can be fatal 20% develop MDS and AMKL by the age of 4 yearsTransient Leukaemia Leukaemic cells in Transient Leukaemia and AMKL can: show variable megakaryocytic differentiation show features of multiple haematopoietic lineages Evidence that Transient Leukaemia is a precursor for AMKL near identical morphology, immunophenotype, ultrastructure clone-specific GATA1 mutations GATA1: X chromosome, zinc-finger transcription factor, essential for differentiation of megakaryocytic, erythroid and basophillic lineages therefore have common cell of originLeukaemic cells in Transient Leukaemia and AMKL in Downs Syndrome can form megakaryocytic, erythroid or basophillic lineages GATA1 all Transient Leukaemia and AMKL cases have GATA1 mutations most abrogate splicing of exon 2 or produce stop codon prior to alternative start codon at position 84 lack N-terminal domain mutations disappear upon remission disease specific mutations leukemogenisis model: transcription factor mutation blocks differentiation GATA1 mutation determines haematopoietic lineage GATA1 mutations present in Transient Leukaemia at birth mutations in utero proportion of Downs Syndrome fetuses acquire GATA1 mutation large clone = Transient Leukaemia small clone = no clinical signs Aetiology Three distinct steps: fetal heamatopoietic cell with trisomy 21 rare Transient Leukaemia cases in people without Downs syndrome acquired trisomy 21 only in haematopoietic cells mutation of GATA1 expression of shortened GATA1 (GATA1s) extra, as of yet unknown event not all cases of Transient Leukaemia progress to AMKL Picture: Hitzler & Zipursky, 2005 Aetiology Transient Leukaemia with clinical signs of disease Transient Leukaemia with no clinical signs of diseasePicture: Ahmed et al, 2004 Future Research Loss of GATA1 function in people without Downs Syndrome results in: accumulation of abnormally differentiated megakaryocytes thrombocytopenia NO LEUKAEMIC TRANSFORMATION discovered by Shivdasani et al, 1997 What is the effect of Trisomy 21 What advantage does GATA1 mutation provide to people with Downs SyndromeWhat is the second-hitImplications for other leukaemias current acute leukaemia model: 2 co-operating mutations 1 leading to impaired differentiation 1 leading to increased proliferation/cell survival This means that that the sequence of Transient Leukaemia to AMKL as seen in Downs Syndrome is a chance to investigate this model of leukaemia and discover the timing and nature of the 2 necessary events. Treatment of Leukaemia in Downs Syndrome AML (AMKL) increased sensitivity to cytarabine 80% 5 year survival failure usually due to toxicity (mucositis and infection)ALL similar treatment as in AML 60-70% cure rate (75-85% in population without Downs Syndrome) no increased sensitivity, but increased toxicity dose reduction would increase risk of relapse supportive care References Ahmed, M., Sternberg, A., Hall, G., Thomas, A., Smith, O., OMarcaigh, A., Wynn, R., Stevens, R., Addison, M., King, D., Stewart, B., Gibson, B., Roberts, I., Vyas, P. (2004). Natural History of GATA1 mutations in Down syndrome, Blood, 103(7):2480-2489. Hitzler, J.K., Cheung, J., Li, Y., Scherer, S.W., Zipursky, A. (2003). GATA1 mutations in transient leukaemia and acute megakaryoblastic leukaemia of Down syndrome, Blood, 101(11):4301-4304. Hitzler, J.K., Zipursky, A. (2005). Origins of leukaemia in children with down syndrome, Cancer, 5:11-20. Puumala, S.E., Ross, J.A., Olshan, A.F., Robison, L.L., Smith, F.O., Spector, L.G. (2007). Reproductive history, infertility treatment, and the risk of acute leukaemia in children with down syndrome, Cancer, [Epub ahead of print]. Shivdasani, R.A., Fujiwara, Y., McDevitt, M.A., Orkin, S.H. (1997). A loneage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development, Embo J., 16:3965-3973. Slordahl, S.H. et al. (1993). Leukaemic blasts with markers of four cell lineages in Down\'s syndrome (megakaryoblastic leukaemia), Med. Pediatr. Oncol., 21:254-258. Vyas, P., Crispino, J.D. (2007). Molecular insights into Down syndrome-associated leukemia, Current Opinion in Pediatrics, 19:9-14. Webb, D., Roberts, I., Vyas, P. (2007). Haematology of Down syndrome, Arch. Dis. Child. Fetal Neonatal Ed., [published online 5 Sep 2007]. http://www.intellectualdisability.info/home.htm http://news.bbc.co.uk/nol/shared/spl/hi/pop_ups/05/health_shifting_perspectives/img/1.jpg Originally described by John Langdon Down Associated with Trisomy 21 by Professor Jerome Lejeune Overall incidence is 1/1000, so 600 babies with Downs syndrome are born in the UK each year It is estimated that there are 60,000 people living with Downs syndrome in the UK 80% of children with Downs Syndrome are born to mothers under 35 years of age Research suggests that infertility treatment increases risk of chromosomal abnormalitiesFacial appearance: flat profile, flat nasal bridge, small nose, eyes that slant upwards and outwards often with an epicanthic fold a fold of skin that runs vertically between the lids at the inner corner of the eye), small mouth. Body appearance: reduced muscle tone, big space between first and second toe, broad hands with short fingers and a little finger that curves inwards, often a single palmar crease. Sensory abnormalities: visual and hearing Congenital Heart Disease is present in 50% of people with Downs SyndromeThere are two methods of classifying leukaemias: acute/chronic or according to the type of WBC that is proliferating abnormally ALL describes leukaemia where the cancerous cell is derived from precursors of B or less commonly T lymphocytes. ALL makes up 80% of all childhood leukaemias. AML describes leukaemia where the cancerous cell is not B or T cell derived and the subtype is determined by the phenotype of the leukaemic cells. AML makes up 20% of childhood leukaemias. AMKL is a subtype of AML where the leukaemic cell looks like platelet precursors. AMKL makes up 6% of childhood AML cases.ALL makes up 80% of childhood leukaemia, but 60% of leukaemia in children with DS. Children with DS have a 20 fold increased risk of developing ALL when compared to children without DS. AML makes up 20% of childhood leukaemia, but 40% of leukaemia in children with DS. AMKL makes up 6% of childhood AML, but in children with Downs Syndrome makes up 62% of AML cases. Children with DS have a 500 fold increased risk of developing AMKL when compared to children without DS.The rest of this talk is going to focus on AMKL in DS. The majority of AML cases in DS are AMKL and have a younger age of onset than in the population without DS. AMKL in DS much more commonly begins as a MDS. This is a process of abnormal megakaryocytic differentiation. Furthermore, children with DS are at risk of Transient Leukaemia a condition that is almost exclusive to children with DS.Tranisent leukaemia is only found in infants with DS and is found in about 10% of newborns with DS. These children are born with a clonal population of megakaryoblasts in their blood. These megakaryoblasts cannot be distinguished from the blasts of AMKL by routine methods and usually spontaneously disappear within the first 3 months of life. TL begins in utero and usually does not cause any symptoms. The majority of cases resolve and the children do not have any lasting haematological problems. There is no evidence as to how TL spontaneously resolves. However, it can also be fatal due liver damage or complications in the lungs or heart and 20% of children with TL proceed to develop MDS and AMKL by the age of 4 years.mutations of GATA1 are present in the cells of TL and AMKL in Downs Syndrome and these cells can become megakaryocytes, erythroid cells or basophils! The megakaryoctic lineage is particularly dependant on the level of expression of GATA1. MULTIPLE HAEMATOPOIETIC LINEAGES: for example precursor cells of erythrocytes and basophils. Ferritin is found in the cytoplasm of DS-AMKL cells. This slide equates the aeitology to the model of leukaemia I mentioned earlier, with points 2 and 3 being the 2 mutations. 2) It is currently not known if it is the absence of normal GATA1 or the presence of GATA1s that causes leukaemic proliferation of megakaryocytes. It could be both, because GATA1s fails to suppress some pro-proliferative genes such as GATA2 and MYC) although these are pro-proliferative for erythrocytes.The previous slide shows us how a child with DS can progress to developing AMKL. Of course we know that not all children with DS or indeed all children with DS and Transient Leukaemia proceed to develop AMKL. This slide shows us all the possible routes children with DS can take. Normal GATA1s small clone or large clone clonal extinction normal clonal expansion plus additional genetic event AMKL AMKL death or remission (normal)Although our understanding of leukaemia in DS have progressed a long way over recent years, there still remain unknowns in the aetiology. Loss of GATA1 function has different effect on people without DS and people with DS therefore what is the effect of Trisomy 21 why are GATA1 mutations so relatively common in children with DS It has been postulated that there may be some selective advantage, but it is only a hypothesis. thirdly, what is the second-hit We know that there must be a second genetic event, with GATA1 mutation being the first, but we do not know what this is yet.NB: GATA1 mutation is the first mutation for DS-AMKL.AML failure of treatment usually due to toxicity due to mucositis and infection. Resistant disease and relapse are rare. ALL there is no increased sensitivity to treatment, but there is increased risk of toxicity. Cannot reduce the dose because of the high risk of relapse and so the emphasis is now on improving supportive care. ' end end end